Programs

Breast Cancer & Melanoma Group

Cristina Saura
Principal Investigator
Biosketch
Principal Investigator Cristina Saura Medical Oncologists and Clinical Fellows Fabiola Amair, Miriam Arumi, Judith Balmaña, Meritxell Bellet, Marta Capelan, Santiago Escriva, Laia Garrigos, Patricia Gomez, Eva Muñoz, Mafalda Oliveira, Carolina Ortiz, Isabel Pimentel, Esther Zamora Clinical Nurse Specialist Anna Suñol Nutritionist Nuria Duran

Summary

The main area of expertise of the Breast Cancer Group led by Cristina Saura is clinical research focused on drug development and associated translational research. In addition to high patient recruitment in our studies, we also play a leading role in many of the clinical trials that we run. This enables us to have a direct impact in applying translational data to guide and accelerate drug development:

  • HER2-positive disease: we are participating in the major trials testing novel therapies and the most promising agents in our field including DS8201, tucatinib, neratinib and SYD985. In collaboration with VHIO's Growth Factors Group, led by Joaquín Arribas, we explore cancer drug resistance to these agents through VHIO’s in-house established PDX models. Alongside Paolo Nuciforo’s Molecular Oncology Group, we are aiming to validate more precise methods to quantify HER2 expression.
  • Luminal disease: In partnership with VHIO's Experimental Therapeutics Group, headed by Violeta Serra, we have developed several PDX models to advance our understanding of mechanisms of resistance to several drugs, and how they may be reversed through treatment with PI3K, AKT, CDK4/6, and BET inhibitors, as well as novel oral SERDs and different PARP inhibitors.
  • Triple negative disease: In additon to our participation in clinical trials testing combinations of immunotherapies, we are collaborating in pioneering projects focused on cell-based therapies directed by Alena Gros, PI of VHIO’s Tumor Immunology and Immunotherapy Group, to develop novel personalized T-cell therapies against cancer.
  • cfDNA: In collaboration with VHIO's Cancer Genomics Group, led by Ana Vivancos, we have analyzed concordance of genomic alterations in synchronous tumor biopsies and ctDNA from metastatic breast cancer patients. We are now participating in various projects to address the challenging scenario of early disease and the identification of cfDNA in unexplored biological samples including breast milk.

Our Melanoma and other skin tumors Group is led by Eva Muñoz. She has actively participated in several phase I, II and III trials focused on melanoma and other skin tumors to study various emerging therapies for the treatment of these diseases. This group leads it own research program incorporating clinical investigators, dermatologists and cancer investigators at VHIO.

The team’s studies focus on new target therapies and resistance to immunotherapy by conducing purely translational research centered on melanoma, skin squamous and basocelular carcinoma resistance acquisition and disease progression. Their efforts also center on mapping new therapeutic avenues, follow up standards and identifying biomarkers for a more precise treatment selection matched to the specificities of our patients.


Strategic goals

Breast:
  • Optimize therapies by introducing novel anti-cancer treatments and adding rational combinations to combat mechanisms of resistance.
  • Incorporate proteomics, genomics, and cfDNA platforms in translational research to advance insights into tumor biology.
  • Apply preclinical and predictive data to help guide innovative clinical trial design in advanced disease.
Melanoma:
  • Our Melanoma Unit spearheads one of the largest networks in Spain and across Europe, and is also one of the most active in metastatic and adjuvant clinical trials in melanoma and other skin tumors. Each trial is tightly connected with the corresponding translational research lines led by VHIO scientists.
  • Exploit the role of non-classical secretion linked to tumor invasion and metastasis to identify biomarkers and therapeutic targets against breast cancer.
  • Characterize the role of extracellular HMGA1 in breast cancer invasion and metastasis.
  • The characterization of mechanisms adopted by tumor cells to communicate with their microenvironment during treatment to establish secreted response/resistance biomarkers to cancer drug therapies.

Highlights

  • Relevant contributions in drug approval: thanks to the leadership position of our investigators we have contributed to the approval of drugs including neratinib in the advanced setting. We are currently involved in the development of some of the most promising therapies that will be approved in the near future including tucatinib and DS8201.
  • Precision medicine: thanks to VHIO’s in-house prescreening program we continue to identify potential patients with molecular alterations as an enrichment strategy for clinical trials with PI3K, ESR1 or HER2 mutations. Our Institute’s proteomics and cfDNA platforms have also helped us to advance insights into tumor biology.

Horizons

Breast:
  • To continue to significantly contribute to drug approval of new compounds in the breast cancer field.
  • Further support precision medicine given through our expertise in the field and VHIO’s pre-screening program to optimize potential benefits obtained from treatments in specific populations of patients with breast cancer.
  • Identification of promising and challenging new indications of ctDNA in breast cancer for early diagnosis in blood or in new biologic samples including breast milk as a potential source for early breast cancer diagnosis associated with pregnancy.
  • Integrate Real World Data, Artificial Intelligence and Machine learning in the diagnostic and therapeutic algorithms of breast cancer management.
  • Establish and develop a program of personalized T-cell therapy in breast cancer.
Melanoma:
  • Maintain the Cutaneous Tumor Unit as a reference center for melanoma and other cutaneous tumors through an established referral network and participation in major clinical trials from the early beginning, with active participation in the clinical design and recruitment strategies.
  • Involvement in the early drug development and design of different clinical trials in melanoma and other skin tumors.
  • Expand our collaboration with VHIO researchers to better understand tumor immunology in melanoma, identify biomarkers of tumor progression, and validate novel therapeutic targets in melanoma and other skin tumors.
  • Expand our seroteca to collect samples for future national and international collaborations.

PI paper pick

  • Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. Epub 2019 Dec 11.
  • Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. doi: 10.1056/NEJMoa1914609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586.
  • Prat A, Saura C, Pascual T, Hernando C, Muñoz M, Paré L, González Farré B, Fernández PL, Galván P, Chic N, González Farré X, Oliveira M, Gil-Gil M, Arumi M, Ferrer N, Montaño A, Izarzugaza Y, Llombart-Cussac A, Bratos R, González Santiago S, Martínez E, Hoyos S, Rojas B, Virizuela JA, Ortega V, López R, Céliz P, Ciruelos E, Villagrasa P, Gavilá J. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020 Jan;21(1):33-43. doi: 10.1016/S1470-2045(19)30786-7. Epub 2019 Dec 11.
  • Hamid O, Molinero L, Bolen CR, Sosman JA, Muñoz-Couselo E, Kluger HM, McDermott DF, Powderly JD, Sarkar I, Ballinger M, Fassò M, O'Hear C, Chen DS, Hegde PS, Hodi FS.Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from Phase I trial of Atezolizumab. Clin Cancer Res. 2019 Oct 15;25(20):6061-6072. doi: 10.1158/1078-0432.CCR-18-3488. Epub 2019 Jul 29.

Full list of Publications

  1. Sanchez-Rovira, Pedro; Zamora, Pilar; Salvador-Bofill, Javier; Morales, Serafin; Martinez-Janez, Noelia; Martinez-de-Duenas, Eduardo; Lluch, Ana; Juan Illarramendi, Jose; GOMEZ PARDO, PATRICIA; Gavila Gregori, Joaquin; Garcia-Palomo, Andres; Garcia-Mata, Jesus; Fernandez, Yolanda; del Barco, Sonia; de Juan, Ana; Ciruelos, Eva; Ignacio Chacon, Jose; Calvo, Lourdes; Barnadas, Agusti; Albanell, Joan. Broad consensus on the optimal sequence for the systemic treatment of metastatic breast cancer: results from a survey of Spanish medical oncologists. Journal Of Drug Assessment. 2019 Apr 8;8(1):62-69. doi: 10.1080/21556660.2019.1604375. Rutgers, Emiel; BALMAÑA GELPI, JUDITH; Beishon, Marc; Benn, Karen; Evans, D. Gareth; Mansel, Robert; Pharoah, Paul; Skinner, Victoria Perry; Stoppa-Lyonnet, Dominique; Travado, Luzia; Wyld, Lynda. European Breast Cancer Council manifesto 2018: Genetic risk prediction testing in breast cancer. Eur J Cancer. 2019 Jan;106:45-53. doi: 10.1016/j.ejca.2018.09.019. Epub 2018 Nov 22.
  2. Schmid, Peter; Zaiss, Matthias; Harper-Wynne, Catherine; Ferreira, Marta; Dubey, Sidharth; Chan, Stephen; Makris, Andreas; Nemsadze, Gia; Brunt, Adrian M; Kuemmel, Sherko; Ruiz, Isabel; Perelló, Antonia; Kendall, Anne; Brown, Janet; Kristeleit, Hartmut; Conibear, John; SAURA MANICH, CRISTINA; Grenier, Julien; Máhr, Károly; Schenker, Michael; Sohn, Joohyuk; Lee, Keun Seok; Shepherd, Christopher J; Oelmann, Elisabeth; Sarker, Shah-Jalal; Prendergast, Aaron; Marosics, Patricia; Moosa, Atiyyah; Lawrence, Cheryl; Coetzee, Carike; Mousa, Kelly; CORTES CASTAN, JAVIER. Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Aug 29. doi: 10.1001/jamaoncol.2019.2526.
  3. Singer, Christian F.; BALMAÑA GELPI, JUDITH; Burki, Nicole; Delaloge, Suzette; Filieri, Maria Elisabetta; Gerdes, Anna-Marie; Grindedal, Eli Marie; Han, Sileni; Johansson, Oskar; Kaufman, Bella; Krajc, Mateja; Loman, Niklas; Olah, Edith; Paluch-Shimon, Shani; Plavetic, Natalija Dedic; Pohlodek, Kamil; Rhiem, Kerstin; Teixeira, Manuel; Evans, D. Gareth.Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer-an European consensus statement and expert recommendations. Eur J Cancer. 2019 Jan;106:54-60. doi: 10.1016/j.ejca.2018.10.007
  4. Chacón López-Muñiz, J I; de la Cruz Merino, L; Gavilá Gregori, J; Martínez Dueñas, E; ANTUNES DE MELO E OLIVEIRA, MAFALDA; Seguí Palmer, M A; Álvarez López, I; Antolin Novoa, S; BELLET EZQUERRA, MERITXEL; López-Tarruella Cobo, S. SEOM clinical guidelines in advanced and recurrent breast cancer (2018). Clin Transl Oncol. 2019 Jan;21(1):31-45. doi: 10.1007/s12094-018-02010-w.
  5. Ignatiadis, Michail; Van den Eynden, Gert; Roberto, Salgado; Fornili, Marco; Bareche, Yacine; Desmedt, Christine; Rothé, Françoise; Maetens, Marion; Venet, David; Holgado, Esther; McNally, Virginia; Kiermaier, Astrid; Savage, Heidi M; Wilson, Timothy R; CORTES CASTAN, JAVIER; Schneeweiss, Andreas; Willard-Gallo, Karen; Biganzoli, Elia; Sotiriou, Christos. Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy. J Natl Cancer Inst. 2019 Jan 1;111(1):69-77. doi: 10.1093/jnci/djy076.
  6. Gao, Meiling; Callari, Maurizio; Beddowes, Emma; Sammut, Stephen-John; Grzelak, Marta; Biggs, Heather; Jones, Linda; Boumertit, Abdelhamid; Linn, Sabine C; CORTES CASTAN, JAVIER; ANTUNES DE MELO E OLIVEIRA, MAFALDA; Baird, Richard; Chin, Suet-Feung; Caldas, Carlos.Next Generation-Targeted Amplicon Sequencing (NG-TAS): an optimised protocol and computational pipeline for cost-effective profiling of circulating tumour DNA. Genome Med. 2019 Jan 4;11(1):1. doi: 10.1186/s13073-018-0611-9.
  7. Gavilá, Joaquín; ANTUNES DE MELO E OLIVEIRA, MAFALDA; Pascual, Tomás; Perez-Garcia, Jose; Gonzàlez, Xavier; Canes, Jordi; Paré, Laia; Calvo, Isabel; Ciruelos, Eva; Muñoz, Montserrat; Virizuela, Juan A; Ruiz, Isabel; Andrés, Raquel; Perelló, Antonia; Martínez, Jerónimo; Morales, Serafín; Marín-Aguilera, Mercedes; Martínez, Débora; Quero, Juan C; Llombart-Cussac, Antonio; Prat, Aleix. Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial. BMC Med. 2019 Jan 9;17(1):8. doi: 10.1186/s12916-018-1233-1.
  8. MONTALBAN CANUDAS, GEMMA; BONACHE REAL, SANDRA; MOLES FERNANDEZ, ALEJANDRO; Gisbert-Beamud, Alexandra; TENES FELIPE, ANNA; Bach, Vanessa; CARRASCO LOPEZ, ESTELA; LOPEZ FERNANDEZ, ADRIA; STJEPANOVIC, NEDA; BALMAÑA GELPI, JUDITH; DIEZ GIBERT, ORLAND; GUTIERREZ ENRIQUEZ, SARA ILIANA.Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer. J Med Genet. 2019 Feb;56(2):63-74. doi: 10.1136/jmedgenet-2018-105606
  9. Riveiro-Barciela, Mar; MUÑOZ COUSELO, EVA; Fernandez-Sojo, Jesús; Diaz-Mejia, Nely; Parra-López, Rafael; Buti, María. Acute liver failure due to immune-mediated hepatitis successfully managed with plasma exchange: New settings call for new treatment strategies?. Journal of Hepatology 2019 vol. 70 j 548–577. Doi.org/10.1016/j.jhep.2018.10.020
  10. Condorelli, R; Mosele, F; Verret, B; Bachelot, T; Bedard, P L; CORTES CASTAN, JAVIER; Hyman, D M; Juric, D; Krop, I; Bieche, I; SAURA MANICH, CRISTINA; Sotiriou, C; Cardoso, F; Loibl, S; Andre, F; Turner, N C. Genomic alterations in breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 2019 Mar 1;30(3):365-373. doi: 10.1093/annonc/mdz036.
  11. Ramos, Javier; Vega, Juan Francisco; Cruz, Victor; Sanchez-Sanchez, Eduardo; CORTES CASTAN, JAVIER; Martinez-Salazar, Javier. Hydrodynamic and Electrophoretic Properties of Trastuzumab/HER2 Extracellular Domain Complexes as Revealed by Experimental Techniques and Computational Simulations. Int J Mol Sci. 2019 Mar 1;20(5). pii: E1076. doi: 10.3390/ijms20051076.
  12. Adams, S; Schmid, P; Rugo, H S; Winer, E P; Loirat, D; Awada, A; Cescon, D W; Iwata, H; Campone, M; Nanda, R; Hui, R; Curigliano, G; Toppmeyer, D; O'Shaughnessy, J; Loi, S; Paluch-Shimon, S; Tan, A R; Card, D; Zhao, J; Karantza, V; CORTES CASTAN, JAVIER. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019 Mar 1;30(3):397-404. doi: 10.1093/annonc/mdy517.
  13. Duran Lozano, Laura; Montalban Canudas, Gemma; Bonache Real, Sandra; Moles Fernandez, Alejandro; Tenes Felipe, Anna; Castroviejo Bermejo, Cristina; Carrasco Lopez, Estela; Lopez Fernandez, Adria; Torres Esquius, Sara; Gadea, Neus; Stjepanovic, Neda; Balmaña Gelpi, Judith; Gutierrez Enriquez, Sara Iliana; Diez Gibert, Orland. Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G > T. Breast Cancer Res Treat. 2019 Apr;174(2):543-550. doi: 10.1007/s10549-018-05094-8. Epub 2018 Dec 14
  14. Ortega, Vanesa; Antón, Antonio; Garau, Isabel; Afonso, Noemia; Calvo, Lourdes; Fernández, Yolanda; Martínez-García, María; Blanco, Esperanza; Zamora, Pilar; García, Mirta; Illarramendi, José Juan; Rodríguez Sánchez, César Augusto; Sampayo, Miguel; Aguirre, Elena; Pérez-García, José Manuel; CORTES CASTAN, JAVIER; Llombart-Cussac, Antonio. Phase II, Multicenter, Single-arm Trial of Eribulin as First-line Therapy for Patients With Aggressive Taxane-pretreated HER2-Negative Metastatic Breast Cancer: The MERIBEL Study.Clin Breast Cancer. 2019 Apr;19(2):105-112. doi: 10.1016/j.clbc.2018.12.012. Epub 2018 Dec 20.
  15. Ferreira, Manuel A; Gamazon, Eric R; Al-Ejeh, Fares; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arason, Adalgeir; Arndt, Volker; Aronson, Kristan J; Arun, Banu K; Asseryanis, Ella; Azzollini, Jacopo; BALMAÑA GELPI, JUDITH; Barnes, Daniel R; Barrowdale, Daniel; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bialkowska, Katarzyna; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Caldés, Trinidad; Caligo, Maria A; Campa, Daniele; Campbell, Ian; Canzian, Federico; Carter, Jonathan; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Christiansen, Hans; Chung, Wendy K; Claes, Kathleen B M; Clarke, Christine L; EMBRACE Collaborators; GC-HBOC Study Collaborators; GEMO Study Collaborators; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Daly, Mary B; de la Hoya, Miguel; Dennis, Joe; Devilee, Peter; DIEZ GIBERT, ORLAND; Dörk, Thilo; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Ejlertsen, Bent; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Fletcher, Olivia; Flyger, Henrik; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gago-Dominguez, Manuela; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; García-Closas, Montserrat; García-Sáenz, José A; Gaudet, Mia M; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; He, Wei; Heyworth, Jane; Hogervorst, Frans B L; Hollestelle, Antoinette; Hoover, Robert N; Hopper, John L; Hulick, Peter J; Humphreys, Keith; Imyanitov, Evgeny N; ABCTB Investigators; HEBON Investigators; BCFR Investigators; Isaacs, Claudine; Jakimovska, Milena; Jakubowska, Anna; James, Paul A; Janavicius, Ramunas; Jankowitz, Rachel C; John, Esther M; Johnson, Nichola; Joseph, Vijai; Karlan, Beth Y; Khusnutdinova, Elza; Kiiski, Johanna I; Ko, Yon-Dschun; Jones, Michael E; Konstantopoulou, Irene; Kristensen, Vessela N; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Lindström, Sara; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Makalic, Enes; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Maurer, Tabea; Mavroudis, Dimitrios; McGuffog, Lesley; Meindl, Alfons; Menon, Usha; Michailidou, Kyriaki; Miller, Austin; Montagna, Marco; Moreno, Fernando; Moserle, Lidia; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Nielsen, Finn C; Nikitina-Zake, Liene; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Osorio, Ana; Papp, Janos; Park-Simon, Tjoung-Won; Parsons, Michael T; Pedersen, Inge Sokilde; Peixoto, Ana; Peterlongo, Paolo; Pharoah, Paul D P; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Presneau, Nadege; Radice, Paolo; Rantala, Johanna; Rennert, Gad; Risch, Harvey A; Saloustros, Emmanouil; Sanden, Kristin; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Sharma, Priyanka; Shu, Xiao-Ou; Simard, Jacques; Singer, Christian F; Soucy, Penny; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stone, Jennifer; Swerdlow, Anthony J; Tapper, William J; Taylor, Jack A; Teixeira, Manuel R; Terry, Mary Beth; Teulé, Alex; Thomassen, Mads; Thöne, Kathrin; Thull, Darcy L; Tischkowitz, Marc; Toland, Amanda E; Torres, Diana; Truong, Thérèse; Tung, Nadine; Vachon, Celine M; van Asperen, Christi J; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Vega, Ana; Viel, Alessandra; Wang, Qin; Wappenschmidt, Barbara; Weitzel, Jeffrey N; Wendt, Camilla; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Ziogas, Argyrios; Kraft, Peter; Antoniou, Antonis C; Zheng, Wei; Easton, Douglas F; Milne, Roger L; Beesley, Jonathan; Chenevix-Trench, Georgia. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nature Communications. Doi: 10.1038/s41467-018-08053-5
  16. Pascual, Tomás; Martin, Miguel; Fernández-Martínez, Aranzazu; Paré, Laia; Alba, Emilio; Rodríguez-Lescure, Álvaro; Perrone, Giuseppe; CORTES CASTAN, JAVIER; Morales, Serafín; Lluch, Ana; Urruticoechea, Ander; González-Farré, Blanca; Galván, Patricia; Jares, Pedro; Rodriguez, Adela; Chic, Nuria; Righi, Daniela; Cejalvo, Juan Miguel; Tonini, Giuseppe; Adamo, Barbara; Vidal, Maria; Villagrasa, Patricia; Muñoz, Montserrat; Prat, Aleix.A Pathology-Based Combined Model to Identify PAM50 Non-luminal Intrinsic Disease in Hormone Receptor-Positive HER2-Negative Breast Cancer. Front Oncol. 2019; 9: 303. Pub online 2019 Apr 26. doi: 10.3389/fonc.2019.00303
  17. Turner, Nicholas C; Telli, Melinda L; Rugo, Hope S; Mailliez, Audrey; Ettl, Johannes; Grischke, Eva-Maria; Mina, Lida A; BALMAÑA GELPI, JUDITH; Fasching, Peter A; Hurvitz, Sara A; Wardley, Andrew M; Chappey, Colombe; Hannah, Alison L; Robson, Mark E. A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin Cancer Res. 2019 May 1;25(9):2717-2724. doi: 10.1158/1078-0432.CCR-18-1891. Epub 2018 Dec 18.
  18. Turner, N C; Alarcón, E; Armstrong, A C; Philco, M; López Chuken, Y A; Sablin, M-P; Tamura, K; Gómez Villanueva, A; Pérez-Fidalgo, J A; Cheung, S Y A; Corcoran, C; Cullberg, M; Davies, B R; de Bruin, E C; Foxley, A; Lindemann, J P O; Maudsley, R; Moschetta, M; Outhwaite, E; Pass, M; Rugman, P; Schiavon, G; ANTUNES DE MELO E OLIVEIRA, MAFALDA.BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Ann Oncol. 2019 May 1;30(5):774-780. doi: 10.1093/annonc/mdz086.
  19. Colomer, Ramon; SAURA MANICH, CRISTINA; Sánchez-Rovira, Pedro; Pascual, Tomás; Rubio, Isabel T; Burgués, Octavio; Marcos, Lourdes; Rodríguez, César A; Martín, Miguel; Lluch, Ana. Neoadjuvant Management of Early Breast Cancer: A Clinical and Investigational Position Statement. 2019 May;24(5):603-611. doi: 10.1634/theoncologist.2018-0228. Epub 2019 Feb 1.
  20. Perez-Garcia, Jose Manuel; CORTES CASTAN, JAVIER. The safety of eribulin for the treatment of metastatic breast cancer. Expert Opinion On Drug Safety. Doi: 10.1080/14740338.2019.1608946
  21. BELLET EZQUERRA, MERITXEL; Ahmad, Faten; Villanueva, Rafael; Valdivia, Carolina; Palomino-Doza, Julián; Ruiz, Ada; Gonzàlez, Xavier; Adrover, Encarna; AZARO, ANALIA BEATRIZ; Valls-Margarit, Maria; Parra, Josep Lluís; Aguilar, Juan; VIDAL LOSADA, Mª JESUS; Martín, Anastasi; Gavilá, Joaquín; ESCRIVA DE ROMANI MUÑOZ, SANTIAGO; Perelló, Antonia; Hernando, Cristina; Lahuerta, Ainhara; Zamora, Pilar; Reyes, Victoria; Alcalde, María; Masanas, Helena; Céliz, Pamela; Ruíz, Isabel; Gil, Miguel; Seguí, Miguel Àngel; de la Peña, Lorena. Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. Ther Adv Med Oncol. 2019 May 10;11:1758835919833867. doi: 10.1177/1758835919833867. eCollection 2019.
  22. Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Buxó, Maria; Pernas, Sonia; Dorca, Joan; Álvarez, Isabel; Martínez, Susana; Pérez-Garcia, Jose Manuel; Batista-López, Norberto; Rodríguez-Sánchez, César A; Amillano, Kepa; Domínguez, Severina; Luque, Maria; Morilla, Idoia; Stradella, Agostina; Viñas, Gemma; CORTES CASTAN, JAVIER; Verdura, Sara; Brunet, Joan; López-Bonet, Eugeni; Garcia, Margarita; Saidani, Samiha; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A. Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients. Aging (Albany NY). 2019 May 15; 11(9): 2874–2888. Published online 2019 May 9. doi: 10.18632/aging.101960
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  54. Joaquín Gavilá; Juan De La Haba; Begoña Bermejo; Álvaro Rodríguez-Lescure; Antonio Antón; Eva Ciruelos; Joan Brunet; Eva Muñoz-Couselo; Marta Santisteban; César Augusto Rodríguez Sánchez; Ana Santaballa; Pedro Sánchez Rovira; José Ángel García-Sáenz; Manuel Ruiz Borrego; Ángel Guerrero-Zotano; Marisol Huerta; Almudena Cotes-Sanchís; Juan Lao Romera; Elena Aguirre; Javier Cortés; Antonio Llombart-Cussac. "A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: The Trastyvere study’. Clinical and Translational Oncology 2019. https://doi.org/10.1007/s12094-019-02145-4
  55. María Julia Lostes Bardaji MD, Carolina Ortiz MD , Analía Azaro MD, Eva Muñoz-Couselo MD PhD. Opciones emergentes en terapias de combinación para el melanoma avanzado (MM): Un nuevo desafío. Cáncer de piel 2019. IS-SN papel 2605-1648, electrónica IS-SN 2605-1669.

Projects

  1. Estudio para evaluar losdesenlaces del embarazo y la seguridad de la interrupción del tratamiento endocrino de mujeres jóvenes con cáncer de mama y respuesta al tratamiento endocrino que deseen quedarse embarazadas (POSITIVE).
  2. Estudio de biomarcadores circulantes en sangre en pacientes con cáncer de mama.
  3. ADN libre circulante en leche materna en la identificación precoz del cáncer de mama.
  4. Inmunoterapia contra tumores HER2 positivos.
  5. PrecIMet: precision imaging for bone metastases.
  6. Modulation of androgen receptor signaling as a therapeutic strategy for oestrogen receptor-positive metastatic breast
  7. Patient stratification based on DNA repair functionality for cancer precision medicineEstratificación de pacientes basada en la funcionalidad de la reparación del daño al ADN para la medicina personalizada contra el cáncer.
  8. Developing integrated clinical, in vivo and ex vivo platforms to understand platinum response and resistance in breast cancerDesarrollo de plataformas integradas clínicas, in vivo y ex vivo quepermitan comprender la sensibilidad y resistencia a los platinos en cáncer de mama.
  9. Validación de la expansión de linfocitos infiltrantes de tumor en condiciones GMP.
  10. Papel de las plataformas genómicas en la predicción de riesgo de recidiva en pacientes con tumores Luminales conenfermedad residual tras tratamiento neoadyuvante (estudio OMPHALOS).
  11. Nuevos factores predictivos de respuesta a terapias dirigidas y factores pronóstico en cáncer de mama con mutaciones hereditarias en BRCA1 y BRCA": capacidad de reparación del daño en el ADN y perfil inmunológico tumoral.
  12. Personalized non-invasive T-cell therapies targeting the mutanome.
  13. AURORA Hacia el entendimiento de las alteraciones moleculares del cáncer de mama metastásico.
  14. Prevención de las recaídas mediante ejercicio, dieta y control de peso en pacientes con cáncer de mama (PREDICOP).
  15. Utilidad del ctDNA para la detección precoz de recidica en cáncer de mama RH+/HER2- mediante el seguimiento de mutaciones presentes en el tumor primario o mutaciones emergentes de ESR1.
  16. Nueva tecnología para la detección de mutaciones puntuales en el oncogen BRAF a partir de sangre periférica y su validación en muestras tisulares/tumorales en pacientes afectos de melanoma metastásico.
  17. Biopsia líquida para detección nanoplasmónica de exosomas: prediciendo respuesta a la inmunoterapia.
  18. Perfil epigenético capaz de predecir la respuesta a inmunoterapia en melanoma.
  19. 360º RESISTANCE: Aplicación de un modelo de investigación traslacional para estudiar predictores de respuesta/toxicidad, y mecanismos de resistencia en pacientes tratados con inmunoterapia.
  20. Estrategias específicas para el cerebro para mejorar la respuesta a inmunoterapia.
  21. Estudio de mecanismos de resistencia primaria y adquirida a inhibidores de "immune checkpoints.
  22. Estudio observacional descriptivo sobre las características yevolución del melanoma avanzado y metastásico en España.
  23. Búsqueda de marcadores predictores de corticoterapia en hepatitis inmunomediadas (Estudio HEPiraes).
  24. Caracterización genética de melanomas cutaneos (tumores primarios y PDX).
  25. Generation of the Melanoma Biobank.

Clinical Trials

Breast:
  • Combination of Talimogene Laherparepvec with Atezolizumab in residual breast cancer following standard neoadjuvant multi-agent chemotherapy (PROMETEO TRIAL).
  • AURORA: Investigación de las alteraciones moleculares en el cáncer de mama metastásico.
  • A PHASE I, MULTICENTER, OPEN-LABEL PREOPERATIVE SHORT-TERM WINDOW STUDY OF GDC-9545 IN POSTMENOPAUSAL WOMEN WITH STAGE I-III OPERABLE, ESTROGEN RECEPTOR-POSITIVE BREAST CANCER.
  • A PHASE IB/III STUDY OF IPATASERTIB PLUS PALBOCICLIB AND FULVESTRANT VERSUS PLACEBO PLUS PALBOCICLIB AND FULVESTRANT IN HORMONE RECEPTOR POSITIVE AND HER2 NEGATIVE LOCALLY ADVANCED UNRESECTABLE OR METASTATIC BREAST CANCER.
  • An Open-Label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR gene amplification.
  • PATRICIA: Ensayo clínico fase II de la combinación de palbociclib y trastuzumab con o sin letrozol en pacientes postmenopáusicas con cáncer de mama localmente avanzado o metastásico HER2-positivo previamente tratado.
  • Ensayo clínico de fase 2 de poliquimioterapia o letrozol más ribociclib (LEE001) como tratamiento neoadyuvante en pacientes posmenopáusicas con cáncer de mama de tipo luminal B y HER2 negativo.
  • Phase I/prospective randomised phase II trial Of the Safety and Efficacy of tamoxifen in combination with the Isoform selective Pi3K inhibitor GDC-0032 compared with tamoxifen alONe in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment
  • Ensayo Clínico Fase II para analizar la Respuesta a Olaparib de pacientes con Metilación del Promotor del BRCA1 y/o 2 diagnosticadas de Cáncer de Mama Avanzado (Estudio COMETA-Breast).
  • A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the antibody-drug conjugate SYD985 to physician's choice in patients with HER2-positive unresectable locally advanced or metastatic breast cancer.
  • Phase 2 Randomized, Double-Blinded, Controlled Study of ONT-380 vs. Placebo in Combination with Capecitabine and Trastuzumab in Patients with Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma.
  • A phase II, multicenter, open-label, two-cohort, noncomparative study to assess the efficacy and safety of alpelisib plus fulvestrant or letrozole in patients withPIK3CA mutant, hormone receptor (HR) positive, HER2- negative advanced breast cancer (aBC), who have progressed on or after CDK 4/6 inhibitor treatment.
  • Phase II study of MCLA-128-based combinations in metastatic breast cancer (MBC): MCLA- 28/trastuzumab/chemotherapy in HER2-positive MBC and MCLA-128/endocrine therapy in estrogen receptor positive and low-HER2 expression MBC.
  • A multicenter, international, non-controlled, phase II trial to identify the molecular mechanisms of resistance and sensitivity to palbociclib re-challenge upon progression to a palbociclib combination in ER-positive metastatic breast cancer patients (BioPER).
  • A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination with Olaparib versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-related Genes (including BRCA1/2) (VIOLETTE).
  • A phase II trial testing durvalumab combined with endocrine therapy in patients with ER+/her2- breast cancer eligible for neoadjuvant endocrine therapy and who present CD8+ T cell infiltration after 4-6 weeks exposure to immune-attractant.
  • Estudio de fase 2 abierto y aleatorizado, en el que se evalúa cómo influyen los alimentos en la tolerabilidad de abemaciclib en pacientes con cáncer de mama metastásico con receptores hormonales positivos y HER2 negativos para el que hayan recibido tratamiento previo.
  • Xenera-1: A multi-centre, double-blind, placebo-controlled, randomised phase II trial to compare efficacy of xentuzumab in combination with everolimus and exemestane versus everolimus and exemestane in post-menopausal women with HR+ / HER2-metastatic breast cancer and non-visceral disease.
  • Effectiveness of olaparib plus trastuzumab in HER2-positive BRCA-mutated or Homologous Recombination Deficiency (HRD) advanced breast cancer patients .The OPHELIA Study.
  • Single Arm, Open Label Phase 1b/2 Study of SGN-LIV1A in Combination with Pembrolizumab for First-Line Treatment of Patients with Unresectable Locally-Advanced or Metastatic Triple-Negative Breast Cancer.
  • NEOADJUVANT LETROZOLE AND PALBOCICLIB IN PATIENTS WITH STAGE II-IIIB BREAST CANCER, HR[+]/HER2[-] PHENOTYPE AND PRE-TREATMENT RECURRENCE SCORE® (RS) RESULT 18-25 OR 26-100 BY THE ONCOTYPE DX BREAST RS ASSAY. ANALYSIS OF RS AND PATHOLOGICAL CHANGES AT SURGERY (DxCARTES TRIAL) .
  • International, multicenter, randomized, open-label, phase II clinical trial to evaluate the efficacy and safety of continuation of palbociclib in combination with second-line endocrine therapy in hormone receptor-positive/HER2-negative Advanced Breast Cancer patients who have achieved clinical benefit during first-line palbociclib-based treatment. (PALMIRA).
  • BARBICAN: A randomised, open-label Phase II study to determine the contribution of ipatasertib to neoadjuvant hemotherapy plus atezolizumab in women with triple-negative breast cancer.
  • Un estudio multinacional, multicéntrico, fase 2 de tesetaxel más una dosis reducida de capecitabina en pacientes con HER2 negativo, receptor hormonal positivo, cáncer de mama localmente avanzado o metastásico que no han recibido previamente el tratamiento con taxanos.
  • A Phase 2 Study of TAS-120 in Metastatic Breast Cancer Harboring Fibroblast Growth Factor Receptor (FGFR) Amplifications.
  • Ensayo fase III, multicéntrico, aleatorizado, doble ciego, de grupos paralelos, controlado con placebo, para evaluar la eficacia y la seguridad de olaparib frente a placebo como tratamiento adyuvante de pacientes con cáncer de mama HER2 negativo de alto riesgo y mutaciones germinales de BRCA1/2, que han finalizado el tratamiento local y la quimioterapia neoadyuvante o adyuvante.
  • Estudio fase III que evalúa palbociclib (PD-0332991), un inhibidor de quinasa dependiente de las ciclinas (CDK) 4/6, en pacientes con cáncer de mama primario con receptores hormonales positivos y HER2 normal y alto riesgo de recidiva tras quimioterapia neoadyuvante “PENELOPE B”.
  • Estudio de fase 3, aleatorizado, doble ciego, controlado con placebo, en el que se evalúa fulvestrant en combinación o no con LY2835219, un inhibidor de las CDK4/6, en mujeres con cáncer de mama localmente avanzado o metastásico, receptor hormonal positivo, HER2 negativo.
  • Estudio En Fase III, Abierto, Aleatorizado y Multicéntrico de Nktr-102 Frente Al Tratamiento Elegido por El Médico En Pacientes Con Cáncer de Mama Metastásico que Tienen Metástasis Cerebrales Estables y Que Han Recibido Tratamiento con una Antraciclina, un Taxano y Capecitabina con Anterioridad.
  • Ensayo de fase III, aleatorizado y abierto para evaluar la eficacia y la seguridad de palbociclib + tratamiento anti-HER2 + tratamiento endocrino frente a tratamiento anti-HER2 + tratamiento endocrino tras el tratamiento de inducción para el cáncer de mama metastásico positivo para receptores hormonales (HR+)/positivo para HER2.
  • A Randomized, Open-Label, Phase 3 Study of Abemaciclib Combined with Standard Adjuvant Endocrine Therapy versus Standard Adjuvant Endocrine Therapy Alone in Patients with High Risk, Node Positive, Early Stage, Hormone Receptor Positive, Human Epidermal Receptor 2 Negative, Breast Cancer.
  • LUCY - Lynparza Breast Cancer Real-World Utility, Clinical Effectiveness and Safety Study. A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Monotherapy in the Treatment of HER2-ve Metastatic Breast Cancer Patients with Germline BRCA1/2 Mutations.
  • A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED PHASE III STUDY OF IPATASERTIB IN COMBINATION WITH PACLITAXEL AS A TREATMENT FOR PATIENTS WITH PIK3CA/AKT1/PTEN-ALTERED, LOCALLY ADVANCED OR METASTATIC, TRIPLE-NEGATIVE BREAST CANCER OR HORMONE RECEPTOR– POSITIVE, HER2-NEGATIVE BREAST CANCER .
  • A PHASE III, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTRE STUDY OF THE EFFICACY AND SAFETY OF ATEZOLIZUMAB PLUS CHEMOTHERAPY FOR PATIENTS WITH EARLY RELAPSING RECURRENT (INOPERABLE LOCALLY ADVANCED OR METASTATIC) TRIPLE-NEGATIVE BREAST CANCER.
  • Estudio en fase III, internacional, multicéntrico, abierto, aleatorizado, de sacituzumab govitecan (IMMU-132) frente al tratamiento elegido por el médico en pacientes con cáncer de mama triple negativo metastásico que recibieron al menos dos tratamientos previos.
  • Estudio de fase III, aleatorizado, multicéntrico y multinacional de tesetaxel más una dosis reducida de capecitabina en comparación con capecitabina en monoterapia en pacientes con cáncer de mama metastásico o localmente avanzado, HER2 negativo y receptor hormonal positivo, tratado previamente con un taxano.
  • A Randomized, Double-Blind, Phase III Study of Pembrolizumab versus Placebo in Combination with Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy for the Treatment of High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2–) Breast Cancer (KEYNOTE-756) .
  • A Phase 3, multicenter, randomized, open-label, active-controlled study of DS-8201a, an anti-HER2-antibody drug conjugate, versus ado-trastuzumab emtansine (T-DM1) for HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane.
  • A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF ATEZOLIZUMAB OR PLACEBO IN COMBINATION WITH NEOADJUVANT DOXORUBICIN,CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL, TRASTUZUMAB,PERTUZUMAB IN EARLY HER2-POSITIVE BREAST CANCER.
  • Estudio en fase III, multicéntrico, aleatorizado, abierto y controlado con principio activo de DS-8201a, un conjugado de fármaco y anticuerpo (CAF) anti-HER2, en comparación con el tratamiento elegido por el médico en sujetos con cáncer de mama irresecable o metastásico (o ambos) con expresión baja de HER-2.
  • DB, Rando study assigned the efficacy and Safety of Capivasertib+pacli VS placebo+pacli as 1L for pa with histologically confirmed , locally advanced (inoparable)or M1 TNBC.
  • An International, Phase 3, Multicenter, Randomized, Open-Label Trial Comparing Balixafortide in combination with Eribulin versus Eribulin alone in Patients with HER2 negative, Locally Recurrent or Metastatic Breast Cancer. CLEE011O12301C.
  • A phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with endocrine therapy versus endocrine therapy alone for patients with hormone receptor positive / HER2-negative resected isolated locoregional recurrence of breast cancer.
  • Phase 3 Study of Sacituzumab Govitecan-hziy (IMMU-132) Versus Treatment of Physician's Choice (TPC) in subjects with Hormonal Receptor-Positive (HR+) Human Epidermal Growth Factor Receptor 2 (HER2) Negative Metastatic Breast Cancer (MBC) who have failed at least two prior chemotherapy regimens.
  • A PHASE IB/III STUDY OF IPATASERTIB PLUS PALBOCICLIB AND FULVESTRANT VERSUS PLACEBO PLUS PALBOCICLIB AND FULVESTRANT IN HORMONE RECEPTOR POSITIVE AND HER2 NEGATIVE LOCALLY ADVANCED UNRESECTABLE OR METASTATIC BREAST CANCER."
  • A Phase 4 long-term follow-up study to define the safety profile of radium-223 dichloride. HER-Seq: A Blood-based Screening Study to Identify Patients with HER2 Mutations for Enrollment into Clinical Research Studies of Neratinib.
  • Estudio en fase I, abierto, de 2 partes, multicéntrico, para evaluar la seguridad, tolerabilidad y eficacia de olaparib en combinación con carboplatino.
  • A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer.
  • A PHASE I, OPEN-LABEL, DOSE-ESCALATION STUDY EVALUATING THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF GDC-0077 AS A SINGLE AGENT IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC PIK3CA-MUTANT SOLID TUMORS AND IN COMBINATION WITH ENDOCRINE AND TARGETED THERAPIES IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC PIK3CA-MUTANT HORMONE-RECEPTOR POSITIVE BREAST CANCER.
  • A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND TOLERABILITY OF PF-06804103 IN PATIENTS WITH HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2) POSITIVE SOLID TUMORS.
  • A Phase Ia/Ib, Multicenter, Open-Label, Dose Escalation, Dose Expansion Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC 9545 Alone or In Combination with Palbociclib and/or LHRH Agonist in Patients with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer.
  • A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE IMMUNOTHERAPY-BASED TREATMENT COMBINATIONS IN PATIENTS WITH METASTATIC TRIPLE NEGATIVE BREAST CANCER (MORPHEUS TNBC).
  • Estudio abierto, multicéntrico, de fase Ib, de escalado de dosis, de MEN1611, un inhibidor de PI3K combinado con trastuzumab ± fulvestrant, en sujetos con cáncer de mama irresecable y localmente recurrente (avanzado) o metastásico (a/m) HER2 positivo con mutación PIK3CA que ha progresado con un tratamiento basado en anti-HER2.
  • A Phase 1 Dose Escalation and Expansion Study of AZD9833 Alone or in Combination with Palbociclib in Women with ER Positive, HER2 Negative Advanced Breast CancerA Phase 1 Dose Escalation and Expansion Study of AZD9833 Alone or in Combination with Palbociclib in Women with ER Positive, HER2 Negative Advanced Breast Cancer.
  • A Phase Ib, multicenter, open-label dose escalation and expansion platform study of select immunotherapy combinations in adult patients with triple negative breast cancer.
  • A Phase 2 Study of ZEN003694 in Combination with Talazoparib in Patients with Triple-Negative Breast Cancer.
  Melanoma
  • CA224047:A Randomized, Double-Blind Phase 2/3 Study of Relatlimab Combined with Nivolumab versus Nivolumab in Participants with Previously Untreated Metastatic or Unresectable Melanoma.
  • KEYNOTE 716: Adjuvant therapy with pembrolizumab versus placebo in resected high-risk stage II melanoma, a randomized, double-blind phase 3 study.
  • CA045-001: A Phase 3, Randomized, Open-Label Study of NKTR-214 Combined with Nivolumab vs. Nivolumab in Participants with Previously Untreated Unresctable or Metastatic Melanoma.
  • A Randomized Phase 3 Comparison of IMO-2125 With Ipilimumab Versus Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (ILLUMINATE-301).
  • A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Pembrolizumab Versus Placebo as Adjuvant TherapyFollowing Surgeryand Radiation in Participants with High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC) (KEYNOTE-630).
  • A Phase 1 Randomized Clinical Studyof Pembrolizumab (MK-3475) to Evaluate the Relative Bioavailabilityof Subcutaneous Injection Versus Intravenous Infusion  in Participants with Advanced Melanoma (KEYNOTE-555).
  • R2810-1540: A phase 2 study ofREGN2810, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with advanced cutaneous squamous cell carcinoma.
  • BP41054: An open-lable, multicenter, phase IB study to evaluate safety and therapeutic activity of RO6874281, an immunocytokine, consisting of interleukin-2 variant 8IL-2V) targeting fibroblast activation protein-A (FAP), in combination with pembrolizumab (anti-PD1), in participants with previously untreated advanced and /or metastatic melanoma.
  • 1612-MG: Combination of targeted therapy (encorafenib and binimetinib) followed by combination of immunoterapy (ipilimumab and nivolumab) vs immediate combination of immunotherapy in patients with unresectable or metastatic melanoma with BRAF v600 mutation: an EORTC phase II randomized study (EBIN).
  • APX005-002: A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer and Subjects with Metastatic Melanoma.
  • APX005M-010: A Study to Evaluate the Safety and efficacy of the CD40 Agonistic Antibody APX005M in Adults with Immunotherapy Naïve Metastatic Melanoma.
  • GEM18-02: Multicentre phase II trial to evaluate the activity of encorafenib and binimetinib before local treatment in patients with BRAF mutated melanoma with metastasis to the brain.
  • NP40435: An open label, multicenter, dose escalation and expansion, phse I study to evaluate safety, pharmacokinetics, and preliminary anti tumor activity of RO7121661, a PD-1/TIM-3 biespecific antibody, in patients with advanced and/or metastatic solid tumors.
  • CA224020: A phase 1/2a dose escalation abnd cohor expansion study of safety, tolerability, and efficacy an anti-LAG-3 monocolonal antibody (BMS-986016) administered alone and in combination with anti-PD1 monoclonal antibody (Nivolumab, BMS-936558) in advanced solid tumors.
  • R2810-ONC-1788: A randomized, placebo-controlled, double-blind study of adjuvant cemiplimab versus placebo after surgery and radiation therapy in patients with high risk cutaneous squamous cell carcinoma.

Early Clinical Drug Development Group

Elena Garralda
Principal Investigator
Biosketch
Director of Clinical Research at VHIO Josep Tabernero Principal Investigator, Early Clinical Drug Development Group, Director, UITM Elena Garralda Associate Investigators Senior Consultants Judith Balmaña, Joan Carles, Enriqueta Felip, Elena Garralda, Teresa Macarulla, Ana Oaknin, Cristina Saura, Josep Tabernero Phase I Investigators Guzman Alonso, Maria Alsina, Guillermo Argiles, Analia Azaro, Irene Braña, Meritxell Bellet, Ana Callejo, Jaume Capdevila, Marta Capelan, Susana Cedres, Elena Elez, Santiago Escriva, Lorena Fariñas, Vladimir Galvao, Patricia Gomez, Itziar Gardeazabal, Macarena Gonzalez, Alberto Hernando, Jorge Hernando, Juan Martin, Alexandre Martinez, Joaquin Mateo, Ignacio Matos, Rafael Morales, Eva Muñoz, Alejandro Navarro, Mafalda Oliveira, Nuria Pardo, Omar Saavedra, Cesar Serrano, Cristina Suarez, Claudia Valverde, Helena Verdaguer, Maria Vieito, Esther Zamora Data Manager Roger Berche Clinical Nurse Specialists Andrea Martinez, Patricia Prieto, Natassia Wornham

Summary

We focus on proof-of-concept and proof-of-mechanism trials with targeted therapies, with particular emphasis on cell signaling, cancer stem cells, and immuno-oncology. These include first-in-human studies of targeted therapies, rational combinations of targeted therapies, biomarker-driven trials, and studies in molecularly selected populations.

We link clinical research at the Research Unit for Molecular Therapy of Cancer (UITM) –”la Caixa”, with different areas of investigation carried out at VHIO, following a truly translational model. For selected projects, we match molecular biology and optimal tumor models with pharmacology and innovative clinical research by involving VHIO scientists in our trials (biomarker development, profound understanding of mechanisms of action and resistance).

We have collaborated with VHIO’s Molecular Oncology and Cancer Genomics Groups, led by Paolo Nuciforo and Ana Vivancos, as well as Rodrigo Dienstmann, PI of our ODysSey Group, together with Susana Aguilar and Jenifer Gonzalez, to perform molecular analysis of patients’ tumors. This enables us to select the optimal treatment for our patients with the experimental therapies available in our portfolio of clinical trials.

Importantly, in relation to precision oncology, VHIO is a founding member of both the WIN (Worldwide Innovative Networking in personalized cancer medicine), and the Cancer Core Europe (CCE), consortia. Both are non-governmental organizations that connect international (WIN) and/or European (CCE) cancer centers, including VHIO, to advance cancer diagnostics and therapeutics.

This year, our group and VHIO’s UITM, have continued to lead the Basket of Baskets (BoB) trial, securing funding to add new modules to the multi-modular trial. This academic study, endorsed by Cancer Core Europe, integrates molecular prescreening, the development of new diagnostic tests such as circulating DNA, with the assessment of targeted therapies in populations of patients who, matched to specific molecular alterations, will be most likely to benefit from these treatments.

Our Early Drug Development Group and Phase I Unit (UITM), continues to establish VHIO as a leading reference in driving drug development and targeted therapies in oncology. Testament to this is the number of patients who entrust us with their care (499 patients enrolled in phase I and basket studies in 2019), the portfolio of different trials available (162 phase I trials including 22 basket studies in 2019), and the novelty of our programs in precision medicine and immunotherapy drug development. This is also evidenced by our leading role in Cancer Core Europe’s Clinical Trials Task Force.

We have also fostered important alliances with the pharmaceutical industry, including this year’s Partner of Choice Initiative with MedImmune, and collaborate closely with other clinical research organizations and academic centers of excellence, as well as companies dedicated to advancing personalized cancer medicine and care.


Strategic goals

  • Early clinical development of the best-in-class targeted therapies, determining the optimal schedule and patient population that would most likely benefit most from these drugs by participating in novel clinical trials.
  • Analyze patients' tumors for molecular aberrations that may predict the efficacy of targeted agents and enable a more precise selection of the most appropriate treatment matched to the specificities of individual patients with advanced cancer.
  • Link clinical research at the UITM with the various preclinical and translational research groups at VHIO, and foster powerful collaborations with different partners involved in drug development and translational research (phase I units, academic centers, consortia, pharmaceutical companies).

Highlights

  • As a leading reference in drug development at global level we clinically test the best in-class drugs. We have expanded our expertise to other cell-signaling pathway inhibitors, such as immunotherapeutics and second generation immunotherapies as well as intratumoral agents.
  • We have carried out many clinical trials with novel-novel combinations including the pairing of targeted therapies (novel/novel) and, in immuno-oncology, coupling checkpoint inhibitors with either chemotherapy, targeted therapies, or other immunomodulatory agents.
  • Within the scope of the VHIO-”la Caixa” Advanced Oncology Research Program, we have performed several clinical trials with patients selected on molecular alterations: mutations in AKT1, EGFR, PIK3CA, PIK3CB, PTEN, IDH1, ALK, ROS1, BRAF, NRAS, KRAS, FGFR1 and 2, MET, HER2, HER3, RET; amplifications in HER2, AKT 1, 2, and 3, FGFR1, MET, NOTCH1-4, rearrangements of NTRK1-3 ROS1, ALK, BRAF, RSPO2/3, RET and FGFR1-3, and alteration in protein expression of PTEN, or overexpression of PDL1, CEA and FAP.
  • Secured funding for a program to explore primary and acquired resistance to targeted therapies. This project integrates patient-derived xenografts and the analysis of next-generation sequencing of multiple tissue samples and circulating-free tumor DNA. In collaboration with VHIO's Ana Vivancos, Violeta Serra, Héctor G. Palmer, and Joaquín Arribas – PI’s of our Cancer Genomics, Experimental Therapeutics, Stem Cells & Cancer, and Growth Factors Groups, respectively we are focusing on the fibroblast growth factor and the RET pathway.
  • Co-development of molecular tests for patient screening (disease-oriented mutation panels for NGS platforms and Nanostring nCounter).
  • As part of our VHIO-BBVA Foundation Comprehensive Program of Cancer Immunotherapy & Immunology - CAIMI, we have continued our line of work to characterize hyperprogressive disease with immunotherapy and are involved in a collaboration with the European Organisation for Research and Treatment of Cancer (EORTC), to advance our understanding of this phenomenon.
  • We have continued our collaboration with Rodrigo Toledo, one of VHIO’s Translational Investigators, to monitor the cfDNA of patients receiving immunotherapy and characterize the clonal evolution of these patients.
  • Also within the context of our VHIO-BBVA Foundation's CAIMI program, we are working with Raquel Perez-Lopez, PI of our Radiomics Group, to establish a radiomic signature to predict response to immunotherapy.
  • We have secured funding to add a new module to the Basket of Basket (BoB) trial, to explore FGFR inhibition (TAS120) in genomically selected populations).
  • Initiated in 2019, we are evaluating the role of specific imaging of immune cell dynamics using novel tracer strategies, supported by the Innovative Medicines Initiative (IMI).
  • We have started our program for advanced therapies in solid tumors, as well as implemented our own academic TILs program in collaboration with Alena Gros, PI of VHIO’s Tumor Immunology & Immunotherapy Group, our CAR-T cell project funded through a grant received from the Spanish Association against Cancer (AECC) in 2019), and NK cells, research in collaboration with colleagues at the Clínica Universitaria de Navarra, in addition to other cell-based therapies.

PI paper pick

  • Rodon J, Soria, JC, Berger R, Miller, W H, Rubin E, Kugel A, Tsimberidou A, Saintigny P, Ackerstein A, Braña I, Loriot Y, Afshar M, Miller V, Wunder F, BressonC, Martini, JF, Raynaud, J, Mendelsohn, J, Batist, G, Onn, A, Tabernero, J, Richard L Schilsky, RL, Lazar, V, Lee, JJ, Kurzrock, R. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med. 2019 May;25(5):751-758.
  • Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, Cuartas I, Sala-Hojman A, Escudero L, Martínez-Ricarte F, Huber-Ruano I, Nuciforo P, Pedrosa L, Marques C, Braña I, Garralda E, Vieito M, Squatrito M, Pineda E, Graus F, Espejo C, Sahuquillo J, Tabernero J, Seoane J. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019 Jun 11;10(1):2416.
  • Hierro C, Matos I, Martin-Liberal J, Ochoa de Olza M, Garralda E. Agnostic-Histology Approval of new drugs in Oncology: are we already there? Clin Cancer Res. 2019 Jun 1;25(11):3210-3219.

Full list of Publications

  1. Actively personalized vaccination trial for newly diagnosed glioblastoma. Hilf N; Kuttruff-Coqui S; Frenzel K; Bukur V; Stevanovic S; Gouttefangeas C; Platten M; Tabatabai G; Dutoit V; van der Burg SH; Thor Straten P; Martínez-Ricarte F; Ponsati B; Okada H; Lassen U; Admon A; Ottensmeier CH; Ulges A; Kreiter S; von Deimling A; Skardelly M; Migliorini D; Kroep JR; Idorn M; Rodon J; et al... 2019. Nature. 565(7738): 240 - 245.
  2. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Herbst RS; Arkenau HT; Santana-Davila R; Calvo E; Paz-Ares L; Cassier PA; Bendell J; Penel N; Krebs MG; Martin-Liberal J; Isambert N; Soriano A; Wermke M; Cultrera J; Gao L; Widau RC; Mi G; Jin J; Ferry D; Fuchs CS; Petrylak DP; Chau I. 2019. Lancet Oncol. 20(8): 1109 - 1123.
  3. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Rodon J; Soria JC; Berger R; Miller WH; Rubin E; Kugel A; Tsimberidou A; Saintigny P; Ackerstein A; Braña I; Loriot Y; Afshar M; Miller V; Wunder F; Bresson C; Martini JF; Raynaud J; Mendelsohn J; Batist G; Onn A; Tabernero J; Schilsky RL; Lazar V; Lee JJ; Kurzrock R. 2019. Nat Med. 25(5): 751 - 751.
  4. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer A Phase 1b Clinical Trial.Juric D; Janku F; Rodón J; Burris HA; Mayer IA; Schuler M; Seggewiss-Bernhardt R; Gil-Martin M; Middleton MR; Baselga J; Bootle D; Demanse D; Blumenstein L; Schumacher K; Huang A; Quadt C; Rugo HS. 2019. JAMA Oncol. 5(2): e184475.
  5. Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial.Siu LL; Even C; Mesía R; Remenar E; Daste A; Delord JP; Krauss J; Saba NF; Nabell L; Ready NE; Braña I; Kotecki N; Zandberg DP; Gilbert J; Mehanna H; Bonomi M; Jarkowski A; Melillo G; Armstrong JM; Wildsmith S; Fayette J. 2019. JAMA Oncol. 5(2): 195 - 203.
  6. Immunotherapy in organ-transplanted cancer patients: efficacy and risk of organ rejection. Ros J; Matos I; Martin-Liberal J. 2019. Ann Oncol. 30(7): 1173 - 1177.
  7. Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic Small-Cell Lung Cancer: Results From the KEYNOTE-028 and KEYNOTE-158 Studies. Hyun Cheol Chung; Sarina A. Piha-Paul; Jose Lopez-Martin; Jan H.M. Schellens; Steven Kao; Wilson H. Miller; Jean-Pierre Delord; Bo Gao; David Planchard; Maya Gottfried; Alona Zer; Shadia I. Jalal; Nicolas Penel; Janice M. Mehnert; Ignacio Matos; Jaafar Bennouna; Dong-Wan Kim; Lei Xu; Suba Krishnan; Kevin Norwood; Patrick A. Ott. 2019. J Thorac Oncol.
  8. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8(+) T cell tumor-infiltration impairing anti-PD1 therapy. Pascual-García M; Bonfill-Teixidor E; Planas-Rigol E; Rubio-Perez C; Iurlaro R; Arias A; Cuartas I;Sala-Hojman A; Escudero L; Martínez-Ricarte F; Huber-Ruano I; Nuciforo P; Pedrosa L; Marques C; Braña I; Garralda E; Vieito M; Squatrito M; Pineda E; Graus F; Espejo C; Sahuquillo J; Tabernero J; Seoane J. 2019. Nat Commun. 10: 2416 - 2416.
  9. A Phase I Dose-Escalation Study of Veliparib Combined with Carboplatin and Etoposide in Patients with Extensive-Stage Small Cell Lung Cancer and Other Solid Tumors. Atrafi F; Groen HJM; Byers LA; Garralda E; Lolkema MP; Sangha RS; Viteri S; Chae YK; Camidge DR; Gabrail NY; Hu B; Tian T; Nuthalapati S; Hoening E; He L; Komarnitsky P; Calles A. 2019. Clin Cancer Res. 25(2): 496 - 505.
  10. A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations.Voss MH; Hierro C; Heist RS; Cleary JM; Meric-Bernstam F; Tabernero J; Janku F; Gandhi L; Iafrate AJ; Borger DR; Ishii N; Hu Y; Kirpicheva Y; Nicolas-Metral V; Pokorska-Bocci A; Vaslin Chessex A; Zanna C; Flaherty KT; Baselga J. 2019. Clin Cancer Res. 25(9): 2699 - 2707.
  11. Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There?. Hierro C; Matos I; Martin-Liberal J; Ochoa de Olza M; Garralda E. 2019. Clin Cancer Res.25(11): 3210 - 3219.
  12. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Bahleda R; Italiano A; Hierro C; Mita AC; Cervantes A; Chan N; Awad MM; Calvo E; Moreno V; Govindan R; Spira AI; Gonzalez MD; Zhong B; Santiago-Walker AE; Poggesi I; Parekh T; Xie H; Infante JR; Tabernero J. 2019. Clin Cancer Res. 25(16): 4888 - 4897.
  13. Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors. Jung KH; LoRusso PM; Burris HA; Gordon MS; Bang YJ; Hellmann MD; Cervantes A; Ochoa de Olza M; Marabelle A; Hodi FS; Ahn MJ; Emens LA; Barlesi F; Hamid O; Calvo E; McDermott DF; Soliman H; Rhee I; Lin R; Pourmohamad T; Suchomel J; Tsuhako A; Morrissey KM; Mahrus S; Morley R; Pirzkall A; Davis SL. 2019. Clin Cancer Res. 25(11): 3220 - 3228.
  14. Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with >= 25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy. Zandberg DP; Algazi AP; Jimeno A; Good JS; Fayette J; Bouganim N; Ready NE; Clement PM; Even C; Jang RW; Wong S; Keilholz U; Gilbert J; Fenton M; Braña I; Henry S; Remenar E; Papai Z; Siu LL; Jarkowski A; Armstrong JM; Asubonteng K; Fan J; Melillo G; Mesía R. 2019. Eur J Cancer.107: 142 - 152.
  15. New clinical trial designs in the era of precision medicine. Garralda E; Dienstmann R; Piris A; Braña I; Rodon J; Tabernero J. 2019. Mol Oncol.13(3): 549 - 557.
  16. Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. Bellet M; Ahmad F; Villanueva R; Valdivia C; Palomino-Doza J; Ruiz A; Gonzàlez X; Adrover E; Azaro A; Valls-Margarit M; Parra JL; Aguilar J; Vidal M; Martín A; Gavilá J; Escrivá-de-Romaní S; Perelló A; Hernando C; Lahuerta A; Zamora P; Reyes V; Alcalde M; Masanas H; Céliz P; Ruíz I; Gil M; Seguí MÀ; de la Peña L. 2019. Ther Adv Med Oncol. 11: 1758835919833867.
  17. Evaluating radiological response in pancreatic neuroendocrine tumours treated with sunitinib: comparison of Choi versus RECIST criteria (CRIPNET_ GETNE1504 study). Solis-Hernandez MP; Fernandez Del Valle A; Carmona-Bayonas A; Garcia-Carbonero R; Custodio A; Benavent M; Alonso Gordoa T; Nuñez-Valdovino B; Sanchez Canovas M; Matos I; Alonso V; Lopez C; Viudez A; Izquierdo M; Calvo-Temprano D; Grande E; Capdevila J; Jimenez-Fonseca P. 2019. Br J Cancer. 121(7): 537 - 544.
  18. Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study. Capdevila J; Teulé A; Barriuso J; Castellano D; Lopez C; Manzano JL; Alonso V; García-Carbonero R; Dotor E; Matos I; Custodio A; Casanovas O; Salazar R; EVERLAR study investigators. 2019. Oncologist. 24(1): 38 - 46.
  19. Investigational therapies in phase II clinical trials for the treatment of soft tissue sarcoma. Martin-Liberal J; Pérez E; García Del Muro X. 2019. Expert Opin Investig Drugs. 28(1): 39 - 50.
  20. Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials. Matos I; Noguerido A; Ros J; Mulet N; Argilés G; Elez É; Tabernero J. 2019. Expert Opin Investig Drugs. 28(5): 463 - 471.
  21. Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer. Cubillo A; Álvarez-Gallego R; Muñoz M; Pond G; Perea S; Sánchez G; Martin M; Rodríguez-Pascual J; Garralda E; Vega E; de Vicente E; Quijano Y; Muñoz C; Ugidos L; Toledo RA; Hidalgo M. 2019. Am J Clin Oncol. 42(1): 56 - 59.
  22. Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor. Harding JJ; Bauer TM; Tan DSW; Bedard PL; Rodon J; Doi T; Schnell C; Iyer V; Baffert F; Radhakrishnan R; Fabre C; Juric D. 2019. Invest New Drugs. 37(2): 271 - 281.
  23. Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules. Sankhala K; Takimoto CH; Mita AC; Xiong H; Rodón J; Mehrvarz Sarshekeh A; Burns K; Iizuka K; Kopetz S. 2019. Invest New Drugs. 37(1): 76 - 86.
  24. KEYNOTE-590: Phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Kato K; Shah MA; Enzinger P; Bennouna J; Shen L; Adenis A; Sun JM; Cho BC; Özgüroglu M; Kojima T; Kostorov V; Hierro C; Zhu Y; McLean LA; Shah S; Doi T. 2019. Future Oncol. 15(10): 1057 - 1066.
  25. RNF43 - and NOTCH1 -Mutated Chemotherapy and Anti–EGFR-Refractory Colorectal Cancer: Should Clonality Guide Target Prioritization With Investigational Therapies?. Aguilar, Susana; Santos, Cristina; Martini, Giulia; Argiles, Guillem; Azaro, Analia; Garralda, Elena; Tabernero, Josep; Nuciforo, Paolo;Vivancos, Ana; Dienstmann, Rodrigo. 2019. JCO Precis Oncol. 1 - 3.

Experimental Hematology Group

Francesc Bosch
Principal Investigator
Biosketch
Principal Investigator Francesc Bosch Translational Research Coordinator Marta Crespo Clinical Research Coordinator Pau Abrisqueta Lab Manager Júlia Carabia Hematologists/Lead Investigators Pere Barba David Beneitez, Gael Roue, Amparo Santamaria, David Valcárcel Hematologists/Lab Specialists Adoracion Blanco, Sabela Bobillo, Olga Benitez, Maria Cerda, Cecilia Carpio, Sally Franco, Maria Laura Fox, Laura Gallur, Mercedes Gironella, Gloria Hidalgo, Gloria Iacoboni, Macarena Izuzquiza, Marta Julia, Ana Marin, Maria Martinez, Alba Mesa, Antonieta Molero, Julia Montoro, Mayda Navarrete, Margarita Ortega, Guillem Orti, Ana Ortuño, Carles Palacio, Gloria Passarelli, Olga Salamero, Silvia Saumell, Milagros Suito, Barbara Tazon, Gustavo Robayo, Elisa Roldan, Marta Villalba Post-Doctoral Scientists Juan Camilo Nieto, Diana Reyes, Marcelo Lima Ribeiro Phd Students Cristina Hernandez, Isabel Jimenez, Daniel Medina, Carlota Pages Technicians Marc Antoni Armengol, Sergio Manresa, Magdalena Munuera, Lluis Puigdefabregas

Summary

VHIO’s Experimental Hematology Group conducts translational, pre-clinical and clinical research on hematological neoplasms of both lymphoid and myeloid origin. Our research team is composed of hematologists and biological scientists who work closely together to design, conduct and lead our programs. Our projects are always based on the unmet medical needs identified by hematologists, with the ultimate goal of translating our results to patients by developing early phase clinical trials and defining novel biomarkers to improve diagnosis, prognosis and outcomes.

We aim to provide new therapeutic options for our patients by deciphering the mechanisms involved in the pathogenesis and progression of hematological malignancies. We also conduct pre-clinical studies of new therapeutic proposals for patients diagnosed with hematological malignancies. Our group fosters the definition of new biomarkers in hematology that will lead to a more rational and precise diagnosis, prognosis and treatment of our patients.

Finally, the Hematology Clinical Trials Unit is currently participating in more than 103 clinical studies, including phase I clinical trials (n=25) and first-in-human studies of targeted therapies, both in lymphoid and myeloid malignancies. Last year 146 patients were included in our clinical trials, with 53 patients enrolled in phase I studies.


Figure: CLL genetic landscape and currently tested targeted drugs. Bosch F, Dalla-Favera R. Nat Rev Clin Oncol. 2019.

Strategic goals

  • We translate preclinical findings into clinical benefit by developing early phase clinical trials and defining new prognostic and predictive factors.

Main research lines currently focus on:

  • Deciphering the mechanisms involved in pathogenesis and progression of hematological neoplasms.
  • The preclinical study of new therapeutic regimens in experimental models that mimic the tumoral microenvironment using primary cells and patient-derived xenograft (PDX) models.
  • Defining new biomarkers for a more rational and precise treatment of patients.

Highlights

  • In 2019 we have participated in the publication of 45 scientific papers, and as principal authors (first, last or corresponding) of 12 of these. 60% of these articles are published in journals in the first quartile, with an accumulative Impact Factor of 95.
  • This year we have initiated six new projects, four of which are supported through grants received from competitive calls, including La Fundació La Marató de TV3.

Horizons

  • We are planning to expand our current research lines by delving into the study of cellular therapy for lymphoid malignancies. This includes the study of determinants of response and resistance to CAR-T cells in lymphoma as well as exploring newer strategies that combine adoptive-T cell therapy with bispecific antibodies.
  • This year we have launched an investigator initiated clinical trial in CLL, where we will determine the role of early treatment with high specific BTK inhibitors. Accompanying the clinical trial, we have designed a translational project to decipher the mechanisms of response and clonal evolution in these patients and in mouse models of CLL. This project is one of the best examples of our multidisciplinary team working together to respond to unmet medical needs from the clinical and translational point of view.

Projects

  1. PSB/17/FIS/1817 Uso de linfocitos T específicos third partycontra antígenos viarles, procedentes de un registro de donantes voluntarios, para el tratamiento de infecciones por CMV, VEB y adenovirus.
    2017 – 2019.
  2. MCM/17/HARMONY/2281 Healthcare Alliance for Resourceful Medicines Offensive against Neoplasms in Hematology.
    2017 – 2021.
  3. MCM/18/FIS/2697 Papel de la vigilancia y evasión inmune en la fisiopatología y inmunoterapia de los linfomas del sistema nervioso central.
    2018 – 2020.
  4. MCM/18/AECC/3229 Macrophage-mediated immunotherapy optimization in lymphomas affecting the central nervous system.
    2018 – 2021.
  5. FBA/18/RETOS/3304 Exploración y prueba de concepto de la eficacia del tratamiento combinado con Ory-1001 en indicaciones oncológicas (COMPO-EPoC).
    2018 – 2020.
  6. FBA/18/FIS/2693 Mecanismos de evasión inmune relacionados con la progresión de la leucemia linfática crónica.
    2018 – 2020.
  7. DVF/18/FIS/2700 Estudio funcional del sistema inmune (SI) en síndromes mielodisplásicos (SMD) según el perfil mutacional. Influencia de las alteraciones evolutivas del SI en la progresión del SMD
    2018 – 2020.
  8. PA/19/FIS/3317: Inhibición de la proteína quinasa ZAP-70 como terapia dirigida en linfomas T periféricos. 2019-2021.
  9. PBS/19/AECC/4198: Optimización del uso de inhibidores de checkpoint en pacientes con neoplasias linfoides que reciben un trasplante alogénico de progenitores hematopoyético.
    2019-2021.

PI paper pick

  • Bosch F, Dalla-Favera R. Chronic Lymphocytic Leukaemia: From Genetics to Treatment. Nat Rev Clin Oncol. 16 (11), 684-701, Nov 2019.
  • Bosch F, Cantin G, Cortelezzi A, Knauf W, Tiab M, Turgut M, Zaritskey A, Merot J-L, Tausch E, Trunzer K, Robson S, Gresko E, Böttcher S, Foà R, Stilgenbauer S, Leblond V. Obinutuzumab plus fludarabine and cyclophosphamide in previously untreated, fit patients with chronic lymphocytic leukemia: a subgroup analysis of the GREEN study. Leukemia, 34 (2), 441-450. 2019.

Full list of Publications

  1. Chronic lymphocytic leukaemia: from genetics to treatment.Bosch F; Dalla-Favera R. 2019.Nat Rev Clin Oncol.16(11): 684 701.
  2. Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide.Horwitz ME; Wease S; Blackwell B; Valcarcel D; Frassoni F; Boelens JJ; Nierkens S; Jagasia M; Wagner JE; Kuball J; Koh LP; Majhail NS; Stiff PJ; Hanna R; Hwang WYK; Kurtzberg J; Cilloni D; Freedman LS; Montesinos P; Sanz G. 2019.J Clin Oncol.37(5): 367 367.
  3. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma.Rosiñol L; Oriol A; Rios R; Sureda A; Blanchard MJ; Hernández MT; Martínez-Martínez R; Moraleda JM; Jarque I; Bargay J; Gironella M; de Arriba F; Palomera L; González-Montes Y; Martí JM; Krsnik I; Arguiñano JM; González ME; González AP; Casado LF; López-Anglada L; Paiva B; Mateos MV; San Miguel JF; Lahuerta JJ; Bladé J. 2019.Blood.134(16): 1337 1345.
  4. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact.Baliakas P; Jeromin S; Iskas M; Puiggros A; Plevova K; NguyenKhac F; Davis Z; Rigolin GM; Visentin A; Xochelli A; Delgado J; Baran-Marszak F; Stalika E; Abrisqueta P; Durechova K; Papaioannou G; Eclache V; Dimou M; Iliakis T; Collado R; Doubek M; Calasanz MJ; Ruiz-Xiville N; Moreno C; Jarosova M; Leeksma AC; Panayiotidis P; Podgornik H; Cymbalista F; Anagnostopoulos A; Trentin L; et al… 2019.Blood.133(11): 1205 1216.
  5. Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines.Schuster, S.J.; Bartlett, N.L.; Assouline, S.; Yoon, S.-S.; Bosch, F.; Sehn, L.H.; Cheah, C.Y.; Shadman, M.; Gregory, G.P.; Ku, M.; Wei, M.C.; Yin, S.; Kwan, A.; Yousefi, K.; Hernandez, G.; Li, C.-C.; O'Hear, C.; Budde, L.E.. 2019.Blood.134(1): 6 6.
  6. Decompensated Liver Disease due to Primary Hepatic Amyloidosis: Is Liver Transplantation Still Mandatory?.Riveiro-Barciela M; Gironella M; Senín A; Salcedo MT; Merino-Casabiel X; Castells L; Esteban R; Buti M; Martínez-Valle F. 2019.Hepatology.69(6): 2701 2703.
  7. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.Monagle P; Lensing AWA; Thelen K; Martinelli I; Male C; Santamaría A; Samochatova E; Kumar R; Holzhauer S; Saracco P; Simioni P; Robertson J; Grangl G; Halton J; Connor P; Young G; Molinari AC; Nowak-Göttl U; Kenet G; Kapsa S; Willmann S; Pap AF; Becka M; Twomey T; Beyer-Westendorf J; Prins MH; Kubitza D; EINSTEIN-Jr Phase 2 Investigators. 2019.LANCET HAEMATOL.6(10): 500 509.
  8. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study.Younes A; Brody J; Carpio C; Lopez-Guillermo A; Ben-Yehuda D; Ferhanoglu B; Nagler A; Ozcan M; Avivi I; Bosch F; Caballero Barrigón MD; Hellmann A; Kuss B; Ma DDF; Demirkan F; Yagci M; et al...2019.LANCET HAEMATOL.6(2): 67 78.
  9. Second cancer in Philadelphia negative myeloproliferative neoplasms (MPN-K). A nested case-control study.Barbui T; Ghirardi A; Masciulli A; Carobbio A; Palandri F; Vianelli N; De Stefano V; Betti S; Di Veroli A; Iurlo A; Cattaneo D; Delaini F; Bonifacio M; Scaffidi L; Patriarca A; Rumi E; Casetti IC; Stephenson C; Guglielmelli P; Elli EM; Palova M; Bertolotti L; Erez D; Gomez M; Wille K; Perez-Encinas M; Lunghi F; Angona A; Fox ML; Beggiato E; Benevolo G; Carli G; Cacciola R; McMullin MF; Tieghi A; Recasens V; Marchetti M; Griesshammer M; Alvarez-Larran A; Vannucchi AM; Finazzi G. 2019.Leukemia.33(8): 1996 2005.
  10. Repurposing dasatinib for diffuse large B cell lymphoma.Scuoppo C; Wang J; Persaud M; Mittan SK; Basso K; Pasqualucci L; Rabadan R; Inghirami G; Grandori C; Bosch F; Dalla-Favera R. 2019.Proc Natl Acad Sci U S A.116(34): 16981 16986.
  11. Phase II Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low-, and Intermediate-Risk Myelodysplastic Syndromes.Santini V; Valcárcel D; Platzbecker U; Komrokji RS; Cleverly A; Lahn MM; Janssen J; Zhao Y; Chiang A; Giagounidis A; Guba SC; Sridharan A; Gueorguieva I; Girvan A; da Silva Ferreira M; Bhagat TD; Pradhan K; Steidl U; Will B; Verma A. 2019.Clin Cancer Res.25(23): 6976 6985.
  12. Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab in High-Risk Smoldering Multiple Myeloma.Brighton TA; Khot A; Harrison SJ; Ghez D; Weiss BM; Kirsch A; Magen H; Gironella M; Oriol A; Streetly M; Kranenburg B; Qin X; Bandekhar R; Hu P; Guilfoyle M; Qi M; Nemat S; Goldschmidt H. 2019.Clin Cancer Res.25(13): 3772 3775.
  13. Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms.Carrillo-Cruz E; García-Lozano JR; Márquez-Malaver FJ; Sánchez-Guijo FM; Montero Cuadrado I; Ferra I Coll C; Valcárcel D; López-Godino O; Cuesta M; Parody R; López-Corral L; Alcoceba M; Caballero-Velázquez T; Rodríguez-Gil A; Bejarano-García JA; Ramos TL; Pérez-Simón JA. 2019.Clin Cancer Res.25(15): 4616 4623.
  14. Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature..Rodríguez-Otero P; Mateos MV; Martínez-López J; Hernández MT; Ocio EM; Rosiñol L; Martínez R; Teruel AI; Gutiérrez NC; Bargay J; Bengoechea E; González Y; de Oteyza JP; Gironella M; Nuñez-Córdoba JM; Encinas C; Martín J; Cabrera C; Palomera L; de Arriba F; Cedena MT; Puig N; Oriol A; Paiva B; Bladé J; Lahuerta JJ; San Miguel JF. 2019.BLOOD CANCER J.9(4): 36 36.
  15. Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma.Recasens-Zorzo C; Cardesa-Salzmann T; Petazzi P; Ros-Blanco L; Esteve-Arenys A; Clot G; Guerrero-Hernández M; Rodríguez V; Soldini D; Valera A; Moros A; Climent F; González-Barca E; Mercadal S; Arenillas L; Calvo X; Mate JL; Gutiérrez-García G; Casanova I; Mangues R; Sanjuan-Pla A; Bueno C; Menéndez P; Martínez A; Colomer D; Estrada-Tejedor R; Teixidó J; Campo E; López-Guillermo A; Borrell JI; Colomo L; Pérez-Galán P; Roué G. 2019.HAEMATOLOGICA.104(4): 778 788.
  16. Pharmacological Targeting of BET Bromodomain Proteins in Acute Myeloid Leukemia and Malignant Lymphomas: From Molecular Characterization to Clinical Applications..Reyes-Garau D; Ribeiro ML; Roué G. 2019.Cancers (Basel).11(10): 1483.
  17. Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group.Ribera JM; García O; Moreno MJ; Barba P; García-Cadenas I; Mercadal S; Montesinos P; Barrios M; González-Campos J; Martínez-Carballeira D; Gil C; Ribera J; Vives S; Novo A; Cervera M; Serrano J; Lavilla E; Abella E; Tormo M; Amigo ML; Artola MT; Genescà E; Bravo P; García-Belmonte D; García-Guiñón A; Hernández-Rivas JM; Feliu E; PETHEMA Group of the Spanish Society of Hematology. 2019.Cancer.125(16): 2810 2817.
  18. Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group.Redondo AM; Valcárcel D; González-Rodríguez AP; Suárez-Lledó M; Bello JL; Canales M; Gayoso J; Colorado M; Jarque I; Del Campo R; Arranz R; Terol MJ; Rifón JJ; Rodríguez MJ; Ramírez MJ; Castro N; Sánchez A; López-Jiménez J; Montes-Moreno S; Briones J; López A; Palomera L; López-Guillermo A; Caballero D; Martín A; Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO). 2019.Br J Haematol.184(5): 797 807.
  19. New prognosis score including absolute lymphocyte/monocyte ratio, red blood cell distribution width and beta-2 microglobulin in patients with diffuse large B-cell lymphoma treated with R-CHOP: Spanish Lymphoma Group Experience (GELTAMO).Bento, L.; Díaz-López, A.; Barranco, G.; Martín-Moreno, A.M.; Baile, M.; Martín, A.; Sancho, J.M.; García, O.; Rodríguez, M.; Sánchez-Pina, J.M.; Novelli, S.; Salar, A.; Bastos, M.; Rodríguez-Salazar, M.J.; González de Villambrosia, S.; Córdoba, R.; García-Recio, M.; Martínez-Serra, J.; del Campo, R.; Luzardo, H.; García, D.; Hong, A.; Abrisqueta, P.; Sastre-Serra, J.; Roca, P.; Rodríguez, J.; Gutiérrez, A.. 2019.Br J Haematol..
  20. Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia..Palomo L; Ibáñez M; Abáigar M; Vázquez I; Álvarez S; Cabezón M; Tazón-Vega B; Rapado I; Fuster-Tormo F; Cervera J; Benito R; Larrayoz MJ; Cigudosa JC; Zamora L; Valcárcel D; Cedena MT; Acha P; Hernández-Sánchez JM; Fernández-Mercado M; Sanz G; Hernández-Rivas JM; Calasanz MJ; Solé F; Such E; Spanish Group of MDS (GESMD). 2019.Br J Haematol..
  21. The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.Ribera J; Granada I; Morgades M; Vives S; Genescà E; González C; Nomdedeu J; Escoda L; Montesinos P; Mercadal S; Coll R; González-Campos J; Abella E; Barba P; Bermúdez A; Gil C; Tormo M; Pedreño M; Martínez-Carballeira D; Hernández-Rivas JM; Orfao A; Martínez-López J; Esteve J; Bravo P; Garcia-Guiñon A; Debén G; Moraleda JM; Queizán JA; Ortín X; Moreno MJ; Feliu E; Solé F; Ribera JM; PETHEMA Group, Spanish Society of Haematology. 2019.Br J Haematol.186(2): 263 268.
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  23. Donor lymphocyte infusion for BK virus hemorrhagic cystitis and nephropathy: a case report.Ortí G; Iacoboni G; Barba P; Gimeno R; Roldán E; Fox L; Salamero O; Bosch F; Valcárcel D. 2019.Bone Marrow Transplant.54(5): 772 774.
  24. Donor lymphocyte infusions for B-cell malignancies relapse after T-cell replete allogeneic hematopoietic cell transplantation.Ortí G; García-Cadenas I; López L; Pérez A; Jimenez MJ; Sánchez-Ortega I; Alonso L; Sisinni L; Fox L; Villacampa G; Badell I; de Heredia CD; Parody R; Ferrà C; Solano C; Caballero D; Martino R; Querol S; Valcárcel D. 2019.Bone Marrow Transplant.54(7): 1133 1137.
  25. Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study..Escamilla Gómez V; García-Gutiérrez V; López Corral L; García Cadenas I; Pérez Martínez A; Márquez Malaver FJ; Caballero-Velázquez T; González Sierra PA; Viguria Alegría MC; Parra Salinas IM; Calderón Cabrera C; González Vicent M; Rodríguez Torres N; Parody Porras R; Ferra Coll C; Orti G; Valcárcel Ferreiras D; De la Cámara LLanzá R; Molés P; Velázquez-Kennedy K; João Mende M; Caballero Barrigón D; Pérez E; Martino Bofarull R; Saavedra Gerosa S; Sierra J; Poch M; Zudaire Ripa MT; Díaz Pérez MA; Molina Angulo B; Sánchez Ortega I; Sanz Caballer J; Montoro Gómez J; Espigado Tocino I; Pérez-Simón JA; Grupo Español de Trasplante Hematopoyético (GETH). 2019.Bone Marrow Transplant..
  26. Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia.Lozano ML; Mingot-Castellano ME; Perera MM; Jarque I; Campos-Alvarez RM; González-López TJ; Carreño-Tarragona G; Bermejo N; Lopez-Fernandez MF; de Andrés A; Valcarcel D; Casado-Montero LF; Alvarez-Roman MT; Orts MI; Novelli S; Revilla N; González-Porras JR; Bolaños E; Rodríguez-López MA; Orna-Montero E; Vicente V. 2019.Sci Rep.9(1): 16680 16680.
  27. Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation.Guglieri-Lopez B; Perez-Pitarch A; Garcia-Cadenas I; Gimenez E; Barba P; Rabella N; Hernandez-Boluda JC; Fox L; Valcarcel D; Esquirol A; Ferriols-Lisart R; Sierra J; Solano C; Navarro D; Martino R; Piñana JL. 2019.Biol Blood Marrow Transplant.25(5): 1022 1030.
  28. Thrombopoietin Receptor Agonists for Severe Thrombocytopenia after Allogeneic Stem Cell Transplantation: Experience of the Spanish Group of Hematopoietic Stem Cell Transplant.Bento L; Bastida JM; García-Cadenas I; García-Torres E; Rivera D; Bosch-Vilaseca A; De Miguel C; Martínez-Muñoz ME; Fernández-Avilés F; Roldán E; Chinea A; Yáñez L; Zudaire T; Vaz CP; Espigado I; López J; Valcárcel D; Duarte R; Cabrera R; Herrera C; González-Porras JR; Gutiérrez A; Solano C; Sampol A; Grupo Español de Trasplante Hematopoyético (GETH). 2019.Biol Blood Marrow Transplant.25(9): 1825 1831.
  29. Recent Advances in the Targeting of Epigenetic Regulators in B-Cell Non-Hodgkin Lymphoma.Ribeiro ML; Reyes-Garau D; Armengol M; Fernández-Serrano M; Roué G. 2019.Front Genet.10: 986 986.
  30. Response-adapted treatment with rituximab, bendamustine, mitoxantrone, and dexamethasone followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma after first-line immunochemotherapy: Results of the RBMDGELTAMO08 phase II trial..Peñalver FJ; Márquez JA; Durán S; Giraldo P; Martín A; Montalbán C; Sancho JM; Ramírez MJ; Terol MJ; Capote FJ; Gutiérrez A; Sánchez B; López A; Salar A; Rodríguez-Caravaca G; Canales M; Caballero MD; GELTAMO (The Spanish Lymphoma Cooperative Group). 2019.Cancer Med.8(16): 6955 6966.
  31. Off-pump technique and replacement therapy for coronary artery bypass surgery in a patient with hemophilia B.Fernández-Caballero M; Martinez MF; Oristrell G; Palmer N; Santamaría A. 2019.J Thromb Thrombolysis.48(2): 299 302.
  32. Molecular profiling refines minimal residual disease-based prognostic assessment in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia.Ribera J; Zamora L; Morgades M; Vives S; Granada I; Montesinos P; Gómez-Seguí I; Mercadal S; Guàrdia R; Nomdedeu J; Pratcorona M; Tormo M; Martínez-Lopez J; Hernández-Rivas JM; Ciudad J; Orfao A; González-Campos J; Barba P; Escoda L; Esteve J; Genescà E; Solé F; Feliu E; Ribera JM; Spanish PETHEMA Group; Spanish Society of Hematology. 2019.Genes Chromosomes Cancer.58(11): 815 819.
  33. Chronic graft-versus-host disease could ameliorate the impact of adverse somatic mutations in patients with myelodysplastic syndromes and hematopoietic stem cell transplantation.Caballero JC; Sánchez Barba M; Hernández Sánchez JM; Such E; Janusz K; Sanz G; Cabrero M; Chillón C; Cervera J; Hurtado AM; Jerez A; Calderón Cabrera C; Valcárcel D; Lumbreras E; Abáigar M; López Cadenas F; Hernández Rivas JM; Del Cañizo MC; Díez Campelo M. 2019.ANN HEMATOL.98(9): 2151 2162.
  34. Safety and efficacy of bosutinib in fourth-line therapy of chronic myeloid leukemia patients..García-Gutiérrez V; Milojkovic D; Hernandez-Boluda JC; Claudiani S; Martin Mateos ML; Casado-Montero LF; González G; Jimenez-Velasco A; Boque C; Martinez-Trillos A; Vázquez IM; Payer ÁR; Senín A; Amustio Díez E; García AB; Carrascosa GB; Ortí G; Ruiz BC; Fernández MÁ; Del Carmen García Garay M; Giraldo P; Guinea JM; De Las Heras Rodríguez N; Hernán N; Pérez AI; Piris-Villaespesa M; Lorenzo JLL; Martí-Tutusaus JMM; Vallansot RO; Ortega Rivas F; Puerta JM; Ramirez MJ; Romero E; Romo A; Rosell A; Saavedra SS; Sebrango A; Tallon J; Valencia S; Portero A; Steegmann JL; Grupo Español de Leucemia Mieloide Crónica (GELMC). 2019.ANN HEMATOL.98(2): 321 330.
  35. An analysis of the impact of CD56 expression in de novo acute promyelocytic leukemia patients treated with upfront all-trans retinoic acid and anthracycline-based regimens.Sobas M; Montesinos P; Boluda B; Bernal T; Vellenga E; Nomdedeu J; González-Campos J; Chillón M; Holowiecka A; Esteve J; Bergua J; González-Sanmiguel JD; Gil-Cortes C; Tormo M; Salamero O; Manso F; Fernández I; de la Serna J; Moreno MJ; Pérez-Encinas M; Krsnik I; Ribera JM; Escoda L; Lowenberg B; Sanz MA; PETHEMA, HOVON, PALG, and GATLA cooperative groups. 2019.Leuk Lymphoma.60(4): 1030 1035.
  36. Dichotomization of the new revised international prognostic scoring system for a better clinical stratification of patients with myelodysplastic syndromes.Montoro J; Pomares H; Villacampa G; Merchán B; Molero A; Alonso E; Gallur L; Grau J; Salamero O; Roldán E; Saumell S; Ortega M; Sureda A; Bosch F; Arnan M; Valcárcel D.2019.Leuk Lymphoma.60(6): 1522 1527.
  37. Real life outcomes of patients aged >= 75 years old with acute promyelocytic leukemia: experience of the PETHEMA registry.Salamero O; Martínez-Cuadrón D; Sobas M; Benavente C; Vives S; De la Serna J; Pérez-Encinas M; Escoda L; Gil C; Brunet S; Ramos F; Esteve J; Amigo M; Krsnik I; Manso F; Arias J; González-Campos J; Serrano J; Oleksiuk J; Barrios M; García-Boyero R; Novo A; Sanz MA; Montesinos P; PETHEMA and PALG Groups. 2019.Leuk Lymphoma.60(11): 2720 2732.
  38. Characteristics and outcome of adult patients with acute promyelocytic leukemia and increased body mass index treated with the PETHEMA Protocols..Sobas M; Rodriguez-Veiga R; Vellenga E; Paluszewska M; De la Serna J; García-Álvarez F; Gil C; Brunet S; Bergua J; González-Campos J; Ribera JM; Tormo M; González M; Fernández I; Benavente C; González-Sanmiguel JD; Esteve J; Pérez-Encinas M; Salamero O; Manso F; Lowenberg B; Sanzs MA; Montesinos P; PETHEMA, HOVON, PALG, GATLA cooperative groups. 2019.EUR J HAEMATOL..
  39. Frequency, characteristics, and outcome of PTLD after allo-SCT: A multicenter study from the Spanish group of blood and marrow transplantation (GETH).García-Cadenas I; Yáñez L; Jarque I; Martino R; Pérez-Simón JA; Valcárcel D; Sanz J; Bermúdez A; Muñoz C; Calderón-Cabrera C; García E; Alonso L; Suárez-Lledó M; González Vicent M; Heras I; Viguria MC; Batlle M; Vázquez L; López J; Solano C; Spanish group of blood and marrow transplantation (GETH). 2019.EUR J HAEMATOL.102(6): 465 471.
  40. Increased survival due to lower toxicity for high-risk T-cell acute lymphoblastic leukemia patients in two consecutive pediatric-inspired PETHEMA trials.Barba P; Morgades M; Montesinos P; Gil C; Fox ML; Ciudad J; Moreno MJ; González-Campos J; Genescà E; Martínez-Carballeira D; Martino R; Vives S; Guardia R; Mercadal S; Artola MT; Cladera A; Tormo M; Esteve J; Bergua J; Vall-Llovera F; Ribera J; Martínez-Sanchez P; Amigo ML; Bermúdez A; Calbacho M; Hernández-Rivas JM; Feliu E; Orfao A; Ribera JM; PETHEMA Group. 2019.EUR J HAEMATOL.102(1): 79 86.
  41. Pomalidomide-dexamethasone for treatment of soft-tissue plasmacytomas in patients with relapsed / refractory multiple myeloma..Jiménez-Segura R; Granell M; Gironella M; Abella E; García-Guiñón A; Oriol A; Cabezudo E; Clapés V; Soler JA; Escoda L; López-Pardo J; Fernández de Larrea C; Cibeira MT; Tovar N; Isola I; Bladé J; Rosiñol L; GEMMAC (Grup per l l'estudi del mieloma mútiple i l'amiloïdosi de Catalunya). 2019.EUR J HAEMATOL.102(5): 389 394.
  42. Facing real-life with direct oral anticoagulants in patients with nonvalvular atrial fibrillation: outcomes from the first observational and prospective study in a Spanish population.Cerdá M; Cerezo-Manchado JJ; Johansson E; Martínez F; Fernández M; Varela A; Rodríguez S; Bosch F; Santamaría A. 2019.J Comp Eff Res.8(3): 165 178.
  43. Allogeneic stem cell transplantationin the era of novel therapies for acute lymphoblastic leukaemia..Barba P; Elorza I. 2019.Med Clin (Barc).153(1): 28 34.
  44. Acquired von Willebrand syndrome in a patient with small lymphocytic lymphoma and Sjogren's syndrome: which associated condition should be prioritized?.Pardos-Gea J; Martínez F; Abrisqueta P; Santamaría A; Bosch F. 2019.Blood Coagul Fibrinolysis.30(5): 239 242.
  45. "The TEAM Project" Results on Management of Placenta-Mediated Pregnancy Complications (PMC): The Impact of Thrombophilia Test and Thromboprophylaxis with Low-Molecular-Weight-Heparin on Recurrences of PMC.SANTAMARIA ORTIZ, AMPARO; Martí, Edelmira; Medina, Carmen; Rodríguez, Ana María; Stevenazzi, Mariana; Mira, Yolanda; López, Mertixell; Redondo, Ana Margarita; Aguinaco, Reyes; Sabater, María C; Oliver,
  46. Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure without the need for immunotherapy..Jiménez-Ubieto A; Grande C; Caballero D; Yáñez L; Novelli S; Hernández-Garcia MT; Manzanares M; Arranz R; Ferreiro JJ; Bobillo S; Mercadal S; Galeo A; Jiménez JL; Moraleda JM; Vallejo C; Albo C; Pérez E; Marrero C; Magnano L; Palomera L; Jarque I; Rodriguez A; Lorza L; Martín A; Coria E; López-Guillermo A; Salar A; José Lahuerta J; GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) Cooperative Stu. 2019.Hematol Oncol Stem Cell Ther.12(4): 194 203.
  47. Thrombosis and hemostasis health in pregnancy: Registries from the International Society on Thrombosis and Haemostasis..Othman M; Santamaría Ortiz A; Cerdá M; Erez O; Minford A; Obeng-Tuudah D; Blondon M; Bistervels I; Middeldorp S; Abdul-Kadir R. 2019.Res Pract Thromb Haemost.3(4): 607 614.

Gastrointestinal & Endocrine Tumors Group

Teresa Macarulla
Principal Investigator
Biosketch
Director Josep Tabernero Principal Investigator Teresa Macarulla Medical Oncologists and Clinical Fellows Daniel Alejandro Acosta, Maria Alsina, Guillermo Argiles, Iosune Baraibar, Elvira Buxo, Jaume Capdevila, Jose Luis Cuadra, Marc Diez, Elena Elez, Jorge Hernando, Nuria Mulet, Javier Ros, Remedios Segura, Helena Verdaguer Clinical Nurse Specialist Ariadna Maria Garcia Translational Investigator Rodrigo A. Toledo Bioinformatician Pol Cusco Translational Technician Ana Belen Moreno Translational Graduate Student Carlota Arenillas Masters Students Davide Ciardiello, Giulia Martini

Summary

Our Gastrointestinal and Endocrine Tumors Group has actively participated in the development of molecular therapies targeting altered signaling pathways of colorectal, pancreatic, gastric and neuroendocrine cancers, among others. We have pioneered early phase clinical trials to potentiate novel anti-cancer strategies against GI cancers, as well as translational studies associated to these novel therapeutic approaches, including biomarker discovery.

We focus on seeking out prognostic and predictive factors related to targeted and immune therapies as well as identifying new response and resistance markers. Our group has also made significant progress in validating and developing liquid biopsy technologies, including BEAMing, for the more effective, less invasive monitoring of cancer in real time. Moreover, our research has shown that genomic and transcriptomic profiling are both useful for guiding treatment decision making and improving patient outcomes.

Through our participation in the OPTIMISTICC Grand Challenge -Opportunity To Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer- five-year consortium funded by Cancer Research UK’s Grand Challenge, we are also studying the microbiome and it is role and relevance in the development of colorectal cancer. Within the same collaborative project we have launched a novel prospective cohort, the MICROCOSM cohort, to longitudinally analyze over 2500 patients and how current colon cancer treatments affect the microbiome.

In 2019, we have participated in several clinical and translational research collaborations. Our group was instrumental in the development of clinical research studies that could well be practice changing for the treatment of two gastrointestinal malignancies: 1) colorectal tumors bearing BRAF V600E mutations and 2) gBRCA1/2 mutated pancreatic cancer (see selected papers below).

The CELAC and European Consortium for a Personalized Medicine Approach to Gastric Cancer (LEGACy), funded through the European Union’s Horizon 2020 research and innovation program, launched in 2019. As a member of this project, we coordinate data integration and perform the molecular characterization of study samples. These efforts are led by María Alsina, Medical Oncologist and Clinical Investigator of our group, and Rodrigo Dienstmann, PI of our Oncology Data Science (ODysSey) Group.

Also funded by the European Union’s Horizon 2020 research and innovation programme, NoCanTher–Nanomedicine upscaling for early clinical phases of multimodal cancer therapy is a multi-center–Consortium represents an important forward step in in utilizing nanoparticles than can better target and more precisely combat cancer cells. During its 8th General Assembly in London (UK) this year, researchers discussed the project's progress and defined the final steps for reaching the clinical setting, under the leadership of our group, expected to start during the next year.

Reflected by publications in some of the most prestigious scientific titles in 2019, our group has both directed and collaborated in important studies, just some of which include:

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer (Kopetz S, et al. N Engl J Med. 2019). For more information about this study which was led by our Director, Josep Tabernero, please see his Foreword.

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer (Golan T, et al. N Engl J Med. 2019).

Metastatic pancreatic cancer is particularly refractory to treatment. Current standard-of-care first-line treatments are associated with a median progression-free survival of approximately 6 months, and fewer than 10% of patients are alive 5 years after the initial diagnosis. In POLO study, co-authored by our PI, Teresa Macarulla, patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. Among patients with this germline BRCA mutation and metastatic pancreatic cancer, results showed that progression-free survival was longer with maintenance olaparib than with placebo.

Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE - a global phase III study (Yoshino T, et al. Ann Oncol. 2019).

The RAISE study, led by Josep Tabernero, showed that the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumor sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumors.

Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC). Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.

Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2. Macarulla T, et al. J Clin Oncol. 2019.

Led by our PI, Teresa Macarulla, this study was designed to evaluate the efficacy and tolerability of different gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) dosing regimens in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a poor PS. NAB-paclitaxel administered at different doses in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor Karnofsky performance status (PS). Moreover, gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel GA significantly improved survival compared with gemcitabine alone in patients with PDAC and a PS of 70% or greater. Due to the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear.


Strategic goals

  • Discovery of novel biomarkers and validation of new prognostic/predictive biomarkers for GI/Endocrine malignancies.
  • Development of relevant preclinical models in vitro (2D/ 3D cell cultures) and in vivo (i.e. PDX) with emphasis on the identification of predictive/ response markers.
  • Molecular characterization of GI cancers: colorectal, gastric, pancreatic, biliary tract.
  • Study of (targetable) molecular subtypes.
  • Early clinical development with novel targets.
  • Clinical research in later stage including translational research endpoints, focusing on the identification of prognostic/ predictive biomarkers.
  • Design, leadership and development of investigator-initiated trials (IIT), including Basket studies.
  • Participation in multidisciplinary/ multinational consortia and collaborative research programs of excellence.
  • Validation of repurposed drugs or candidate drugs, in partnership with pharma companies or academic groups.
  • Expansion of research lines in GI cancers including the study of microbiota & immunology/ immunotherapy.
  • Further validation of liquid biopsies for monitoring and diagnostics of GI tumors.

Highlights

  • We have advanced insights into prognostic and predictive factors for response and efficacy with targeted agents across various gastrointestinal malignancies.
  • Our group has launched a non-invasive genomic platform for monitorization and discovery of resistance mechanisms for colorectal cancer using whole-exome sequencing of sequential samples of tumor and circulating tumor DNA samples
  • Establishment of MAF (Mutant Allele Fraction) of BRAFV600E in plasma as a tool for the therapeutic monitoring of patients with a poor prognosis.
  • Understanding the colorectal cancer microbiome: implications in therapy (studies with Fusobacterium and other microbiota, such as OPTIMISTICC).
  • Participation in ongoing EU Horizon 2020-funded projects and consortia including MoTriColor, IntraColor COLOSSUS, as Principal Investigators. 2019 celebrated the launch of a Horizon 2020-supported consortium: LEGACY.
  • Our group is partner of many national and international consortia and networks including Cancer Core Europe (CCE), WIN, and the CIBERONC.
  • Elena Élez was awarded by the Catalonian Department of Health’s Strategic Plan for Research and Innovation in Health (Pla Estratègic de Recerca i Innovació en Salut, PERIS), to continue working on a personalized molecular signature for liquid biopsy.

Horizons

  • Consolidate our leadership in the design of novel trials, with new study design including baskets, among others.
  • Continue to lead/participate in multidisciplinary and multinational consortia and collaborative research programs of excellence, as well as drive new partnerships through EU-supported projects (among others, Cancer Research UK).
  • Lead phase I and II studies with pharmacodynamic endpoints with novel agents directed to cancer and immune cells’ targets.
  • Advance insights into the microbiome’s impact on CRC development and treatment.
  • Further establish and clinically validate liquid biopsy as a diagnostic/prognostic tool.
  • Expand studies on clonal evolution and (intra/inter) tumor heterogeneity.
  • Use new preclinical/ innovative tools to assess GI tumor dynamics (i.e. new organ-on-a-chip systems).
  • Co-develop new diagnostic and screening tools using machine learning technologies (artificial intelligence), taking advantage of standardized bio-repositories (ongoing collaborations).
  • New holistic approaches for GI cancers directed towards understanding/ controlling the evolutionary process in tumors, with particular attention to genomic/transcriptomic profiles and interactions with immune system, tumor microenvironment, and the microbiome.

Awards and Recognition

  • TheWeb of Science Group announced its who’s who on the annual and global Highly Cited Researchers list for 2019, curated by the Institute for Scientific Information. For the fourth consecutive year, our Director, Josep Tabernero, was selected for his exceptional advancements in cancer research under the category of Clinical Medicine that lists a total of 436 named leaders this year.
  • Josep Tabernero, featured among the Spanish edition of Forbes magazine’s pick of the 100 most influential leaders in healthcare across Spain.
  • Succeeding the European Commission’s Horizon 2020 funding program for research and innovation, Horizon Europeis an ambitious €100 billion undertaking consisting of three main pillars – Excellent Science, Global Challenges and European Industrial Competitiveness, Innovative Europe, as well as the overarching ambition of Widening Participation and Strengthening the European Research Area.
  • Within Horizon Europe’s framework, five key research and innovation missions have been identified to increase the effectiveness of funding by pursuing clearly defined targets. They are: Adaptation to climate change including societal transformation, Cancer, Climate-neutral and smart cities, Healthy oceans, seas, coastal and inland waters, oil health and food.
  • Each mission has an appointed Board comprised of acclaimed leaders to shape and spur new research and innovation. All missions are also flanked by their respective Assemblies consisting of up to 30 high-level experts. The main role of these bodies is to help guide the Board members and provide an additional pool of ideas and knowledge to contribute to the successes of the respective missions. The Cancer panel consists of 26 members, including our Director, Josep Tabernero.
  • Elena Élez, Medical Oncologist and Clinical Investigator of our group, received an AECC Senior Clinician Award. This particular category provides experienced medical professionals in oncology with support to develop and consolidate research at the clinical level.
  • Elena’s awarded project will enable her to continue developing minimally and non-invasive approaches for the early detection and/or progression of colorectal cancer including the study of prognostic and predictive values of circulating tumor DNA (ctDNA in advanced disease. Given that cancer relapse and metastatic cell spread are responsible for between 50-70% of colorectal cancer mortality, the need to bring these exciting methods closer to the clinic is critical.
  • The third edition of the Catalonian Department of Health’s Strategic Plan for Research and Innovation in Health (Pla Estratègic de Recerca i Innovació en Salut,PERIS), announced 66 award recipients in 2019. The selected projects, recognized for their promise to yet further strengthen research throughout the region, are set to deliver on PERIS’ ambitions of promoting health and wellbeing among Catalonia’s citizens, increase international competitiveness to reaffirm the community as a leading hub of research and innovation of excellence, as well as further establish health as a key driver of social and economic development.
  • PERIS funding will facilitate the recruitment of an additional group member which will enable Elena Élez to dedicate the necessary time to implement and lead a project for detecting relapse in advanced colon cancer patients by longitudinally following a personalized molecular signature liquid biopsy.
  • Thanks to the fundraising efforts of the 2018 annual telethon La Marató organized and led by media channels, TV3 and Catalunya Ràdio, dedicated that year to cancer research, seven VHIO-led projects, as well as one more in which VHIO will participate as a partner, were selected and prized this year.
  • Elena Élez, Medical Oncologist and Clinical Investigator of our Gastrointestinal & Endocrine Tumors Group, headed by Teresa Macarulla, will advance liquid biopsy as an approach to less invasively and more precisely track, monitor and evaluate individual patients suffering from colorectal cancer. She will seek to establish whether this technique can more effectively predict response to anti angiogenic therapies that can stop tumors from growing their own blood vessels, and thus slow and even shrink tumor growth.

PI paper pick

  • Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643.
  • Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019 Jul 25;381(4):317-327.
  • Macarulla T, Pazo-Cid R, Guillén-Ponce C, López R, Vera R, Reboredo M, Muñoz Martin A, Rivera F, Díaz Beveridge R, La Casta A, Martín Valadés J, Martínez-Galán J, Ales I, Sastre J, Perea S, Hidalgo M. Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2. J Clin Oncol. 2019 Jan 20;37(3):230-238.
  • Yoshino T, Portnoy DC, Obermannová R, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, García-Alfonso P, Cohn AL, Van Cutsem E, Yamazaki K, Lonardi S, Muro K, Kim TW, Yamaguchi K, Grothey A, O'Connor J, Taieb J, Wijayawardana SR, Hozak RR, Nasroulah F, Tabernero J. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol. 2019 Jan 1;30(1):124-131.

Full list of Publications

  1. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. Kopetz S; Grothey A; Yaeger R; Van Cutsem E; Desai J; Yoshino T; Wasan H; Ciardiello F; Loupakis F; Hong YS; Steeghs N; Guren TK; Arkenau HT; Garcia-Alfonso P; Pfeiffer P; Orlov S; Lonardi S; Elez E; Kim TW; Schellens JHM; Guo C; Krishnan A; Dekervel J; Morris V; Calvo Ferrandiz A; Tarpgaard LS; Braun M; Gollerkeri A; Keir C; Maharry K; Pickard M; Christy-Bittel J; Anderson L; Sandor V; Tabernero J. 2019. N Engl J Med. 381(17): 1632 - 1643.
  2. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. Golan T; Hammel P; Reni M; Van Cutsem E; Macarulla T; Hall MJ; Park JO; Hochhauser D; Arnold D; Oh DY; Reinacher-Schick A; Tortora G; Algül H; O'Reilly EM; McGuinness D; Cui KY; Schlienger K; Locker GY; Kindler HL. 2019. N Engl J Med. 381(4): 317 - 327.
  3. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Eng C; Kim TW; Bendell J; Argilés G; Tebbutt NC; Di Bartolomeo M; Falcone A; Fakih M; Kozloff M; Segal NH; Sobrero A; Yan Y; Chang I; Uyei A; Roberts L; Ciardiello F; IMblaze370 Investigators. 2019. Lancet Oncol. 20(6): 849 - 861.
  4. ESMO-MCBS: setting the record straight. Cherny NI; Tabernero J; de Vries EGE. 2019. Lancet Oncol. 20(4): 192 - 192.
  5. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Fuchs CS; Shitara K; Di Bartolomeo M; Lonardi S; Al-Batran SE; Van Cutsem E; Ilson DH; Alsina M; Chau I; Lacy J; Ducreux M; Mendez GA; Alavez AM; Takahari D; Mansoor W; Enzinger PC; Gorbounova V; Wainberg ZA; Hegewisch-Becker S; Ferry D; Lin J; Carlesi R; Das M; Shah MA; RAINFALL Study Group. 2019. Lancet Oncol. 20(3): 420 - 435.
  6. Shortages of inexpensive essential medicines. Vyas M; de Vries EGE; Casali PG; Tabernero J. 2019. Lancet Oncol. 20(5): 224 - 225.
  7. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Rodon J; Soria JC; Berger R; Miller WH; Rubin E; Kugel A; Tsimberidou A; Saintigny P; Ackerstein A; Braña I; Loriot Y; Afshar M; Miller V; Wunder F; Bresson C; Martini JF; Raynaud J; Mendelsohn J; Batist G; Onn A; Tabernero J; Schilsky RL; Lazar V; Lee JJ; Kurzrock R. 2019. Nat Med. 25(5): 751 - 751.
  8. Looking forward 25 years: the future of medicine. Regev, Aviv; Zhang, Feng; Jaffee, Elizabeth; Farrar, Jeremy; Nkengasong, John; Topol, Eric; Partridge, Linda; Mundel, Trevor; Tabernero, Josep; Sabeti, Pardis; Toreele, Els. 2019. Nat Med. 25(12): 1804 - 1807.
  9. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. Van Cutsem E; Huijberts S; Grothey A; Yaeger R; Cuyle PJ; Elez E; Fakih M; Montagut C; Peeters M; Yoshino T; Wasan H; Desai J; Ciardiello F; Gollerkeri A; Christy-Bittel J; Maharry K; Sandor V; Schellens JHM; Kopetz S; Tabernero J. 2019. J Clin Oncol. 37(17): 1460 - 1460.
  10. Comparative Assessment of Clinical Benefit Using the ESMO-Magnitude of Clinical Benefit Scale Version 1.1 and the ASCO Value Framework Net Health Benefit Score. Cherny NI; de Vries EGE; Dafni U; Garrett-Mayer E; McKernin SE; Piccart M; Latino NJ; Douillard JY; Schnipper LE; Somerfield MR; Bogaerts J; Karlis D; Zygoura P; Vervita K; Pentheroudakis G; Tabernero J; Zielinski C; Wollins DS; Schilsky RL. 2019. J Clin Oncol. 37(4): 336 - 336.
  11. Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2. Macarulla T; Pazo-Cid R; Guillén-Ponce C; López R; Vera R; Reboredo M; Muñoz Martin A; Rivera F; Díaz Beveridge R; La Casta A; Martín Valadés J; Martínez-Galán J; Ales I; Sastre J; Perea S; Hidalgo M. 2019. J Clin Oncol. 37(3): 230 - 230.
  12. Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study. Carmona-Bayonas A; Jiménez-Fonseca P; Lamarca Á; Barriuso J; Castaño Á; Benavent M; Alonso V; Riesco-Martínez MDC; Alonso-Gordoa T; Custodio A; Sánchez Cánovas M; Hernando Cubero J; López C; Lacasta A; Fernández Montes A; Marazuela M; Crespo G; Escudero P; Diaz JÁ; Feliciangeli E; Gallego J; Llanos M; Segura Á; Vilardell F; Percovich JC; Grande E; Capdevila J; Valle JW; García-Carbonero R. 2019. J Clin Oncol. 37(28): 2571 - 2571.
  13. Reply to I. Pecora et al. Macarulla T; Hidalgo M. 2019. J Clin Oncol. 37(22): 1979 - 1979.
  14. First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma. Kim RD; Sarker D; Meyer T; Yau T; Macarulla T; Park JW; Choo SP; Hollebecque A; Sung MW; Lim HY; Mazzaferro V; Trojan J; Zhu AX; Yoon JH; Sharma S; Lin ZZ; Chan SL; Faivre S; Feun LG; Yen CJ; Dufour JF; Palmer DH; Llovet JM; Manoogian M; Tugnait M; Stransky N; Hagel M; Kohl NE; Lengauer C; Sherwin CA; Schmidt-Kittler O; Hoeflich KP; Shi H; Wolf BB; Kang YK. 2019. Cancer Discov. 9(12): 1696 - 1707.
  15. Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma The GEMCAD 1402 Randomized Clinical Trial. Fernández-Martos C; Pericay C; Losa F; García-Carbonero R; Layos L; Rodríguez-Salas N; Martin-Richard M; Alonso-Orduña V; Vera R; Gallego J; Capdevila J; Salud A; Nogué M; Maurel J; Guash I; Montagut C; Lopez C; Macias I; Jain RK; Garcia-Albeniz X. 2019. JAMA Oncol. 5(11): 1566 - 1573.
  16. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Yoshino T; Portnoy DC; Obermannová R; Bodoky G; Prausová J; Garcia-Carbonero R; Ciuleanu T; García-Alfonso P; Cohn AL; Van Cutsem E; Yamazaki K; Lonardi S; Muro K; Kim TW; Yamaguchi K; Grothey A; O'Connor J; Taieb J; Wijayawardana SR; Hozak RR; Nasroulah F; Tabernero J. 2019. Ann Oncol. 30(1): 124 - 131.
  17. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Hammel P; Kindler HL; Reni M; Cutsem EV; Macarulla T; Hall MJ; Park JO; Hochhauser D; Arnold D; Oh DY; Reinacher-Schick A; Tortora G; Algül H; O'Reilly EM; McGuinness D; Cui KY; Joo S; Yoo HK; Patel N; Golan T. 2019. Ann Oncol. 30(12): 1959 - 1968.
  18. Immunotherapy in organ-transplanted cancer patients: efficacy and risk of organ rejection. Ros J; Matos I; Martin-Liberal J. 2019. Ann Oncol. 30(7): 1173 - 1177.
  19. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Muro K; Van Cutsem E; Narita Y; Pentheroudakis G; Baba E; Li J; Ryu MH; Zamaniah WIW; Yong WP; Yeh KH; Kato K; Lu Z; Cho BC; Nor IM; Ng M; Chen LT; Nakajima TE; Shitara K; Kawakami H; Tsushima T; Yoshino T; Lordick F; Martinelli E; Smyth EC; Arnold D; Minami H; Tabernero J; Douillard JY. 2019. Ann Oncol. 30(1): 19 - 33.
  20. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Muro K; Lordick F; Tsushima T; Pentheroudakis G; Baba E; Lu Z; Cho BC; Nor IM; Ng M; Chen LT; Kato K; Li J; Ryu MH; Zamaniah WIW; Yong WP; Yeh KH; Nakajima TE; Shitara K; Kawakami H; Narita Y; Yoshino T; Van Cutsem E; Martinelli E; Smyth EC; Arnold D; Minami H; Tabernero J; Douillard JY. 2019. Ann Oncol. 30(1): 34 - 43.
  21. Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial. Santos C; Azuara D; Viéitez JM; Páez D; Falcó E; Élez E; López-López C; Valladares M; Robles-Díaz L; García-Alfonso P; Bugés C; Durán G; Salud A; Navarro V; Capellá G; Salazar R; Aranda E. 2019. Ann Oncol. 30(5): 796 - 803.
  22. Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy. Vidal J; Bellosillo B; Santos Vivas C; García-Alfonso P; Carrato A; Cano MT; García-Carbonero R; Élez E; Losa F; Massutí B; Valladares-Ayerbes M; Viéitez JM; Manzano JL; Gallego J; Pairet S; Capellá G; Salazar R; Tabernero J; Aranda E; Montagut C. 2019. Ann Oncol. 30(3): 439 - 446.
  23. Value assessment frameworks in oncology: championing concordance through shared standards. Bertagnolli M; Tabernero J. 2019. Ann Oncol. 30(4): 505 - 506.
  24. Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the KEYNOTE-028 and KEYNOTE-158 Studies. Chung, HC; Piha-Paul, SA; Lopez-Martin, J; Schellens, J., Kao, S., Miller, W. H., Jr, Delord, J. P., Gao, B., Planchard, D., Gottfried, M., Zer, A., Jalal, S. I., Penel, N., Mehnert, J. M., Matos, I., Bennouna, J., Kim, D. W., Xu, L., Krishnan, S., Norwood, K., … Ott, P. A. 2020. J Thorac Oncol. 15(4): 618 - 627.
  25. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8(+) T cell tumor-infiltration impairing anti-PD1 therapy. Pascual-García M; Bonfill-Teixidor E; Planas-Rigol E; Rubio-Perez C; Iurlaro R; Arias A; Cuartas I; Sala-Hojman A; Escudero L; Martínez-Ricarte F; Huber-Ruano I; Nuciforo P; Pedrosa L; Marques C; Braña I; Garralda E; Vieito M; Squatrito M; Pineda E; Graus F; Espejo C; Sahuquillo J; Tabernero J; Seoane J. 2019. Nat Commun. 10: 2416 - 2416.
  26. A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations. Voss MH; Hierro C; Heist RS; Cleary JM; Meric-Bernstam F; Tabernero J; Janku F; Gandhi L; Iafrate AJ; Borger DR; Ishii N; Hu Y; Kirpicheva Y; Nicolas-Metral V; Pokorska-Bocci A; Vaslin Chessex A; Zanna C; Flaherty KT; Baselga J. 2019. Clin Cancer Res. 25(9): 2699 - 2707.
  27. Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There?Hierro C; Matos I; Martin-Liberal J; Ochoa de Olza M; Garralda E. 2019. Clin Cancer Res. 25(11): 3210 - 3219.
  28. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Bahleda R; Italiano A; Hierro C; Mita AC; Cervantes A; Chan N; Awad MM; Calvo E; Moreno V; Govindan R; Spira AI; Gonzalez MD; Zhong B; Santiago-Walker AE; Poggesi I; Parekh T; Xie H; Infante JR; Tabernero J. 2019. Clin Cancer Res. 25(16): 4888 - 4897.
  29. Optimizing the management of locally advanced pancreatic cancer with a focus on induction chemotherapy: Expert opinion based on a review of current evidence. Seufferlein T; Hammel P; Delpero JR; Macarulla T; Pfeiffer P; Prager GW; Reni M; Falconi M; Philip PA; Van Cutsem E. 2019. Cancer Treat Rev. 77: 1 - 10.
  30. Colorectal Neuroendocrine Neoplasms: Areas of Unmet Need. Ramage JK; Valle JW; van Dijkum JMN; Sundin A; Pascher A; Couvelard A; Kloeppel G; Bartsch D; Arnold R; Baudin E; Bodei L; Borbath I; Capdevila J; Caplin M; Chen J; Costa F; Couvelard A; Cwikla JB; Davies P; de Herder WW; Falconi M; Falkerby J; Fazio N; Ferone D; Frilling A; Garcia-Carbonero R; Glasberg S; Gorbunova V; Grossman A; Hoersch D; Jensen R; Kaltsas G; Kloeppel G; Kingge UP; Kos-Kudla B; Krejs GJ; Krenning E; Kulke M; Lamberts SWJ.; Van Dijkum JM; O'Connor JM; O'Toole D; Pape UF; Partelli S; Pavel ME; Peeters M; Ramage JK; Reed NS; Rindi G; Rinke A; Ruszniewski P; Sorbye H; Sundin A; Scoazec JY; Taal BG; Janson TE; Toumpanakis C; Valle JW; Vullierme MP; Staffan W; Wiedenmann B; ENETS 2016 Munich Advisory Board. 2019. Neuroendocrinology. 108(1): 45 - 53.
  31. Unmet Medical Needs in Metastatic Lung and Digestive Neuroendocrine Neoplasms. Capdevila J; Bodei L; Davies P; Gorbounova V; Jensen RT; Knigge U; J G; Krenning E; O''Connor J; Peeters M; Rindi G; Salazar R; Vullierme MP; Pavel M. 2019. Neuroendocrinology. 108(1): 18 - 25.
  32. Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms. Baudin E; Hayes AR; Scoazec JY; Filosso PL; Lim E; Kaltsas G; Frilling A; Chen J; Kos-Kudla B; Gorbunova V; Wiedenmann B; Nieveen van Dijkum E; Cwikla JB; Falkerby J; Valle JW; Kulke MH; Caplin ME; ENETS 2016 Munich Advisory Board Participants; ENETS 2016 Munich Advisory Board Participants. 2019. Neuroendocrinology. 108(1): 7 - 17.
  33. Unmet Needs in Appendiceal Neuroendocrine Neoplasms. Toumpanakis C; Fazio N; Tiensuu Janson E; Hörsch D; Pascher A; Reed N; O Apos Toole D; Nieveen van Dijkum E; Partelli S; Rinke A; Kos-Kudla B; Costa F; Pape UF; Grozinsky-Glasberg S; Scoazec JY; The ENETS 2016 Munich Advisory Board Participants; ENETS 2016 Munich Advisory Board Participants. 2018. Neuroendocrinology. 108(1): 37 - 44.
  34. Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms. Jensen RT; Bodei L; Capdevila J; Couvelard A; Falconi M; Glasberg S; Kloppel G; Lamberts S; Peeters M; Rindi G; Rinke A; Rothmund M; Sundin A; Welin S; Fazio N; The ENETS 2016 Munich Advisory Board Participants. 2019. Neuroendocrinology. 108(1): 26 - 36.
  35. Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3). Sorbye H; Baudin E; Borbath I; Caplin M; Chen J; Cwikla JB.; Frilling A; Grossman A; Kaltsas G; Scarpa A; Welin S; Garcia-Carbonero R; Arnold R; Bartsch D; Baudin E; Bodei L; Borbath I; Capdevila J; Caplin M; Chen J; Costa F; Lima R; Couvelard A; Cwikla JB.; Davies P; de Herder WW; Falconi M; Falkerby J; Fazio N; Ferone D; Frilling A; Garcia-Carbonero R; Glasberg S; Gorbunova V; Grossman A; Hoersc D; Jensen R; Kaltsas G; Kloeppel G; Tumors Endocrine group; Knigge UP; Kos-Kudla B; Krejs GJ.; Krenning E; Kulke M; Lamberts SWJ.; van Dijkum EN; Manuel O'Connor J; O'Toole D; Pape UF; Partelli S; Pavel M; Peeters M; Ramage J; Reed N; Rindi G; Rinke A; Ruszniewski P; Sorbye H; Sundin A; Scoaze JY; Taal BG; Janson EV; Toumpanakis C; Valle J; Vullierme MP; Welin S; Wiedenmann B; ENETS 2016 Munich Advisory Board. 2019. Neuroendocrinology. 108(1): 54 - 62.
  36. Unmet Needs in the Field of Neuroendocrine Neoplasms of the Gastrointestinal Tract, Pancreas, and Respiratory System: Reports by the ENETS Group. de Herder WW; Capdevila J. 2019. Neuroendocrinology. 108(1): 5 - 6.
  37. Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer. Argilés G; André T; Hollebecque A; Calvo A; Dahan L; Cervantes A; Leger C; Amellal N; Fougeray R; Tabernero J. 2019. Eur J Cancer. 112: 12 - 19.
  38. Clinical Practice Use of Liquid Biopsy to Identify RAS/BRAF Mutations in Patients with Metastatic Colorectal Cancer (mCRC): A Single Institution Experience. Vitiello PP; De Falco V; Giunta EF; Ciardiello D; Cardone C; Vitale P; Zanaletti N; Borrelli C; Poliero L; Terminiello M; Arrichiello G; Caputo V; Famiglietti V; Mattera Iacono V; Marrone F; Di Liello A; Martini G; Napolitano S; Caraglia M; Lombardi A; Franco R; De Vita F; Morgillo F; Troiani T; Ciardiello F; Martinelli E. 2019. Cancers (Basel). 11(10): 1504.
  39. Nomogram for Predicting Survival in Patients Treated with Liposomal Irinotecan Plus Fluorouracil and Leucovorin in Metastatic Pancreatic Cancer. Chen LT; Macarulla T; Blanc JF; Mirakhur B; Jong FA; Belanger B; Bekaii-Saab T; Siveke JT. 2019. Cancers (Basel). 11(8): 1068.
  40. Cancer Core Europe: A translational research infrastructure for a European mission on cancer. Eggermont AMM; Apolone G; Baumann M; Caldas C; Celis JE; de Lorenzo F; Ernberg I; Ringborg U; Rowell J; Tabernero J; Voest E; Calvo F. 2019. Mol Oncol. 13(3): 521 - 527.
  41. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer. Elez E; Chianese C; Sanz-García E; Martinelli E; Noguerido A; Mancuso FM; Caratù G; Matito J; Grasselli J; Cardone C; Esposito Abate R; Martini G; Santos C; Macarulla T; Argilés G; Capdevila J; Garcia A; Mulet N; Maiello E; Normanno N; Jones F; Tabernero J; Ciardello F; Salazar R; Vivancos A. 2019. Mol Oncol. 13(9): 1827 - 1835.
  42. New clinical trial designs in the era of precision medicine. Garralda E; Dienstmann R; Piris A; Braña I; Rodon J; Tabernero J. 2019. Mol Oncol. 13(3): 549 - 557.
  43. Towards a Cancer Mission in Horizon Europe. Berns A; Ringborg U; Eggermont A; Baumann M; Calvo F; Eggert A; Espina C; Hanahan D; Lacombe D; de Lorenzo F; Oberst S; Philip T; Schüz J; Tabernero J; Celis JE. 2019. Mol Oncol. 13(11): 2301 - 2304.
  44. Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines. Vitiello PP; Cardone C; Martini G; Ciardiello D; Belli V; Matrone N; Barra G; Napolitano S; Della Corte C; Turano M; Furia M; Troiani T; Morgillo F; De Vita F; Ciardiello F; Martinelli E. 2019. J Exp Clin Cancer Res. 38: 41 - 41.
  45. Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression. Napolitano S; Matrone N; Muddassir AL; Martini G; Sorokin A; De Falco V; Giunta EF; Ciardiello D; Martinelli E; Belli V; Furia M; Kopetz S; Morgillo F; Ciardiello F; Troiani T. 2019. J Exp Clin Cancer Res. 38(1): 492 - 492.
  46. A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer. Gorbunova, V.; Beck, J.T.; Hofheinz, R.-D.; Garcia-Alfonso, P.; Nechaeva, M.; Cubillo Gracian, A.; Mangel, L.; Elez Fernandez, E.; Deming, D.A.; Ramanathan, R.K.; Torres, A.H.; Sullivan, D.; Luo, Y.; Berlin, J.D.. Br J Cancer. 120(2): 183 - 189.
  47. A phase 2 study of panitumumab with irinotecan as salvage therapy in chemorefractory KRAS exon 2 wild-type metastatic colorectal cancer patients. Elez E; Pericay C; Valladares-Ayerbes M; Bando I; Safont MJ; Gallego J; Grávalos C; Arrivi A; Carrato A; Conde V; Ortiz MJ; López C; Alonso B; Ruiz de Mena I; Díaz-Rubio E; Tabernero J; Aranda E. 2019. Br J Cancer. 121(5): 378 - 383.
  48. Association of post-operative CEA with survival and oxaliplatin benefit in patients with stage II colon cancer: a post hoc analysis of the MOSAIC trial. Auclin E; André T; Taieb J; Banzi M; Van Laethem JL; Tabernero J; Hickish T; de Gramont A; Vernerey D. 2019. Br J Cancer. 121(4): 312 - 317.
  49. Evaluating radiological response in pancreatic neuroendocrine tumours treated with sunitinib: comparison of Choi versus RECIST criteria (CRIPNET_ GETNE1504 study). Solis-Hernandez MP; Fernandez Del Valle A; Carmona-Bayonas A; Garcia-Carbonero R; Custodio A; Benavent M; Alonso Gordoa T; Nuñez-Valdovino B; Sanchez Canovas M; Matos I; Alonso V; Lopez C; Viudez A; Izquierdo M; Calvo-Temprano D; Grande E; Capdevila J; Jimenez-Fonseca P. 2019. Br J Cancer. 121(7): 537 - 544.
  50. Meta-Analysis of Randomized Clinical Trials Comparing Active Treatment with Placebo in Metastatic Neuroendocrine Tumors. Capdevila J; Hernando J; Perez-Hoyos S; Roman-Gonzalez A; Grande E. 2019. 24(12): 1315 - 1320.
  51. Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study. Capdevila J; Teulé A; Barriuso J; Castellano D; Lopez C; Manzano JL; Alonso V; García-Carbonero R; Dotor E; Matos I; Custodio A; Casanovas O; Salazar R; EVERLAR study investigators. Oncologist. 24(1): 38 - 46.
  52. Recent Therapeutic Advances and Change in Treatment Paradigm of Patients with Merkel Cell Carcinoma. Garcia-Carbonero R; Marquez-Rodas I; de la Cruz-Merino L; Martinez-Trufero J; Cabrera MA; Piulats JM; Capdevila J; Grande E; Martin-Algarra S; Berrocal A. 2019. 24(10): 1375 - 1383.
  53. Carcinoembryonic Antigen Levels and Survival in Stage III Colon Cancer: Post hoc Analysis of the MOSAIC and PETACC-8 Trials. Auclin E; Taieb J; Lepage C; Aparicio T; Faroux R; Mini E; Folprecht G; Salazar R; Benetkiewicz M; Banzi M; Louvet C; Van Laethem JL; Tabernero J; Hickish T; de Gramont A; André T; Vernerey D. 2019. Cancer Epidemiol Biomarkers Prev. 28(7): 1153 - 1161.
  54. Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials. Yao JC; Garg A; Chen D; Capdevila J; Engstrom P; Pommier R; Van Cutsem E; Singh S; Fazio N; He W; Riester M; Patel P; Voi M; Morrissey M; Pavel ME; Kulke MH. 2019. Endocr Relat Cancer. 26(4): 391 - 403.
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  56. Combination of KIR2DS4 and Fc gamma RII alpha polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer (vol 9, 2589, 2019). Borrero-Palacios A; Cebrián A; Gómez Del Pulgar MT; García-Carbonero R; Garcia-Alfonso P; Aranda E; Elez E; López-López R; Cervantes A; Valladares M; Nadal C; Viéitez JM; Guillén-Ponce C; Rodríguez J; Hernández I; García JL; Vega-Bravo R; Puime-Otin A; Martínez-Useros J; Del Puerto-Nevado L; Rincón R; Rodríguez-Remírez M; Rojo F; García-Foncillas J. 2019. Sci Rep. 9: 7706 - 7706.
  57. Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples. Vivancos A; Aranda E; Benavides M; Élez E; Gómez-España MA; Toledano M; Alvarez M; Parrado MRC; García-Barberán V; Diaz-Rubio E. 2019. Sci Rep. 9: 8976 - 8976.)
  58. Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer. Serna G; Ruiz-Pace F; Cecchi F; Fasani R; Jimenez J; Thyparambil S; Landolfi S; Elez E; Vivancos A; Hembrough T; Tabernero J; Dienstmann R; Nuciforo P. 2019. Sci Rep. 9: 13568 - 13568.
  59. 3-month versus 6-month adjuvant chemotherapy for patients with high-risk stage II and III colorectal cancer: 3-year follow-up of the SCOT non-inferiority RCT. Iveson T; Boyd KA; Kerr RS; Robles-Zurita J; Saunders MP; Briggs AH; Cassidy J; Hollander NH; Tabernero J; Haydon A; Glimelius B; Harkin A; Allan K; McQueen J; Pearson S; Waterston A; Medley L; Wilson C; Ellis R; Essapen S; Dhadda AS; Harrison M; Falk S; Raouf S; Rees C; Olesen RK; Propper D; Bridgewater J; Azzabi A; Farrugia D; Webb A; Cunningham D; Hickish T; Weaver A; Gollins S; Wasan H; Paul J. 2019. Health Technol Assess. 23(64): 1 - 88.
  60. Economics of gastroenteropancreatic neuroendocrine tumors: a systematic review. Grande E; Díaz Á; López C; Munarriz J; Reina JJ; Vera R; Bernárdez B; Aller J; Capdevila J; Garcia-Carbonero R; Jimenez Fonseca P; Trapero-Bertran M. 2019. Ther Adv Endocrinol Metab. 10: UNSP 2042018819828217.
  61. Health-related Quality of Life in the Phase III LUME-Colon 1 Study: Comparison and Interpretation of Results From EORTC QLQ-C30 Analyses. Lenz HJ; Argiles G; Yoshino T; Lonardi S; Falcone A; Limón ML; Sobrero A; Hastedt C; Peil B; Voss F; Griebsch I; Van Cutsem E. 2019. Clin Colorectal Cancer. 18(4): 269 - 269.
  62. Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer - A subgroup analysis of the pivotal NAPOLI-1 trial. Macarulla T; Blanc JF; Wang-Gillam A; Chen LT; Siveke JT; Mirakhur B; Chen J; de Jong FA. 2019. J GERIATR ONCOL. 10(3): 427 - 435.
  63. Management and supportive treatment of frail patients with metastatic pancreatic cancer. Macarulla T; Carrato A; Díaz R; García A; Laquente B; Sastre J; Álvarez R; Muñoz A; Hidalgo M. 2019. J GERIATR ONCOL. 10(3): 398 - 404.
  64. Pharmacokinetic and exposure-response analysis of pertuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer. Kirschbrown WP; Wang B; Nijem I; Ohtsu A; Hoff PM; Shah MA; Shen L; Kang YK; Alsina M; Girish S; Garg A. 2019. Cancer Chemother Pharmacol. 84(3): 539 - 550.
  65. Population pharmacokinetics and exposure-overall survival analysis of the transforming growth factor-beta inhibitor galunisertib in patients with pancreatic cancer. Gueorguieva I; Tabernero J; Melisi D; Macarulla T; Merz V; Waterhouse TH; Miles C; Lahn MM; Cleverly A; Benhadji KA. 2019. Cancer Chemother Pharmacol. 84(5): 1003 - 1015.
  66. TGF beta receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Melisi D; Garcia-Carbonero R; Macarulla T; Pezet D; Deplanque G; Fuchs M; Trojan J; Kozloff M; Simionato F; Cleverly A; Smith C; Wang S; Man M; Driscoll KE; Estrem ST; Lahn MMF; Benhadji KA; Tabernero J. 2019. Cancer Chemother Pharmacol. 83(5): 975 - 991.
  67. Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors. Dromain C; Pavel ME; Ruszniewski P; Langley A; Massien C; Baudin E; Caplin ME; CLARINET Study Group. 2019. BMC Cancer. 19(1): 66 - 66.
  68. Vemurafenib-induced histiocytoid neutrophilic panniculitis simulating myeloid leukaemia cutis A novel variant of BRAF inhibitor associated panniculitis with histiocytoid infiltrate of immature neutrophils. Richarz NA; Puig L; Pérez N; Cuadra-Urteaga J; Elez E; Fernández-Figueras MT. 2019. CANCER BIOL THER. 20(3): 237 - 239.
  69. First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors. Elez E; Gomez-Roca C; Soto Matos-Pita A; Argiles G; Valentin T; Coronado C; Iglesias J; Macarulla T; Betrian S; Fudio S; Zaragoza K; Tabernero J; Delord JP. 2019. Invest New Drugs. 37(4): 674 - 683.
  70. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Maciel RMB; Camacho CP; Assumpção LVM; Bufalo NE; Carvalho AL; de Carvalho GA; Castroneves LA; de Castro FM; Ceolin L; Cerutti JM; Corbo R; Ferraz TMBL; Ferreira CV; França MIC; Galvão HCR; Germano-Neto F; Graf H; Jorge AAL; Kunii IS; Lauria MW; Leal VLG; Lindsey SC; Lourenço DM; Maciel LMZ; Magalhães PKR; Martins JRM; Martins-Costa MC; Mazeto GMFS; Impellizzeri AI; Nogueira CR; Palmero EI; Pessoa CHCN; Prada B; Siqueira DR; Sousa MSA; Toledo RA; Valente FOF; Vaisman F; Ward LS; Weber SS; Weiss RV; Yang JH; Dias-da-Silva MR; Hoff AO; Toledo SPA; Maia AL. 2019. Endocr Connect. 8(3): 289 - 298.
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  74. CanStem111P trial: a Phase III study of napabucasin plus nab-paclitaxel with gemcitabine. Sonbol MB; Ahn DH; Goldstein D; Okusaka T; Tabernero J; Macarulla T; Reni M; Li CP; O'Neil B; Cutsem EV; Bekaii-Saab T. 2019. FUTURE ONCOL. 15(12): 1295 - 1302.
  75. KEYNOTE-585: Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Bang YJ; Van Cutsem E; Fuchs CS; Ohtsu A; Tabernero J; Ilson DH; Hyung WJ; Strong VE; Goetze TO; Yoshikawa T; Tang LH; Hwang PMT; Webb N; Adelberg D; Shitara K. 2019. FUTURE ONCOL. 15(9): 943 - 952.
  76. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Qin S; Finn RS; Kudo M; Meyer T; Vogel A; Ducreux M; Macarulla TM; Tomasello G; Boisserie F; Hou J; Li X; Song J; Zhu AX. 2019. FUTURE ONCOL. 15(16): 1811 - 1822.
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  79. Educational needs in gastrointestinal cancer: a consensus position paper from the ESMO Gastrointestinal Cancer Faculty. Lordick F; Obermannova R; Vola D; Douillard JY; Mcgregor K; Van Cutsem E; Tabernero J; Ciardiello F; Cervantes A. 2019. ESMO Open. 4(3): UNSP e000533.
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Clinical Trials

  • CLXH254X2101 Estudio fase I, de búsqueda de dosis de LXH254 oral en pacientes adultos con tumores sólidos avanzados portadores de alteraciones en la vía de señalización MAPK. Phase I ARRAY-162-202 An Open-label Phase 1b/2 Study of Binimetinib Administered in Combination with Nivolumab or Nivolumab Plus Ipilimumab in Patients with Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer with RAS MutationPhase I
  • GEMCAD 1602 A single arm Phase I-II multicenter trial with avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients. Phase I
  • M15-913 An Open Label Phase 1, First-In-Human Study of TRAIL Receptor Agonist ABBV-621 in Subjects with Previously-Treated Solid Tumors and Hematologic Malignancies. Phase I
  • MK3475-158 Ensayo clínico de evaluación de biomarcadores predictivos con pembrolizumab (MK-3475) en pacientes con tumores sólidos avanzados (KEYNOTE 158). Basket trials
  • TTD-16-03 Randomised, multicentre, phase II pilot study to assess the efficacy and safety of treatment with FOLFIRI-aflibercept compared to initial treatment with FOLFIRI-aflibercept (for 6 cycles) followed by maintenance with 5FU-aflibercept, in an elderly population with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen. Phase II
  • PM60184-B-002-17 Estudio Fase II, Multicéntrico, Abierto de PM060184 en Pacientes con Cáncer Colorrectal Avanzado tras Tratamiento Estándar. Phase II
  • CA209-9X8 An Open-Label Exploratory Phase 2/3 Study of Nivolumab with Standard of Care Therapy vs Standard of Care Therapy for First-Line Treatment of Metastatic Colorectal Cancer. Phase II
  • DS8201-A-J203 A Phase 2, multicenter, open-label study of DS-8201a in subjects with HER2-expressing advanced colorectal cancer. Phase II
  • M14-064 Phase 2 Study Comparing Efficacy and Safety of ABT-165 plus FOLFIRI vs Bevacizumab plus FOLFIRI in Metastatic Colorectal Cancer Previously Treated with Fluoropyrimidine/Oxaliplatin and Bevacizumab. Phase II
  • W00090GE201 Estudio en fase II, multicéntrico, abierto y de un solo grupo de encorafenib, binimetinib más cetuximab en sujetos con cáncer colorrectal metastásico con mutación BRAFV600E sin tratamiento previo. Phase II
  • M16VIB MoTriColor: A phase II study of vinorelbine in advanced BRAF-like colon cancer. Phase II
  • PP06489 A Phase 3, double-blind, multicenter, placebo-controlled study of PledOx used on top of modified
  • FOLFOX6 (5-FU/FA and Oxaliplatin) to prevent chemotherapy induced peripheral neuropathy (CIPN) in the adjuvant treatment of patients with Stage III or high-risk Stage II colorectal cancer. Phase III
  • PP06490 Estudio de fase III, doble ciego, multicéntrico, controlado con placebo de PledOx usado junto con FOLFOX6 modificado (5 FU/FA y oxaliplatino) para prevenir la neuropatía periférica inducida por quimioterapia (NPIQ) en pacientes con cáncer colorrectal metastásico en tratamiento de primera línea. Phase III
  • TTD-18-01 Phase III randomized sequential open-label study to evaluate the efficacy of FOLFOX + panitumumab followed by FOLFIRI + bevacizumab (Sequence 1) versus FOLFOX + bevacizumab followed by FOLFIRI + panitumumab (Sequence 2) in ntreated patients with wild-type RAS metastatic, primary left-sided, unresectable colorectal cancer: The CRSEQUENCE. Phase III
  • ISO-CC-007 A randomized, multicenter, parallel-group, Phase III study to compare the efficacy of arfolitixorin versus leucovorin in combination with 5-fluorouracil, oxaliplatin, and bevacizumab in patients with advanced colorectal cancer. Phase III
  • CA209-8HW A Phase 3b Randomized Clinical Trial of Nivolumab alone, Nivolumab in Combination with Ipilimumab, or an Investigator’s Choice Chemotherapy in Participants with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer. Phase III
  • 20180293 A Non-interventional Biomarker Study on the Molecular Evaluation of Archival Tumor Tissue in Subjects with Gastric Cancer. Phase IV
  • CLGK974X2101 ESTUDIO FASE I, ABIERTO, DE ESCALADA DE DOSIS DE LGK974 ORAL, EN PACIENTES CON ENFERMEDADES MALIGNAS DEPENDIENTES DE LIGANDOS DE WNT2.Phase I
  • CL1-95005-001 Estudio de fase I de escalada de dosis con S 95005 (TAS-102) en combinación con oxaliplatino (TAS-OX) en cáncer colorrectal metastásico. Phase I
  • 1401-0001 An open-label, Phase I trial to determine the maximum-tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 905677 administered intravenously in patients with advanced solid tumours. Phase I
  • MCLA-158-CL01 Phase 1 dose escalation and cohort expansion study evaluating single-agent MCLA-158 in metastatic colorectal cancer and other advanced solid tumors. Phase I
  • SMS-0472B A Randomized, Multicentre, Open-Label Controlled Phase II Trial of Foxy-5 as Neo-Adjuvant Therapy in Subjects with Wnt-5a Low Colon Cancer. Phase II
  • BB608-303CRC A Phase III Study of BBI-608 in combination with 5- Fluorouracil, Leucovorin, Irinotecan (FOLFIRI) in Adult Patients with Previously Treated Metastatic Colorectal Cancer (CRC). Phase III
  • CL3-95005-006 Estudio abierto, aleatorizado, fase 3 comparando trifluridina/tipiracilo (S95005) en combinación con bevacizumab y capecitabina en combinación con bevacizumab en primera línea de tratamiento de pacientes con cáncer colorrectal metastásico que no son candidatos a terapia intensiva (Estudio SOLSTICE). Phase III
  • BGB-A317-208 A Phase 2, Open-label, Multicenter Study to Investigate the Efficacy, Safety, and Pharmacokinetics of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Patients with Previously Treated Hepatocellular Unresectable Carcinoma. Phase II
  • MS200647-0047 A Phase II, Multicenter, Open-label Study to Investigate the Clinical Efficacy of M7824 Monotherapy in Participants With Locally Advanced or Metastatic Biliary Tract Cancer Who Fail or are Intolerant to First-line Platinum-Based Chemotherapy. Phase II
  • D4200C00104 Estudio europeo observacional y prospectivo para evaluar el beneficio/riesgo de vandetanib (CAPRELSA™) 300 mg en pacientes con cáncer medular de tiroides (CMT) sintomático, agresivo, esporádico, localmente avanzado o metastásico, no resecable, con o sin mutación del RET. Phase IV
  • IPS-LAN-2018-01 “Efectividad de la dosis de 120 mg de lanreotida en pacientes con tumores neuroendocrinos pancreáticos (TNEP) localmente avanzados o metastásicos en la práctica clínica habitual”. Phase IV
  • CC-90011-ST-001 A PHASE 1, OPEN-LABEL, DOSE FINDING STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PRELIMINARY EFFICACY OF CC-90011 IN SUBJECTS WITH RELAPSED AND/OR REFRACTORY SOLID TUMORS AND NON-HODGKIN’S LYMPHOMAS. Phase I
  • AXI-IIG-02 A PHASE II RANDOMIZED DOUBLE-BLIND STUDY OF SANTOSTATIN LAR IN COMBINATION WITH AXITINIB VERSUS PLACEBO IN PATIENTS WITH PROGRESSIVE ADVANCED WELL-DIFFERENTIATED NEUROENDOCRINE CARCINOMAS OF NON-PANCREATIC ORIGIN (CARCINOIDS). Phase II
  • GETNE-2016-01 Estudio Fase II para evaluar la eficacia dek retratamiento con sunitinib en pacientes con tumores neuroendocrinos pancreáticos bien diferenciados G1/2 (pNET) avanzados o metastásicos que ya han fracasado a un tratamiento con sunitinib previo (Estudio RESUNET). Phase II
  • GEMCAD 1601 Tratamiento preoperatorio de inducción con 12 semanas de Panitumumab combinado con FOLFOX 6m en una población enriquecida (Quádruple Wild-Type) de pacientes con cáncer de recto de tercio medio mrT3 y fascia mesorrectal no invadida. Phase II
  • ESR 15-11561-61 A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin (the DUNE trial). Phase II GEMCAD 1701 Estudio aleatorizado de fase II para evaluar la eficacia de FOLFIRI + panitumumab en el tratamiento en segunda línea de pacientes con cáncer colorrectal metastásico RAS no mutado que han recibido FOLFOX + panitumumab en primera línea de tratamiento. Phase II
  • INCMGA0012-202 A Phase 2 Study of INCMGA00012 in Participants With Squamous Carcinoma of the Anal Canal Who Have Progressed Following Platinum-Based Chemotherapy. Phase II
  • INCMGA0012-201 Estudio en fase II de INCMGA00012 en participantes con carcinoma de células de Merkel metastásico. Phase II
  • GETNE-T1812 A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of patients with progressive, refractory advanced thyroid carcinoma-The DUTHY trial. Phase II
  • GETNE-T1913 A phase II study of platinum-doublet chemotherapy in combination with nivolumab as first-line treatment in subjects with unresectable, locally advanced or metastatic G3 neuroendocrine neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin. Phase II
  • GETNE-1206 Estudio abierto y aleatorizado para comparar la eficacia y la seguridad de everolimus seguido de quimioterapia con STZ-5FU tras la progresión o la secuencia invertida, quimioterapia con STZ-5FU seguida de everolimus tras la progresión, en tumores neuroendocrinos pancreáticos (TNEP) avanzados y progresivos (estudio SEQTOR). Phase III
  • XL184-401 Estudio aleatorizado y doble ciego para evaluar la eficacia y la seguridad de cabozantinib (XL184) con dosis de 60 mg/día en comparación con 140 mg/día en pacientes con cáncer medular de tiroides metastásico progresivo III
  • A-US-52030-328 A Phase 3, prospective, randomized, double-blind, multi-center study of the efficacy and safety of lanreotide Autogel/Depot 120 mg plus BSC vs. placebo plus BSC for tumor control in subjects with well differentiated, metastatic and/or unresectable, typical or atypical, lung neuroendocrine tumors. Phase III
  • MK3475-913 A Phase 3 Open-label, Single Arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) as First-line Therapy in Participants With Advanced Merkel Cell Carcinoma (KEYNOTE-913). Phase III
  • XL184–311 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects with Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed after Prior VEGFR-Targeted Therapy. Phase III
  • ITM-LET-01 A prospective, randomised, Controlled, Open-label, Multicentre phase III study to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somato-statin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET). Phase III
  • VHIO18001 Identificación de los diferentes patrones de captación mediante PET con 18F-FDG y 68Ga-DOTApéptidos en los tumores neuroendocrinos avanzados. Phase IV
  • C13-1 Follow-up to the AVANT study up to 8 and 10 years (median follow-up) in patients with colon carcinoma. IV
  • DEBIO 1347-101 A phase I, gene alteration-based, open label, multicenter study of oral Debio1347 (CH5183284) in patients with advanced solid malignancies, whose tumours have an alteration of the FGFR 1, 2 or 3 genes. Phase I
  • TPU-TAS-120-101 A DOSE-FINDING PHASE 1 STUDY OF TAS-120 IN PATIENTS WITH ADVANCED SOLID TUMORS WITH OR WITHOUT FIBROBLAST GROWTH FACTOR/RECEPTOR (FGF/FGFR)-RELATED ABNORMALITIES FOLLOWED BY A PHASE 2 STUDY IN PATIENTS WITH ADVANCED SOLID TUMORS OR MULTIPLE MYELOMA WITH FGF/FGFR-RELATED ABNORMALITIES Phase I
  • TED13751 Estudio de primera administración en humanos para evaluar la seguridad, farmacocinética y actividad antitumoral de SAR408701 en pacientes con tumores sólidos avanzados. Phase I
  • PCYC-1128-CA A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors.Phase I
  • CO39083 A PHASE IB OPEN-LABEL STUDY EVALUATING THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF COBIMETINIB IN COMBINATION WITH BEVACIZUMAB AND IMMUNOTHERAPY WHEN ADMINISTERED IN PATIENTS WITH GASTROINTESTINAL AND OTHER TUMORS. Phase I
  • GO39733 A PHASE IA/IB OPEN-LABEL, DOSE-ESCALATION STUDY OF THE SAFETY AND PHARMACOKINETICS OF RO7198457 AS A SINGLE AGENT AND IN COMBINATION WITH ATEZOLIZUMAB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC TUMORS. Phase I
  • BP40087 ESTUDIO DE FASE IA/IB, ABIERTO, MULTICÉNTRICO, DE ESCALADA DE DOSIS, PARA EVALUAR LA SEGURIDAD, LA FARMACOCINÉTICA Y LA ACTIVIDAD ANTITUMORAL PRELIMINAR DE RO7122290, UN LIGANDO 4-1BB (CD137L) DIRIGIDO CONTRA LA PROTEÍNA _ DE ACTIVACIÓN DE FIBROBLASTOS (FAP), CON O SIN PRETRATAMIENTO CON OBINUTUZUMAB, EN PACIENTES CON TUMORES SÓLIDOS AVANZADOS Y/O METASTÁSICOS, EN MONOTERAPIA O EN COMBINACIÓN CON ATEZOLIZUMAB, SEGUIDO DE COHORTE(S) DE EXPANSIÓN ESPECÍFICA(S) DEL TUMOR. Phase I
  • BP40092 A FIRST-IN-HUMAN, OPEN-LABEL,MULTICENTER, DOSE-ESCALATION PHASE I CLINICAL STUDY OF SINGLE-AGENT RO7172508 IN PATIENTS WITH LOCALLY ADVANCED AND/OR METASTATIC CEA-POSITIVE SOLID TUMORS. Phase I
  • CO40939 A PHASE Ib, MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFETY, EFFICACY, AND PHARMAKOKINETICS OF RO6958688 IN COMBINATION WITH ATEZOLIZUMAB AFTER PRETREATMENT WITH OBINUTUZUMAB IN PATIENTS WITH PREVIOUSLY TREATED METASTATIC, MICROSATELLITE-STABLE COLORECTAL ADENOCARCINOMA WITH HIGH CEACAM5 EXPRESSION. Phase I
  • MO29518 AN OPEN-LABEL, MULTICOHORT, PHASE II STUDY OF MPDL3280A IN ADVANCED SOLID TUMORS Basket trials
  • CA017-003-II Estudio fase 1/2a de BMS-986205 administrado en combinación con nivolumab (BMS-936558, anticuerpo monoclonal anti-PD-1) en tumores malignos avanzados Basket trials
  • VHIO16001 - EORTC 1604 A phase II open-label study with the anti-PD-L1 Atezolizumab monoclonal antibody in combination with Bevacizumab in patients with advanced chemotherapy resistant colorectal cancer and MSI-like molecular signature . Phase II
  • TO-TAS0728-101 Estudio multicéntrico, abierto, en fase I/II para investigar la seguridad, farmacocinética y eficacia de TAS0728, un inhibidor oral de la unión covalente de HER2 en sujetos con tumores sólidos avanzados con anomalías en HER2 o HER3. Basket trials
  • D910CC00001 A Phase 1b/2, Open-label, Multicenter Study of Novel Oncology Therapies in Combination with Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1). Phase II
  • TPU-TAS-120-101-II TPU-TAS-120-101-II II ARRAY-818-302 A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab with a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients with BRAF V600E-mutant Metastatic Colorectal Cancer. Phase III
  • VHIO19001 Phase II Study of Avelumab plus chemotherapy in the peri-operative treatment for patients with respectable Gastric cancer (GC) or Gastroesophageal Junction cancer (GEJC) – MONEO Study. Phase II
  • ML40677 ESTUDIO OBSERVACIONAL PARA LA RECOGIDA DE LA SUPERVIVENCIA GLOBAL DE LOS PACIENTES INCLUIDOS EN EL ESTUDIO NEOHX (ML25189). Phase IV
  • YO39609 A phase Ib/II, open-label, multicenter, randomized, umbrella study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer (morpheus-gastric cancer). Phase I
  • MCLA-128-CL01 A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors Basket trials
  • CA209-648 Estudio fase 3, aleatorizado, de nivolumab más ipilimumab o nivolumab en combinación con fluorouracilo más cisplatino frente a fluorouracilo más cisplatino en pacientes con carcinoma de células escamosas de esófago avanzado irresecable, recurrente o metastásico, previamente no tratado. Phase II
  • CA224-060 Ensayo clínico fase 2, aleatorizado, abierto, de relatlimab (anti-LAG-3) y nivolumab en combinación con quimioterapia frente a nivolumab en combinación con quimioterapia como tratamiento de primera línea en pacientes con adenocarcinoma gástrico o de la unión gastroesofágica. Phase II
  • DS8201-A-U205 A Phase 2, open-label, single-arm trial of trastuzumab deruxtecan (DS-8201a) in HER2-positive, unresectable or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma subjects who have progressed on or after a trastuzumab-containing regimen. Phase II
  • 1203-GITCG INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL. Phase III
  • CA209-649 Estudio fase 3, aleatorizado, multicéntrico, abierto, de nivolumab más ipilimumab frente a oxaliplatino más fluoropirimidina en sujetos con cáncer gástrico o de la unión gastroesofágica, avanzado o metastásico, no tratado previamente. Phase III
  • BGB-290-303 Estudio de fase 3, en doble ciego y aleatorizado, de BGB-290 frente a placebo como tratamiento de mantenimiento en pacientes con cáncer gástrico localmente avanzado o metastásico, inoperable, que han respondido a una quimioterapia de primera línea basada en el platino. Phase III
  • BGB-A317-302 Estudio de Fase 3, aleatorizado, controlado, abierto y global, comparativo de la eficacia de BGB-A317, un anticuerpo anti-PD-1, frente a quimioterapia como segunda línea de tratamiento en pacientes con carcinoma esofágico epidermoide avanzado no resecable/metastásico. Phase III
  • 8951-CL-0301 Estudio de fase 3 internacional, multicéntrico, doble ciego y aleatorizado, de la eficacia de IMAB362 más mFOLFOX6, en comparación con placebo más mFOLFOX6, como tratamiento de primera línea en sujetos con adenocarcinoma gástrico o de la unión gastroesofágica localmente avanzado irresecable o metastásico, claudin
  • (CLDN)18.2 positivo y HER2 negativo. Phase III
  • MK3475-811 Ensayo de fase III, aleatorizado y doble ciego para comparar trastuzumab más quimioterapia y pembrolizumab con trastuzumab más quimioterapia y placebo como tratamiento de primera línea en participantes con adenocarcinoma gástrico o de la unión gastroesofágica avanzado con HER2 positivo (KEYNOTE 811).Phase III
  • MK3475-859 A Phase 3, randomized, double-blind clinical study of pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy as first-line treatment in participants with HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (KEYNOTE-859). Phase III BGB-A317-306 Estudio de fase 3, aleatorizado, controlado con placebo y en doble ciego, para evaluar la eficacia y la seguridad de tislelizumab (BGB-A317) en combinación con quimioterapia como tratamiento de primera línea en pacientes con carcinoma esofágico epidermoide recurrente localmente avanzado o metastásico, no resecable. Phase III
  • BLU-554-1101 A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of BLU-554 in Patients with Hepatocellular Carcinoma and Cholangiocarcinoma. Phase I
  • CC-122-HCC-002 A PHASE 1/2, MULTICENTER, OPEN-LABEL, DOSE FINDING STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND PRELIMINARY EFFICACY OF CC-122 IN COMBINATION WITH NIVOLUMAB IN SUBJECTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (HCC). Phase I
  • H3B-6527-G000-101 An Open-Label Multicenter Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Subjects With Advanced Hepatocellular Carcinoma. Phase I
  • BAY94-9343/15834 ?Estudio de fase Ib de múltiples indicaciones con anetumab ravtansina (BAY-94-9343) en pacientes con cáncer avanzado o recurrente que expresan mesotelina?. Phase I CTMT212X2106 “Estudio fase I/II de seguridad y eficacia de ribociclib (LEE011) en combinación con trametinib
  • (TMT212), en pacientes con tumores sólidos avanzados o metastásicos”. Phase I
  • P-VCNA-001 A phase I, multicenter, open-label, dose escalation study of intravenous administration of VCN-01 oncolytic adenovirus with or without gemcitabine and Abraxane® in patients with advanced solid tumors. Phase I
  • I5B-MC-JGDP A Phase 1b (Open-Label) / Phase 2 (Randomized, Double-Blinded) Study Evaluating Nab-Paclitaxel and Gemcitabine With or Without Olaratumab in the Treatment of First-Line Metastatic Pancreatic Cancer I WO39608 A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE IMMUNOTHERAPY-BASED TREATMENT COMBINATIONS IN PATIENTS WITH METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA (MORPHEUS-PANCREATIC CANCER). Phase  I
  • CBGJ398X2204 Estudio fase II, multicéntrico, con un único brazo de tratamiento, de BGJ398 oral en pacientes adultos con colangiocarcinoma avanzado o metastásico, con fusiones del gen FGFR2 u otras alteraciones genéticas del FGFR que han progresado o que son intolerantes a quimioterapia basada en platino. Phase II
  • TTD-14-05 Estudio fase I-II con Nab-paclitaxel (Abraxane®) y gemcitabina seguido de FOLFOX modificado (AG-mFOLFOX) en pacientes con cáncer de páncreas metastásico no tratado. II
  • EF-30 HEPANOVA: A Phase II Trial of Tumor Treating Fields (TTFields, 150kHz) Concomitant With Sorafenib For Advanced Hepatocellular Carcinoma (HCC). Phase II
  • CA025-006 A Phase 2 Study of Cabiralizumab (BMS-986227, FPA008) Administered in Combination with Nivolumab (BMS-936558) with and without Chemotherapy in Patients with Advanced Pancreatic Cancer. Phase II
  • I5B-MC-JGDP-II A Phase 1b (Open-Label) / Phase 2 (Randomized,Double-Blinded) Study Evaluating Nab-Paclitaxel and Gemcitabine With or Without Olaratumab in the Treatment of First-Line Metastatic Pancreatic Cancer. Phase II
  • D6070C00005 A Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of Oleclumab (MEDI9447) with or without Durvalumab in Combination with Chemotherapy in Subjects with Metastatic Pancreatic Ductal Adenocarcinoma. Phase II
  • FiHM006 Ensayo fase II para evaluar la evolución de la carga de mutación de KRAS por biopsia líquida en pacientes con adenocarcinoma ductal pancreático resecable tratados con tratamiento neoadyuvante NALIRINOX. Phase II
  • BL-8040.PAC.201 A PHASE IIA, MULTICENTER, OPEN-LABEL STUDY TO ASSESS THE SAFETY AND EFFICACY OF THE COMBINATION OF BL-8040 AND PEMBROLIZUMAB IN SUBJECTS WITH METASTATIC PANCREATIC CANCER, THE COMBAT STUDY. Phase II
  • HALO-109-301 Estudio de Fase 3, aleatorizado, doble ciego, controlado con placebo y multicéntrico, de la forma PEGilada de la hialuronidasa recombinante humana (PEGPH20) en combinación con nabpaclitaxel y gemcitabina, comparados con placebo más nab-paclitaxel y gemcitabina, en sujetos con adenocarcinoma ductal pancreático en estadio IV con elevación de hialuronano no tratados previamente. Phase III
  • AM0010-301 A Randomized Phase 3 Study of AM0010 in Combination with FOLFOX Compared with FOLFOX Alone as Second-line Therapy in Patients with Metastatic Pancreatic Cancer that has Progressed During or Following a First-Line Gemcitabine Containing Regimen. Phase III AG120-C-005 A Phase 3, Multicenter, Randomized, Double-Blind Study of AG-120 vs. Placebo in Previouslytreated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation. Phase III
  • CanStem111P Estudio en fase III de la combinación de BBI-608, nab-paclitaxel y gemcitabina en pacientes adultos con adenocarcinoma pancreático metastásico. Phase III
  • BGB-A317-301 A Randomized, Open-label, Multicenter Phase 3 Study to Compare the Efficacy and Safety of BGB-A317 versus Sorafenib as First-Line Treatment in Patients with Unresectable Hepatocellular Carcinoma. Phase III
  • EF-27 PANOVA-3: Pivotal, randomized, open-label study of Tumor Treating Fields (TTFields, 150kHz) concomitant with gemcitabine and nab-paclitaxel for front-line treatment of locally-advanced pancreatic adenocarcinoma. Phase III
  • GRASPANC-2018-01 A Randomized, Phase 3 Study of Eryaspase in Combination with Chemotherapy versus Chemotherapy Alone as Second-Line Treatment in Patients with Pancreatic Adenocarcinoma. Phase III
  • INCB 54828-302 A Phase 3, Open-Label, Randomized, Active-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Gemcitabine Plus Cisplatin Chemotherapy in First-Line Treatment of Participants With Unresectable or Metastatic Cholangiocarcinoma With FGFR2 Rearrangement (FIGHT-302). Phase III
  • MK3475-966 A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin as First-Line Therapy in Participants with Advanced and/or Unresectable Biliary Tract Carcinoma. Phase III

Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group

Joan Carles
Principal Investigator
Biosketch
Principal Investigator Joan Carles Medical Oncologists and Clinical Fellows Macarena Gonzalez, Joaquin Mateo, Rafael Morales, Cesar Serrano, Cristina Suarez, Claudia Valverde, Maria Vieito Clinical Nurse Specialist Alexandre Sierra

Summary

We are dedicated to advancing clinical and translational research against cancer and have extensive experience and expertise in treating various neoplasms. We design and develop clinical trials for genitourinary malignancies at different stages of disease in collaboration with urologists and radiation therapists.

During 2019 we continued to consolidate our expert Prostate Task Force. By closely connecting clinical and translational researchers at VHIO and the Vall d’Hebron Research Institute (VHIR), we have initiated translational projects focused on prostate cancer. We are also doing the same for kidney cancer in pursuit of similar goals in collaboration with other partners including Biomedical Research Institute of Bellvitge (IDIBELL).

Over recent years, several advances have been reported in the more effective treatment of GU malignancies. Immunotherapy (IO) is proving increasingly important against bladder and kidney cancers. Concerning the latter, immune-based therapies in combination with others or paired with antiangiogenics is considered the new standard treatment for first-line therapy. Both approaches have proven more effective compared with antiangiogenic therapy alone.

In bladder cancer immunotherapy has also been shown as superior to chemotherapy in second line and in first-line for ineligible patients. It has recently been shown that immunotherapy in combination with concurrent chemotherapy or as maintenance after 4/6 cycles of chemotherapy in first-line improves progression-free survival (PFS).

Our group –along with others- has observed that immunotherapy could also be effective for certain subgroups of patients with castration-resistant prostate cancer. We are currently participating in phase I studies to assess immune-based cancer medicines for the treatment of this patient population.

We have also participated in various clinical trials using checkpoint inhibitors for the adjuvant treatment of bladder and kidney cancers with high risk of recurrence. Working closely with our Vall d’Hebron University Hospital’s Urology Department and other experts in high-risk tumors, we are currently running studies aimed at improving outcomes for patients with non-muscle- invasive bladder cancer.

We collaborate with various other renowned research centers including the Cleveland Clinic (Ohio, USA), University of California, San Francisco (California, USA). We also participate in studies carried out in partnership with the Gustave Roussy Institute (Paris, France), Barts Health NHS Trust – Hospital (London, UK), and Kantonsspital St. Gallen (Switzerland).

This year we have expanded our translational research program in prostate cancer working alongside VHIO’s Prostate Cancer Translational Research Group, led by Principal Investigator Joaquin Mateo. We have performed 20 biopsies (16 bone and 4 prostate biopsies) and aim to correlate blood samples with these tests.

Our main focus is metastatic castration-resistant prostate cancer and we are working on a project led by Joaquin, entitled: Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays. This research is supported by the US Department of Defense’s (DoD) Congressionally Directed Medical Research Program. Additionally, we are participating in the IRONMAN project lead by the Memorial Sloan Kettering Cancer Center (MSKCC – New York, USA). Led by VHIO we collect patients’ reported outcomes in parallel with serum. This research is supported by Movember and the FERO Foundation.

We are also partnering with VHIO’s Radiomics Group headed by Raquel Perez-Lopez, to analyze MRI alterations in patients who have started hormonal treatments for metastatic prostate cancer and correlate these data with bone biopsies performed in parallel.

This particular project, iPROMET: a study for clinical validation of whole-body diffusion-weighed MRI as a response biomarker of bone metastases in patients with prostate cancer, counts on the combined expertise of a urologist, radio-oncologist, radiologist and medical oncologist to establish a circuit for the systematic metastatic tissue acquisition from prostate cancer patients at our Hospital.

We have also expanded our avatar program for kidney cancer tumors in collaboration with IDIBELL and implanted more than 30 samples. Additionally, we continue to participate in the REVOLUTION project, pREdiction of niVOLUmab acTION metastatic renal cancer patients: Treg function, tumoral access and NK interactions as predictive biomarkers of immunotherapy, supported by TRANSCAN-2 ERA-NET, under the scope of the EU Framework Programme Horizon 2020.

In collaboration with other professionals in neurosurgery and radiation therapy, we lead and develop several multidisciplinary clinical studies and phase I trials in CNS tumors. Additionally, it is thanks to a project with our Gene Expression & Cancer Group led by Joan Seoane, that we continue to develop VHIO’s translational research platform for glioblastoma. We analyze cfDNA in blood and cephaloraquidic liquid for assessing primary CNS tumors and metastases.

Our group also collaborates in a project directed by the European Organisation for Research and Treatment of Cancer (EORTC, Brussels, Belgium), against several tumor types, working on CNS tumors: Cancer Patients for Efficient Clinical Trial Access (SPECTA). The main objective is to screen patients and develop academic clinical trials based on molecular stratification. This initiative is supported by the European Cancer Research Fund (ECRF) and Walgreens Boots Alliance (WBA). We are also active at the national level in a medulloblastoma platform to better define and classify these cancers.

We continue to work closely with the Spanish Sarcoma Group (GEIS) on clinical trials at different stages of disease with emphasis on a histology-tailored design and are currently setting up a translational platform for sarcomas and basic research in partnership with IDIBELL and the Cancer Research Center of Salamanca – CIC (Spain). For GIST tumors we are working with Jonathan Fletcher’s lab at the Brigham and Women’s Hospital (Boston, USA).

Importantly, we have been recognized by the Spanish Ministry of Health as a Spanish National Health System Reference Service (Centros, Servicios y Unidades de Referencia del Sistema Nacional de Salud - CSUR), to treat sarcoma patients. This accreditation enables us to participate in the European References Network (ERN) for sarcoma tumors and other rare diseases.

One of our group members, César Serrano, who carried out a three-year fellowship at the Dana Farber Cancer Institute (Boston, USA), has established an independent line of experimental research on sarcomas. Notably, his translational studies have led to novel treatment strategies against sarcoma, including the design of a phase Ib clinical trial to assess – for the first time in oncology – a rapid-alternation drug schedule of targeted therapies (NCT02164240). In 2019 he set up his own research group, VHIO’s Sarcoma Translational Research.

During this year we have consolidated different clinical trials with new drugs in GIST by leading and participating in phase I-II-III studies. As this report went to print, one of these studies led to the U.S. Food and Drug Administration’s (FDA) January 2020 approval of avapritinib for the treatment of adult patients harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including D842V mutations.

Our Serum Bank now incorporates the majority of tumor types that we study (CNS tumors, GIST; renal cell carcinoma and CRPC), and we will continue to collect samples from our patients.

Dedicated to promoting education and exchange, in 2019 we welcomed six fellows from in (5) and outside (1) of Spain for three-month short stays.


Strategic goals

  • Design and develop clinical trials covering all malignancies studied by our group. We seek to provide our patients with the most novel and optimal treatments including immune-based therapeutics, targeted therapies and new chemotherapies.
  • Conduct clinical trials at different stages of disease with emphasis on a histology-tailored design and multidisciplinary approach.
  • Develop new tools and techniques including liquid biopsy for our patients to more precisely tailor treatments against mCRPC, GIST and kidney cancer.
  • Microbiota studies as a biomarker for immunotherapies to treat bladder and kidney cancers.
  • Consolidate our biopsy program (mainly in bone), for patients with mCRPC to target genomic alterations including PI3K pathways, DNA repair genes, and androgen receptor alterations.
  • Further consolidate our Kidney Cancer Task Force at VHIO in collaboration with researchers at the Vall d'Hebron Research Institute (VHIR) and Biomedical Research Institute of Bellvitge (IDIBELL).
  • Expand our translational research platform for glioblastoma in collaboration with VHIO's Gene Expression & Cancer Group.
  • Develop our translational platform for GIST and expand research in collaboration with the Spanish Sarcoma Group (GEIS), and other European referral centers. We are also an active member of the European References Network (ERN).

Highlights

  • We have consolidated our Task Force and our Serum Bank in Prostate Cancer. This allows us to participate in different translational studies a sell as lead the IRONMAN Project in Spain.
  • Expansion of our Phase I program across all tumor types studied by our group.
  • Fostered and developed new collaborations with different VHIO as well as external research groups.

Horizons

  • We will continue to consolidate our Prostate Task Force to expand our translational research lines.
  • Our group will continue to lead and participate in Immunotherapy studies that are driving major advances in the treatment of kidney and bladder cancers.

PI paper pick

  • De Wit R, De Bono J, Sternberg CN, Fizazi K, Tombal B, Wulfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdottir A, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D, CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518.
  • Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, Pook, David W; Rathenborg P, Flaig TW, Carles J, Saad F, Shore ND, Chen L, Heery CR, Gerritsen WR, Priou F, Langkilde NC, Novikov A, Kantoff PW. Phase III Trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. J Clin Oncol. 2019 May 1;37(13):1051-1061.
  • Carles J, Pichler A, Korunkova H, Tomova A, Ghosn M, El Karak F, Makdessi J, Koroleva I, Barnes G, Bury D, Ozatilgan A, Hitier S, Katolicka J. An observational, multicentre study of cabazitaxel in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (CAPRISTANA). BJU Int. 2019 Mar;123(3):456-464.
  • Carles J, Gallardo E, Domenech M, Font A, Bellmunt J, Figols M, Mellado B, Saez MI, Suarez C, Mendez MJ, Maroto P, Luque R, de Portugal T, Aldabo R, Bonfill T, Morales-Barrera R, Garcia J, Macia, S, Maldonado X, Foro P. Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients. Int J Radiat Oncol Biol Phys. 2019 Feb 1;103(2):344-352.

Full list of Publications

  1. Heidenreich A, Gillessen S, Heinrich D, Keizman D, O'Sullivan JM, Carles J, Wirth M, Miller K, Reeves J, Seger M, Nilsson S, Saad F. Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program. BMC Cancer2019 19:12.
  2. González Del Alba A, De Velasco G, Lainez N, Maroto P, Morales-Barrera R, Muñoz-Langa J, Pérez-Valderrama B, Basterretxea L, Caballero C, Vazquez S. SEOM clinical guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer. Clin Transl Oncol. 2019 Jan;21(1):64-74.
  3. Zafeiriou Z, Bianchini D, Chandler R, Rescigno P, Yuan W,Carreira S, Barrero M, Petremolo A, Miranda S, Riisnaes R, Rodrigues DN, Gurel B, Sumanasuriya S, Paschalis A, Sharp A, Mateo J, Tunariu N, Chinnaiyan AM, Pritchard CC, Kelly K, de Bono JS. Genomic analysis of three metastatic prostate cancer patients with exceptional responses to carboplatin indicating different types of DNA repair deficiency. Eur Urol. 2019 Jan;75(1):184-192.
  4. Carles J, Gallardo E, Domenech M, Font A, Bellmunt J, Figols M, Mellado B, Saez MI, Suarez C, Mendez MJ, Maroto P, Luque R, de Portugal T, Aldabo R, Bonfill T, Morales-Barrera R, Garcia J, Macia, S, Maldonado X, Foro P. Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients. Int J Radiat Oncol Biol Phys. 2019 Feb 1;103(2):344-352.
  5. Castro E, Romero-Laorden N, Del Pozo A, Lozano R, Medina A, Puente J, Piulats JM, Lorente D, Saez MI, Morales-Barrera R, Gonzalez-Billalabeitia E, Cendón Y, García-Carbonero I, Borrega P, Mendez Vidal MJ, Montesa A, Nombela P, Fernández-Parra E, Gonzalez Del Alba A, Villa-Guzmán JC, Ibáñez K, Rodriguez-Vida A, Magraner-Pardo L, Perez-Valderrama B, Vallespín E, Gallardo E, Vazquez S, Pritchard CC, Lapunzina P, Olmos D. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2019 Feb 20;37(6):490-503.
  6. Font A, Luque R, Villa JC, Domenech M, Vázquez S, Gallardo E, Virizuela JA, Beato C, Morales-Barrera R, Gelabert A, Maciá S, Puente J, Rubio G, Maldonado X, Perez-Valderrama B, Pinto A, Fernández Calvo O, Grande E, Garde-Noguera J, Fernández-Parra E, Arranz JÁ. The Challenge of Managing Bladder Cancer and Upper Tract Urothelial Carcinoma: A Review with Treatment Recommendations from the Spanish Oncology Genitourinary Group (SOGUG). Target Oncol. 2019 Feb;14(1):15-32. Review.
  7. Ravegnini G, Sammarini G, Serrano C, Nannini M, Pantaleo MA, Hrelia P, Angelini S. Clinical relevance of circulating molecules in cancer: focus on gastrointestinal stromal tumors. Ther Adv Med Oncol. 2019 Mar 1;11:1758835919831902. Review.
  8. Carles J, Pichler A, Korunkova H, Tomova A, Ghosn M, El Karak F, Makdessi J, Koroleva I, Barnes G, Bury D, Ozatilgan A, Hitier S, Katolicka J. An observational, multicentre study of cabazitaxel in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (CAPRISTANA).BJU Int.2019 Mar;123(3):456-464.
  9. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith M, ARAMIS Investigators. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med2019; 380:1235-1246.
  10. O'Sullivan JM, Carles J, Cathomas R, Gomez-Iturriaga A, Heinrich, D,  Kramer G, Ost P, van Oort I, Tombal B. Radium-223 Within the Evolving Treatment Options for Metastatic Castration-resistant Prostate Cancer: Recommendations from a European Expert Working Group. Eur Urol Oncol. 2019 Mar 25. pii: S2588-9311(19)30031-8.
  11. Athie A, Arce-Gallego S, Gonzalez M, Morales-Barrera R, Suárez C, Casals Galobart T, Hernandez Viedma G, Carles J, Mateo J. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Curr Oncol Rep.2019 Mar 27;21(5):42.
  12. Conteduca V, Jayaram A, Romero-Laorden N, Wetterskog D, Salvi S, Gurioli G, Scarpi E, Castro E, Marin-Aguilera M, Lolli C, Schepisi G, Maugeri A, Wingate A, Farolfi A, Casadio V, Medina A, Puente J, Vidal MJM, Morales-Barrera R, Villa-Guzmán JC, Hernando S, Rodriguez-Vida A, González-Del-Alba A, Mellado B, Gonzalez-Billalabeitia E, Olmos D, Attard G, De Giorgi U. Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2019 Mar;75(3):368-373.
  13. Morales-Barrera R, Suárez C, Mateo J, González M, Carles J. Nanoparticles as theranostic vehicles in prostate cancer. Ann Transl Med. 2019 Mar;7(Suppl 1):S29.
  14. Serrano C, Marino-Enriquez Adrian, Tao DL, Ketzer J, Eilers G, Zhu M, Yu C, Mannan AM, Rubin BP, Demetri GD, Raut CP, Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019 Mar;120(6):612-620.
  15. Ravegnini G, Serrano C, Simeon V, Sammarini G, Nannini M, Roversi E, Urbini M, Ferre F, Ricci R, Tarantino G, Pantaleo MA, Hrelia P, Angelini S. The rs17084733 variant in the KIT 3' UTR tumour: a sponge-like mechanism conferring disease susceptibility. Epigenetics. 2019 Jun;14(6):545-557.
  16. Serrano C, Garcia del Muro X, Valverde C, Sebio A, Duran J, Manzano A, Pajares I, Hindi N, Landolfi S, Jimenez Laura, Rubio-Casadevall J, Estival A, Lavernia J, Safont MJ, Pericay C, Diaz-Beveridge R, Martinez-Marin V, Vicente-Baz D, Vivancos A, Hernandez-Losa J, Arribas J, Carles J. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib. Oncologist. 2019 May;24(5):680-687.
  17. Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, Pook DW, Rathenborg P, Flaig TW, Carles J, Saad F, Shore ND, Chen L, Heery CR, Gerritsen WR, Priou F, Langkilde NC, Novikov A, Kantoff PW. Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. J Clin Onc.May 2019; 37 (13): 1051-/+.
  18. Athie A, Arce-Gallego S, Gonzalez M, Morales-Barrera R, Suarez C, Casals Galobart T, Hernandez Viedma G, Carles J, Mateo J. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Curr Oncol Rep. 2019 May 27; 21 (5): 42. doi: 10.1007/s11912-019-0790-6. Review.
  19. Serrano C, García-Del-Muro X, Valverde C, Sebio A, Durán J, Manzano A, Pajares I, Hindi N, Landolfi S, Jiménez L, Rubió-Casadevall J, Estival A, Lavernia J, Safont MJ, Pericay C, Díaz-Beveridge R, Martínez-Marín V, Vicente-Baz D, Vivancos A, Hernández-Losa J, Arribas J, Carles J. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib. Oncologist. May 2019; 24 (5): 680-687.
  20. Abida W CJ, Heller G, Prandi D, Armenia J, Coleman I, Cieslik M, Benelli M, Robinson D, Van Allen EM, Sboner A, Fedrizzi T, Mosquera J, Robinson BD, De Sarkar N, Kunju LP, Tomlins S, Wu YM, Rodrigues DN, Loda M, Gopalan A, Pritchard CC, Colin C, Mateo J, Bianchini D, Miranda S, Carreira S, Rescigno P, Filipenko J, Vinson J, Montgomery RB, Beltran H, Heath EI, Scher HI, Howard I, Kantoff PW, Taplin ME, Schultz N, de Bono JS, Demichelis F, Nelson PS, Rubin MA, Chinnaiyan AM, Sawyers CL, Sawyers Charles L. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. Jun 2019; 116 (23): 11428-11436.
  21. Martin-Broto J, Hindi N, Cruz J, Martinez-Trufero J, Valverde C, De Sande LM, Sala A, Bellido L, De Juan A, Rubió-Casadevall J, Diaz-Beveridge R, Cubedo R, Tendero O, Salinas D, Gracia I, Ramos R, Baguè S, Gutierrez A, Duran-Moreno J, Lopez-Pousa A. Relevance of Reference Centers in Sarcoma Care and Quality Item Evaluation: Results from the Prospective Registry of the Spanish Group for Research in Sarcoma (GEIS). Oncologist. Jun 2019 24 (6):e338-e346.
  22. Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, Cuartas I, Sala-Hojman A, Escudero L, Martínez-Ricarte F, Huber-Ruano I, Nuciforo P, Pedrosa L, Marques C, Braña I, Garralda E, Vieito M, Squatrito M, Pineda E, Graus F, Espejo C, Sahuquillo J, Tabernero J, Seoane J. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun.Jun 2019; 10 2416.
  23. Procopio G, Bamias A, Schmidinger M, Hawkins R, Sánchez AR, Estevez SV, Srihari N, Kalofonos H, Bono P, Pisal CB, Hirschberg Y, Dezzani L, Ahmad Q, Rodriguez CS, Jonasch E. Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell Carcinoma. Clin Gen Can. Jun 2019; 17(3): E526-E533
  24. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ, IMmotion151 Study Group. (2019). Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. Jun 2019; 393 (10189): 2404-2415.
  25. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y,  Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A; Siefker-Radtke A O; BLC2001 Stud y Grp. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. Jul 2019; 381 (4): 338-348.
  26. Serrano C, Marino-Enriquez A, Tao DL, Ketzer J, Eilers G, Zhu MJ, Yu CN, Mannan AM, Rubin BP, Demetri GD, Raut CP, Chandrajit P, Presnell A, McKinley A, Heinrich MC, Michael C, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer.2019 Mar;120(6):612-620. Correction.
  27. Saad F, Gillessen S, Heinrich D, Keizman D, O'Sullivan JM, Nilsson S, Miller K, Wirth Ma, Reeves M; Carles J, Heidenreich A. Disease Characteristics and Completion of Treatment in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Radium-223 in an International Early Access Program. Clin Gen Can. Oct 2019, 17 (5): 348+/-.
  28. Marín-Aguilera M, Reig Ò, Milà-Guasch M, Font A, Domènech M, Rodríguez-Vida A, Carles J, Suárez C, Del Alba AG, Jiménez N, Victoria I, Sala-González N, Ribal MJ, López S, Etxaniz O, Anguera G, Maroto P, Fernández PL, Prat A, Mellado B. The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as biomarker of taxane resistance in castration-resistant prostate cancer. Int J Cancer.2019 Oct; 145 (7): 1970 – 1981.
  29. Mateo J, Carreira S, de Bono JS. PARP Inhibitors for Advanced Prostate Cancer: Validating Predictive Biomarkers. Eur Urol. Oct 2019; 76 (4): 459-460.
  30. Pérez-Gracia JL, Castellano D, Climent MÁ, Mellado B, Suárez C. Best treatment options for advanced renal cell carcinoma (RCC) patients: a Delphi consensus study. Med Oncol. 2019 Mar; 19; 36 (3):29.
  31. Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov; 25(11): 1706-1714.
  32. Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, Aversa C, Figueiredo I, Fraser J, Ahmad Z, Lu CX, Rescigno P, Kolinsky M, Bertan C, Seed G, Riisnaes R, Miranda S, Crespo M, Pereira R, Ferreira A, Fowler G, Ebbs B, Flohr P, Neeb Antje, Bianchini D, Petremolo A, Sumanasuriya S, Paschalis A, Mateo J, Tunariu N, Yuan W,  Carreira S, Plymate SR, Luo J, de Bono JS. Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. Eur Urol. Nov 2019; 76 (5): 676-685.
  33. De Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wulfing C,Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B,  Sverrisdottir A, Theodore C,  Feyerabend S, Helissey C, Ozatilgan  A, Geffriaud-Ricouard C, Castellano D, CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. Dec 2019; 381 (26): 2506-2518.
  34. Khaki AR, Li A, Diamantopoulos LN, Bilen MA, Santos V, Esther J, Morales-Barrera R, Devitt M, Nelson A, Hoimes CJ, Shreck E, Assi H, Gartrell BA, Sankin A, Rodriguez-Vida A, Lythgoe M, Pinato DJ, Drakaki A, Joshi M, Isaacsson Velho P, Hahn N, Liu S, Alonso Buznego L, Duran I, Moses M, Jain J, Murgic J, Baratam P, Barata P, Tripathi A, Zakharia Y, Galsky MD, Sonpavde G, Yu EY, Shankaran V, Lyman GH, Grivas P. Impact of performance status on treatment outcomes: A real-world study of advanced urothelial cancer treated with checkpoint inhibitors. Cancer. 2019, Dec 12. doi: 10.1002/cncr.32645. [Epub ahead of print].
  35. Serrano C, Leal A, Kuang Y, Morgan JA, Barysauskas CM, Phallen  J, Triplett O, Marino-Enriquez A,  Wagner Andrew J, Demetri GD, Velculescu VE, Paweletz C,  Fletcher JA, George S. Phase I study of rapid alternation of sunitinib and regorafenib for the treatment of tyrosine kinase inhibitor refractory gastrointestinal stromal tumors. Clin Can Res. Dec 2019; 25 (24): 7287 – 7293.

Clinical Trials

  • pREdiction of niVOLUmab acTION in metastatic renal cancer patients: Treg function, tumoral access and NK interactions as predictive biomarkers of immunotherapy.ERA-NET Transcan 2015. GCB14-2170.
  • Coordinator: Stefania Scala – Istituto Nazionale per lo studio e la cura dei tumori di Napoli) Partner 3: Vall d’Hebron Institute of Oncology (VHIO). PI: Joan Carles.
  • A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone. PI: Joan Carles.
  • PROSTRATEGY: A multi-arm, multi-stage, randomized phase II/III trial of immunotherapy strategies in metastatic hormone-sensitive prostate cancer. PI: Joan Carles.
  • A Phase 1/2 open-label, multi-center, dose-escalation study of safety, tolerability, pharmacokinetics, dosimetry, and response to repeat dosing of 177Lu-PSMA-R2 radio-ligand therapy in patients with prostate specific membrane antigen (PSMA) positive (68Ga-PSMA-R2) progressive metastatic castration-resistant prostate cancer, following previous systemic treatment. PI: Joan Carles.
  • Estudio en Fase III, Aleatorizado, Doble Ciego, Controlado con Placebo de Talazoparib con Enzalutamida en el Cáncer de Próstata Metastásico Resistente a la castración. PI: Joan Carles.
  • A phase 2, randomized, double-blind, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer. PI: Joan Carles.
  • Estudio de fase 3, aleatorizado y abierto de pembrolizumab (MK-3475) más olaparib frente a acetato de abiraterona o enzalutamida en participantes con cáncer de próstata resistente a la castración metastásico (CPRCm) que no son seleccionados por defectos en la reparación por recombinación homóloga y que han mostrado fracaso con el tratamiento previo con un fármaco hormonal de última generación (FHUG) y quimioterapia (KEYLYNK-010). PI: Joan Carles.
  • A phase ib, open-label, multicenter study evaluating the safety and efficacy of ipatasertib in combination with rucaparib in patients with advanced breast, ovarian, or prostate cancer. PI: Joan Carles.
  • Estudio observacional para describir retrospectivamente la evolución de los pacientes con cáncer de próstata a lo largo de la enfermedad a través de la reutilización de los registros electrónicos de salud con inteligencia artificial. Estudio OVERVIEW. PI: Joan Carles.
  • IROMAN: International Registry for Men with Advanced Prostate Cancer (IRONMAN). Movember Foundation. PI: Joaquin Mateo.
  • A Multicenter, Randomized, Open-Label, Two-Arm, Phase II Clinical Trial of enZalutamide and talaZoparib for the Treatment of metastatic hormone-naïve PCa‒ The ZZ-First Study. Ref WP2134370. PI: Joaquin Mateo.
  • A non-randomized, multicenter, Phase Ib/II study of the selective inhibitor of nuclear export Selinexor (KPT-330) in combination with imatinib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) refractory to imatinib, sunitinib and regorafenib. Degree of contribution: Coordinator of total project, network or consortium. PI: César Serrano.

Gynecological Malignancies Group

Ana Oaknin
Principal Investigator
Biosketch
Principal Investigator Ana Oaknin Medical Oncologists Lorena Fariñas Francisco Grau

Summary

Our clinical research group focuses on gynecological malignancies and the development of novel therapies against these tumor types. We are also members of some of the most relevant societies in gynecological oncology including the Gynecologic Cancer InterGroup (GCIG) for which we are appointed as the Spanish Representative on the Cervical Cancer as well as phase II trial Committees, the Gynecologic Oncology Group (GOG), as the Spanish clinical lead, as well as the European Network of Gynecological Oncology Trial Groups (ENGOT).

Our group contributes to the advancement of the treatment of gynecological malignancies. Over the past few years, we have participated in the development of a number of therapies that constitute the current standard of care in different malignancies. As an example, our PI, Ana Oaknin, is one of the co-authors of the SOLO-1 trial (Olaparib as maintenance therapy in BRCA mut Ovarian Cancer patients) – Moore et al. N Engl J Med. 2018. This clinical trial has changed first line therapy for those patients diagnosed with ovarian cancer harboring a BRCA mutation.

In 2019 we have participated in several important clinical trials that have generated new and compelling data in gynecologic malignancies. As an example, we co-authored a study showing that the addition of veliparib to standard chemotherapy based on paclitaxel/carboplatin, and as maintenance therapy, significantly prolonged progression free survival of all our patients recently diagnosed with high-grade ovarian cancer (Coleman RL et al. N Engl J Med. 2019).

As part of our evolving knowledge on PARPi and mechanisms of resistance, our deep liquid biopsy analysis performed on patients’ blood samples collected during their participation in the ARIEL-2 study, has enabled us to identify BRCA reversion mutations as one of the key players (Lin KK et al. Cancer Discov. 2019).

While metastatic cervical cancer is a devastating disease, over recent years we have succeeded in broadening our therapeutic approaches which have mainly been driven by immunotherapy. We have been studying the role of the anti-PD1 molecule nivolumab in those patients who have progressed after failure to respond to platinum therapy. We have observed encouraging activity in this patient population with a notoriously poor prognosis which certainly warrants further investigation (Naumann RW et al. J Clin Oncol. 2019).

In addition, our Principal Investigator, Ana Oaknin, also serves on the Executive Board as Vice President for the Grupo Español de Investigación en Cáncer de Ovario – GEICO (the Spanish Ovarian Cancer Research Group), and as Faculty of the European Society for Medical Oncology’s (ESMO) Annual Meeting’s Gynecological Tumors Track, for which she was appointed as the Track Chair at the ESMO Congress 2019 (Barcelona, Spain, 27 September-01 October), where she discussed the selected presentations of the Track’s Presidential Symposium.


Strategic goals

  • Determine the best treatment approaches against advanced gynecologic malignancies through optimally designed international clinical trials.
  • Contribute to early drug development in gynecologic cancers.
  • Expand our translational research program to advance precision medicine.
  • Specifically, we strive to:
    • Further develop novel immunotherapeutics for the treatment of endometrial cancer and cervical cancer.
    • Apply cellular therapy to metastatic cervical cancer through the adoptive cell transfer of tumor infiltrating lymphocytes (TILs).
  • Consolidate our position as a reference site for clinical research in gynecologic malignancies.
  • Continue to be a referral center for patients who seek to participate in our clinical studies.

Highlights

Our group continues to take the lead on other clinical trials that might define the next generation of treatment regimens, including:
  • Ana Oaknin signed the FDA filling of dostarlimab (PD-1 inhibitor) in MSI-H recurrent endometrial cancer after successfully presenting the results of the clinical trial included in the file at the Society of Gyencologic Oncology’s (SGO) 2019 Annual Meeting (Honolulu, Hawaii, March 16-19).
  • Ana is global lead of a phase III Investigator initiated trial for first line metastatic cervical cancer (the BEATcc trial) running in USA, EU and Japan. She is also the European lead investigator of the EMPOWER trial, a phase III study aimed at testing cemiplimab in recurrent cervical cancer. Both of these trials promise potentially practice-changing data.
  • She is also the lead investigator of the ATOMICC Trial to investigate the role of dostarlimab as maintenance therapy in locally advanced cervical cancer.
These efforts have positioned Ana Oaknin as a Key Opinion Leader in our field which is also reflected by her participation at some of the largest, global oncology conferences and meetings.

Awards and Recognition

  • Ana Oaknin delivered the Plenary Presentation at the Society of Gynecological Oncology’s (SGO) Annual Meeting 2019 (Honolulu, Hawaii, March 16-19), presenting the results on dostarlimab for the treatment of endometrial cancer. These results have subsequently led to a request of approval to the U.S. Food and Drug Administration (FDA). Ana Oaknin has signed the Clinical Science file supporting this request.
  • She also served as Chair of Gynecological Tumors Track at the European Society for Medical Oncology’s Annual Congress 2019 (Barcelona, Spain, 27 September – 01 October). Moreover, she was also Discussant of the Track’s Presidential Symposium where the results of two Phase III trials were presented. It is important to highlight that the results of both studies were simultaneously published inTheNew England Journal of Medicine(NEJM), and one of the drugs involved (niraparib) has already been approved for the treatment of ovarian cancer.

PI paper pick

  • Lin KK, Harrell MI, Oza AM, Oaknin A, Ray-Coquard I, Tinker AV, Helman E, Radke MR, Say C, Vo LT, Mann E, Isaacson JD, Maloney L, O'Malley DM, Chambers SK, Kaufmann SH, Scott CL, Konecny GE, Coleman RL, Sun JX, Giordano H, Brenton JD, Harding TC, McNeish IA, Swisher EM. BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov. 2019 Feb;9(2):210-219.
  • Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, López-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019 Nov 1;37(31):2825-2834.
  • Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019 Jan 12;393(10167):169-182. Review.
  • Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, Okamoto A, Moore KN, Efrat Ben-Baruch N, Werner TL, Cloven NG, Oaknin A, DiSilvestro PA, Morgan MA, Nam JH, Leath CA 3rd, Nicum S, Hagemann AR, Littell RD, Cella D, Baron-Hay S, Garcia-Donas J, Mizuno M, Bell-McGuinn K, Sullivan DM, Bach BA, Bhattacharya S, Ratajczak CK, Ansell PJ, Dinh MH, Aghajanian C, Bookman MA. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2403-2415.

Full list of Publications

  1. I, Martin-Liberal J, Garcia-Ruiz A, Hierro C, Ochoa de Olza M, Viaplana C, Azaro A, Vieito M, Brana I, Mur G, Ros J, Mateos J, Villacampa G, Berché R, Oliveira M, Alsina M, Élez E, Oaknin A, Muñoz-Couselo E, Carles J, Felip E, Rodon J, Tabernero J, Dienstmann R, Perez-Lopez R, Garralda E. Capturing Hyperprogressive disease with immune checkpoint inhibitors using RECIST 1.1 criteria.Clin Cancer Res. 2019 Nov 22. pii: clincanres.2226.2019. doi: 10.1158/1078-0432.CCR-19-2226
  2. Rodriguez-Freixinos V, Fariñas-Madrid L, Gil-Martin M, Barretina-Ginesta P, Romeo M, Villacampa G, Pardo B, Ahmed H, Recalde S, Piulats JM, Gomez-Plaza MC, Gil-Moreno A, Sala E, Martínez-Roman S, Ponce J, Melendez C, Carballas E, Dienstmann R, Oaknin A. Corrigendum to 'Chemotherapy and PARP inhibitors in heavily pretreated BRCA1/2 mutation ovarian cancer (BMOC) patients' Gynecologic Oncology 152 (2019) 270-277].Gynecol Oncol. 2019 Nov 16.
  3. Kristeleit RS, Oaknin A, Ray-Coquard I, Leary A, Balmaña J, Drew Y, Oza AM, Shapira-Frommer R, Domchek SM, Cameron T, Maloney L, Goble S, Lorusso D, Ledermann JA, McNeish IA. Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety. Int J Gynecol Cancer. 2019 Nov;29(9):1396-1404. doi: 10.1136
  4. Grau JF, Farinas-Madrid L, Oaknin A. A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030).Int J Gynecol Cancer. 2019 Oct 23. pii: ijgc-2019-000880. doi: 10.1136.
  5. Drew Y, Kristeleit RS, Oaknin A, Ray-Coquard I, Haris NM, Swisher EM. Real-World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10.Oncologist. 2019 Oct 1. pii: theoncologist.2019-0229. doi: 10.1634.
  6. Drew Y, Kristeleit RS, Oaknin A, Ray-Coquard I, Haris NM, Swisher EM.Real-World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10. Oncologist. 2019 Oct 1. pii: theoncologist.2019-0229. doi: 10.1634/theoncologist.2019-0229.
  7. Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, Okamoto A, Moore KN, Efrat Ben-Baruch N, Werner TL, Cloven NG, Oaknin A, DiSilvestro PA, Morgan MA, Nam JH, Leath CA 3rd, Nicum S, Hagemann AR, Littell RD, Cella D, Baron-Hay S, Garcia-Donas J, Mizuno M, Bell-McGuinn K, Sullivan DM, Bach BA, Bhattacharya S, Ratajczak CK, Ansell PJ, Dinh MH, Aghajanian C, Bookman MA.Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa190970.
  8. Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, López-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial.J Clin Oncol. 2019 Sep 5: JCO1900739. doi: 10.1200/JCO.19.00739.
  9. Mateo J, Lord CJ, Serra V, Tutt A, Balmaña J, Castroviejo-Bermejo M, Cruz C, Oaknin A, Kaye SB, de Bono JS.A decade of clinical development of PARP inhibitors in perspective. Ann Oncol. 2019 Jun 20.
  10. Liu JF, Gordon M, Veneris J, Braiteh F, Balmanoukian A, Eder JP, Oaknin A, Hamilton E, Wang Y, Sarkar I, Molinero L, Fassò M, O'Hear C, Lin YG, Emens LA. Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol Oncol. 2019 Jun 13.
  11. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, Raspagliesi F, Sonke GS, Birrer M, Provencher DM, Sehouli J, Colombo N, González-Martín A, Oaknin A, Ottevanger PB, Rudaitis V, Katchar K, Wu H, Keefe S, Ruman J, Ledermann JA. Antitumor Activity and Safety of Pembrolizumab in Patients with Advanced Recurrent Ovarian Cancer: Results from the Phase 2 KEYNOTE-100 Study. Ann Oncol.2019 May 2.
  12. Rodriguez-Freixinos V, Ruiz-Pace F, Fariñas-Madrid L, Garrido-Castro AC, Villacampa G, Nuciforo P, Vivancos A, Dienstmann R, Oaknin A. Genomic heterogeneity and efficacy of PI3K pathway inhibitors in patients with gynaecological cancer.ESMO Open. 2019 Mar 8.
  13. Felip I, Moiola CP, Megino-Luque C, Lopez-Gil C, Cabrera S, Solé-Sánchez S, Muñoz-Guardiola P, Megias-Roda E, Pérez-Montoyo H, Alfon J, Yeste-Velasco M, Santacana M, Dolcet X, Reques A, Oaknin A, Rodríguez-Freixinos V, Lizcano JM, Domènech C, Gil-Moreno A, Matias-Guiu X, Colas E, Eritja N. Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer. Gynecol Oncol. 2019 Mar 7. pii: S0090-8258(19)30150-7.
  14. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer.Lancet. 2019 Jan 12;393(10167):169-182. doi: 10.1016/S0140-6736(18)32470-X. Review.

Clinical Trials

  • Protocol: R2810-ONC-1676/GOG-3016 (CVP1601).AN OPEN-LABEL, RANDOMIZED, PHASE 3 CLINICAL TRIAL OF REGN2810 VERSUS THERAPY OF NVESTIGATOR'S CHOICE CHEMOTHERAPY IN RECURRENT OR METASTATIC PLATINUMREFRACTORY  CERVICAL CARCINOMA. ENGOT PI
  • Protocol: ENGOT-Cx10/GEICO 68-C/ BEAT cc. A Randomized Phase III Trial of Platinum Chemotherapy plus Paclitaxel with Bevacizumab and Atezolizumab versus Platinum Chemotherapy plus Paclitaxel and Bevacizumab in Metastatic (stage IVB), Persistent, or Recurrent Carcinoma of the Cervix. GLOBAL PI
  • Protocol: GEICO 78-C ATOMICC. A randomized, open label, phase II trial of Anti-PD1, TSR-042, as maintenance therapy for patients with high-risk locally advanced cervical cancer after chemo-radiation. GLOBAL PI
  • Protocol:TOPIC VHIO17001. Phase II trial of Pembrolizumab in combination with Doxorubicin in Advanced, Recurrent or Metastatic Endometrial CancerTOPIC. GLOBAL PI
  • Protocol: GINECO-OV236b. A randomized, double blinded, phase III study of atezolizumab versus placebo in patients with late relapse of epithelial ovarian, fallopian tube, or peritoneal cancer treated by platinum-based chemotherapy and bevacizumab. Principal Investigator 2017.

Hereditary Cancer Genetics Group

Judith Balmaña
Principal Investigator
Biosketch
Principal Investigator Judith Balmaña Senior Scientists Orland Díez, Sara Gutiérrez Enríquez Post-Doctoral Fellow Sandra Bonache Graduate Students Ester Aguado, Joanna Domènech, Alejandro Moles, Clinical Nurse Specialist, Neus Gadea Genetic Counselors Estela Carrasco , Adria Lopez Auxiliary Clinician Carmen Aguilar Data Curator Sara Torres

Summary

We focus on the clinical development of PARP inhibitors (PARPi) in early gBRCA1/2 breast cancer and novel combinations in the advanced setting. The consolidation of our collaboration with VHIO’s Experimental Therapeutics Group, led by Violeta Serra, has resulted in a large collection of BRCA1/2-associated patient-derived xenografts (PDX) implanted in athymic mice. We are using these murine models to identify mechanisms of resistance to targeted therapies, identify novel biomarkers, and assess new combinatorial treatments at progression. We have identified a functional biomarker for PARPi sensitivity that has been tested preclinically and in human samples, and we are now collecting samples for a larger clinical validation.

Our group is also interested in unravelling the challenges of implementing the advances in diagnosis of hereditary cancer susceptibility and applying these insights to clinical practice. In partnership with the hereditary cancer program at the Catalan Institute of Oncology (ICO), we are investigating the genetic complexity of hereditary cancer through the multidimensional analysis of a customized panel, as well as the psychological impact in our population. Ongoing research centers on the role of personality traits in predicting the psychological impact of genetic results and the uptake of prevention strategies. We have recently received funding to assess genome-based cancer risk estimation and cancer-risk adapted approaches incorporating polygenic risk score (PRS) analysis. A longitudinal national-based registry of mutation carriers incorporates prospective data for the analysis of health outcomes.

We pursue our interest in the genetic epidemiology of hereditary breast and ovarian cancer (HBOC) in collaboration with Senior Scientist of our group, Sara Gutiérrez-Enríquez. This joint research has shed important light on the characterization of new pathogenic variants in HBOC genes, and provided discriminatory tools to interpret variants of uncertain significance in BRCA genes. Our group is devoted to deciphering the role of intronic, splicing, and missense variants in major HBOC genes and investigate the yield of long-read RNA-seq. Sara Gutiérrez-Enríquez is also independently leading research into predictive genetic and cellular markers for susceptibility to radiotherapy-induced clinical toxicity.


BRCA1 c.4185+4105C>T characterisation in patient RNA. (A): QIAxcel electrophoresis of RT -PCR assay covering exons 11–13 (275 bp). An extra band of ~400 bp was detected in variant carrier (ins114nt), not present in controls. (B): Sanger electropherogram showing allelic imbalance at polymorphisms c.4308T>C and c.4837A>G. (C): Sanger sequencing confirmed the insertion of 114 nucleotides (nt) between exons 12 and 13, generating a new transcript that we annotated as ▾12A (r.4185_4186ins4185+3990_4185+4103). This transcript is predicted to encode for a truncated BRCA1 protein (p.Gln1395_Gln1396insSerLysSerLeu*).

Strategic goals

  • Characterization of new hereditary breast and ovarian cancer (HBOC) genes, psychological impact of multigene testing, and feasibility of Polygenic Risk Score (PRS) in HBOC.
  • Targeting DNA damage response in breast cancer and implementing our RAD51 assay as a clinical biomarker for PARPi therapy.
  • Evaluation of the preventive effect of denosumab on breast cancer prevention in BRCA1 mutation carriers (BRCA-P trial).
  • New disease models and diagnostic tools for head and neck squamous cell carcinoma in Fanconi Anemia patients.
  • Unravel the genetic diagnosis of HBOC.
  • Identify cellular and genomic biomarkers as predictors of late toxicity after radiotherapy.

Highlights

  • In 2019 we published a part of our work analyzing the complexity of hereditary cancer susceptibility through multidimensional analysis in our population. As a result, phenotype-driven panels with opportunistic testing of BRCA1/2 and MMR genes have been implemented in our national health system. Simultaneously, we initiated our longitudinal registry of mutations carriers in new genes and are investigating personality traits as predictors of the psychological impact of multigene testing, especially regarding uncertainty.
  • We have received funding through several competitive grants to study the RAD51Predict assay as a functional biomarker of homologous recombination repair deficiency and predictor of PARPi resistance.
  • Our group has published findings on the role of spliceogenic variants and its pathogenicity in BRCA genes, and the incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in these genes. We have described the first pathogenic deep intronic BRCA1 variant that results in loss of function explaining part of the missing genetic susceptibility to breast and ovarian cancer.
  • We have developed a specific in silico predictor for BRCA1/2 to evaluate the effect of genetic variants with uncertain clinical significance. The predictive software is freely available online at: https://www.biotoclin.org/BRASS#about. Our computational algorithm was presented at the latest edition of the international CAGI Challenge (Critical Assessment of Genome Interpretation https://genomeinterpretation.org/content/BRCA1_BRCA2), and our methodology was ranked in second place.
  • We are now participating in the RADprecise - Personalized radiotherapy: Incorporating cellular response to irradiation in personalized treatment planning to minimise radiation toxicity. This collaborative project launched in 2019 and is supported through funding received from ERAPerMed.
  • We are leading the search for clinically relevant microRNAs as novel biomarkers for radiosensitivity.
  • Two PhD theses were defended in 2019.

Horizons

  • Characterization of new HBOC genes, psychological impact of multigene testing, and feasibility of PRS in HBOC:
    • Characterization of RAD51C/Dgermline mutation carriers in the Spanish population.
    • Cancer penetrance and phenotype of PALB2 germline mutations.
    • Analysis of personality traits to predict psychological impact and cancer-risk reduction strategies.
    • Feasibility and mediation analysis of PRS to improve cancer risk estimation and risk-adapted strategies in HBOC.
  • Targeting DNA damage response in BC and implement RAD51 assay as a clinical biomarker for PARPi therapy:
    • Clinical development of PARPi in combination with other DDR agents or immunotherapy.
    • Clinical validation of RAD51 assay.
  • Evaluation of the preventive effect of denosumab on breast cancer prevention in BRCA1 mutation carriers (BRCA-P trial).
  • New disease models and diagnostic tools for head and neck squamous cell carcinoma in Fanconi Anemia patients.
  • Unravelling the genetic diagnosis of HBOC:
    • Unveil the pathogenicity of VUS, new mechanisms of gene inactivation, and new genes in HBOC.
    • Identify cellular and genomic biomarkers as predictors of late toxicity after radiotherapy
    • Clinically relevant microRNAs as novel biomarkers of radiosensitivity.

Awards and Recognition

  • Gemma Montalban Canudas, formerly a Graduate Student in our group and now a postdoctoral researcher at the Genome Stability Laboratory, Laval University Cancer Research Center (Quebec, Canada), was awarded a PhD for her work entitled: Molecular analysis and clinical interpretation of alternative mRNA transcripts and altered splicing in hereditary breast/ovarian cancer genes.
  • Irene Esteban was awarded a PhD for her work entitled: Clinical application of cancer gene panels: characterization of genetic variants and psychological impact.
  • Sara Gutiérrez-Enríquez was accredited by the Spanish Association of Human Genetics.
  • Judith Balmaña was re-accredited as an expert in hereditary cancer by the Spanish Society of Medical Oncology (SEOM).

PI paper pick

  • Montalban G, Bonache S, Moles-Fernández A, Gisbert-Beamud A, Tenés A, Bach V, Carrasco E, López-Fernández A, Stjepanovic N, Balmaña J, Diez O, Gutiérrez-Enríquez S. Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer. J Med Genet. 2019 Feb;56(2):63-74.
  • Padilla N, Moles-Fernández A, Riera C, Montalban G, Özkan S, Ootes L, Bonache S, Díez O, Gutiérrez-Enríquez S, de la Cruz X. BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge. Hum Mutat. 2019 Sep;40(9):1593-1611.
  • Montalban G, Bonache S, Moles-Fernández A, Gadea N, Tenés A, Torres-Esquius S, Carrasco E, Balmaña J, Diez O, Gutiérrez-Enríquez S. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. Hum Mutat. 2019 Dec;40(12):2296-2317. (Editor’s Choice).
  • Feliubadaló L, López-Fernández A, Pineda M, Díez O, Del Valle J,Gutiérrez-Enríquez S, Teulé A, González S, Stjepanovic N, Salinas M, Capellá G,Brunet J, Lázaro C, Balmaña J; Catalan Hereditary Cancer Group. Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype-driven hereditary cancer gene panels. Int J Cancer. 2019 Nov15;145 (10): 2682-2691.

Full list of Publications

  1. Montalban G, Bonache S, Moles-Fernández A, Gadea N, Tenés A, Torres-Esquius S, Carrasco E, Balmaña J, Diez O, Gutiérrez-Enríquez S. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. Hum Mutat. 2019 Dec;40(12):2296-2317. (Editor’s Choice).
  2. Singer CF, Balmaña J, Bürki N, Delaloge S, Filieri ME, Gerdes AM, Grindedal EM, Han S, Johansson O, Kaufman B, Krajc M, Loman N, Olah E, Paluch-Shimon S, Plavetic ND, Pohlodek K, Rhiem K, Teixeira M, Evans DG. Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer-an European consensus statement and expert recommendations. Eur J Cancer. 2019 Jan.
  3. Rutgers E, Balmana J, Beishon M, Benn K, Evans DG, Mansel R, Pharoah P, Perry Skinner V, Stoppa-Lyonnet D, Travado L, Wyld L.European breast cancer council manifesto 2018: Gentic risk prediction testing in breast cancer. Eur J Cancer. 2019 Jan;106:45-53. doi: 10.1016/j.ejca.2018.09.019. Epub 2018 Nov 22.
  4. Esteban I, Lopez-Fernandez A, Balmaña J. A narrative overview of the patients' outcomes after multigene cancer panel testing, and a thorough evaluation of its implications for genetic counselling. Eur J Med Genet. 2018 Nov 23. pii: S1769-7212(18)30422-1.
  5. Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke EM, Mina LA, Balmaña J, Fasching PA, Hurvitz SA, Wardley AM, Chappey C, Hannah AL, Robson ME; ABRAZO Study Group. A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin Cancer Res. 2019 May 1;25(9):2717-2724. doi: 10.1158/1078-0432. CCR-18-18
  6. .
  7. González-Santiago S, Ramón Y Cajal T, Aguirre E, Alés-Martínez JE, Andrés R, Balmaña J, Graña B, Herrero A, Llort G, González-Del-Alba A; SEOM Hereditary Cancer Working Group. SEOM clinical Guidelines in hereditary breast and ovarian cancer (2019) Clin Transl Oncol. 2019 Dec 30. doi: 10.1007/s12094-019-02262-0
  8. .
  9. Mateo J, Lord CJ, Serra V, Tutt A, Balmaña J, Castroviejo-Bermejo M, Cruz C, Oaknin A, Kaye SB, de Bono JS. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol. 2019 Sep 1;30(9):1437-1447. doi:10.1093/annonc/mdz192.
  10. Gómez-Miragaya J, Díaz-Navarro A, Tonda R, Beltran S, Palomero L, Palafox M, Dobrolecki LE, Huang C, Vasaikar S, Zhang B, Wulf GM, Collado-Sole A, Trinidad EM, Muñoz P, Paré L, Prat A, Bruna A, Caldas C, Arribas J, Soler-Monso MT, Petit A, Balmaña J, Cruz C, Serra V, Pujana MA, Lewis MT, Puente XS, González-Suárez E. Chromosome 12p amplification in triple negative/BRCA1 mutated breast cancer associates with emergence of docetaxel resistance and carboplatin sensitivity. Cancer Res. 2019 Aug 15;79(16):4258-4270. doi: 10.1158/0008-5472.CAN-18-3835. Epub 2019 Jun 18.
  11. Cline MS, Babbi G, Bonache S, Cao Y, Casadio R, de la Cruz X, Díez O, Gutiérrez-Enríquez S, Katsonis P, Lai C, Lichtarge O, Martelli PL, Mishne G,Moles-Fernández A, Montalban G, Mooney SD, O'Conner R, Ootes L, Özkan S, Padilla N, Pagel KA, Pejaver V, Radivojac P, Riera C, Savojardo C, Shen Y, Sun Y, Topper S, Parsons MT, Spurdle AB, Goldgar DE; ENIGMA Consortium. Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants. Hum Mutat. 2019 Sep;40(9):1546-1556
  12. .
  13. Wang Y, Bernhardy AJ, Nacson J, Krais JJ, Tan YF, Nicolas E, Radke MR, Handorf E, Llop-Guevara A, Balmaña J, Swisher EM, Serra V, Peri S, Johnson N. BRCA1 intronic ALu elements drive gen mrearrangemetns and PARPinhibitor resistance. Nat Commun. 2019 Dec 11;10(1):5661. doi: 10.1038/s41467-019-13530-6.
  14. Seibold P, Webb A, Aguado-Barrera ME, Azria D, Bourgier C, Brengues M, Briers E, Bultijnck R, Calvo-Crespo P, Carballo A, Choudhury A, Cicchetti A, Claßen J,Delmastro E, Dunning AM, Elliott RM, Fachal L, Farcy-Jacquet MP, Gabriele P,Garibaldi E, Gómez-Caamaño A, Gutiérrez-Enríquez S, Higginson DS, Johnson K,Lobato-Busto R, Mollà M, Müller A, Payne D, Peleteiro P, Post G, Rancati T,Rattay T, Reyes V, Rosenstein BS, De Ruysscher D, De Santis MC, Schäfer J,Schnabel T, Sperk E, Symonds RP, Stobart H, Taboada-Valladares B, Talbot CJ, Valdagni R, Vega A, Veldeman L, Ward T, Weißenberger C, West CML, Chang-Claude J; REQUITE consortium. REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer. Radiother Oncol. 2019 Sep;138:59-67.
  15. Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, …., Diez O,….., Gutiérrez-Enríquez S, …., Spurdle AB. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578.
  16. Padilla N, Moles-Fernández A, Riera C, Montalban G, Özkan S, Ootes L, Bonache S, Díez O, Gutiérrez-Enríquez S, de la Cruz X. BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge. Hum Mutat. 2019 Sep;40(9):1593-1611.
  17. Feliubadaló L, López-Fernández A, Pineda M, Díez O, Del Valle J, Gutiérrez-Enríquez S, Teulé A, González S, Stjepanovic N, Salinas M, Capellá G, Brunet J, Lázaro C, Balmaña J; Catalan Hereditary Cancer Group. Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels. Int J Cancer. 2019 Nov 15;145(10):2682-2691
  18. .
  19. Brandão RD, Mensaert K, López-Perolio I, Tserpelis D, Xenakis M, Lattimore V, Walker LC, Kvist A, Vega A, Gutiérrez-Enríquez S, Díez O; KConFaB Investigators, de la Hoya M, Spurdle AB, De Meyer T, Blok MJ. Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes. Int J Cancer. 2019 Jul 15;145(2):401-414.
  20. Duran-Lozano L, Montalban G, Bonache S, Moles-Fernández A, Tenés A, Castroviejo-Bermejo M, Carrasco E, López-Fernández A, Torres-Esquius S, Gadea N, Stjepanovic N, Balmaña J, Gutiérrez-Enríquez S, Diez O. Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T. Breast Cancer Res Treat. 2019 Apr;174(2):543-550.
  21. Montalban G, Bonache S, Moles-Fernández A, Gisbert-Beamud A, Tenés A, Bach V,  Carrasco E, López-Fernández A, Stjepanovic N, Balmaña J, Diez O, Gutiérrez-Enríquez S. Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer. J Med Genet. 2019 Feb;56(2):63-74.
  22. Johnson K, Chang-Claude J, Critchley AM, Kyriacou C, Lavers S, Rattay T, Seibold P, Webb A, West C, Symonds RP, Talbot CJ; REQUITE Consortium. Genetic Variants Predict Optimal Timing of Radiotherapy to Reduce Side-effects in Breast Cancer Patients. Clin Oncol (R Coll Radiol). 2019 Jan;31(1):9-16.
  23. Friebel TM, Andrulis IL, Balmaña J, Blanco AM, Couch FJ, Daly MB, Domchek SM, Easton DF, Foulkes WD, Ganz PA, Garber J, Glendon G, Greene MH, Hulick PJ, Isaacs C, Jankowitz RC, Karlan BY, Kirk J, Kwong A, Lee A, Lesueur F, Lu KH, Nathanson KL, Neuhausen SL, Offit K, Palmero EI, Sharma P, Tischkowitz M, Toland AE, Tung N, van Rensburg EJ, Vega A, Weitzel JN, Collaborators GS, Hoskins KF, Maga T, Parsons MT, McGuffog L, Antoniou AC, Chenevix-Trench G, Huo D, Olopade OI, Rebbeck TR. BRCA1 and BRCA2 pathogenic sequence variants inwomen of African origin or ancestry. Hum Mutat. 2019 Oct;40(10):1781-1796. doi: 10.1002/humu.23804. Epub 2019 Jul 3.
  24. Gourley C, Balmaña J, Ledermann JA, Serra V, Dent R, Loibl S, Pujade-Lauraine E, Boulton SJ.Moving from Poly(ADP-ribose) Polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy. J Clin Oncol. 2019 Sep 1;37(25):2257-2269. doi: 10.1200/JCO.18.02050. Epub 2019 May 3.
  25. Ferreira MA, Gamazon ER, Al-Ejeh F, Aittomäki K, Andrulis IL, Anton-Culver H, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Azzollini J, Balmaña J,…Chenevix-Trench G. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nat Commun. 2019 Apr 15;10(1):1741. doi: 10.1038/s41467-018-08053-5.

Projects

  • Project Title: Identification of new clinical phenotypes of hereditary cancer through multiplex panel testing, clinical and psychological impact.
    PI16/01363
    PI: Judith Balmaña
    Funding agency: ISCIII
    Duration: 2017-2020
  • Project Title: Towards an accurate estimation of cancer risk and individualization of medical management by applying the Polygenic Risk Score (PRS) in hereditary breast and ovarian cancer.
    PI19/01195
    PI: Judith Balmaña
    Funding agency: ISCIII
    Duration: 2020-2023
  • Project Title: Patient stratification based on DNA repair functionality for cancer precision medicine.
    Coordinator: Violeta Serra.
    Research Collaborators: Judith Balmaña and Sara Gutiérrez-Enríquez.
    Funding Agency: ERA PerMed (ERA Net)
    Duration: 2020-2022
  • Project Title: Liquid biopsies for the identification of mechanisms of resistance to PARP inhibitors in BRCA1/2-associated cancers.
    PI/Coordinator: Violeta Serra
    Research Collaborator: Judith Balmaña
    Funding Agency:LA MARATO TV3
    Duration: 2020-2022
  • Project Title: Comprehensive RNA expression and DNA repair functional analysis of clinically actionable hereditary breast/ovarian cancer genes in patients with uninformative multi-gene panel result. PI19/01303
    PI: Sara Gutiérrez-Enríquez
    Funding Agency: Instituto De Salud Carlos III
    Duration: 2020-2023
  • Project Title: RADprecise Personalized radiotherapy: incorporating cellular response to irradiation in personalized treatment planning to minimize radiation toxicity.
    PI: Sara Gutiérrez-Enríquez
    Funding Agency:ERA PerMed
    Duration: 2019-2021 
  • Project Title: Discovery of new genes and genetic variants in hereditary cancer: functional studies, regulation of splicing and population frequency of variants for application in the clinic.
    PI16/01218
    PI:Sara Gutiérrez-Enríquez
    Funding Agency: Instituto De Salud Carlos III
    Duration: 2017-2020
  • Project Title:Prospective SEOM-registry of new cancer susceptibility gene mutation carriers in hereditary cancer.
    Judith Balmaña
    Funding agency: FUNDACIÓN SEOM
    Duration: 2020-2021
  • Project Title: Development of a liquid biopsy test to assess the homologous recombination function status in BRCA1/2 mutation carriers with breast cancer to inform therapy selection.
    PIs: Judith Balmaña, Violeta Serra
    Funding Agency:FERO
    Duration: 2019-2021
  • Project Title: Analysis of the pathogenic effect of genetic variants in regulatory (promoter, 5'UTR and 3'UTR) and intronic regions of BRCA1, BRCA2 and other genes of susceptibility to breast and ovarian cancer.
    PI15/00355
    PI: Orland Diez
    Funding Agency: Instituto de Salud Carlos III.
    Duration: 2016-2019

Clinical Trials

  • Ensayo fase III, multicéntrico, aleatorizado, doble ciego, de grupos paralelos, controlado con placebo, para evaluar la eficacia y la seguridad de olaparib frente a placebo como tratamiento adyuvante en pacientes con cáncer de mama HER2 negativo de alto riesgo y mutaciones germinales de BRCA1/2, que han finalizado el tratamiento local y la quimioterapia neoadyuvante o adyuvante. OLYMPIA trial, D081CC00006
  • “LUCY - Lynparza Breast Cancer Real-World Utility, Clinical Effectiveness and Safety Study. A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Monotherapy in the Treatment of HER2-ve Metastatic Breast Cancer Patients with Germline BRCA1/2 Mutations”. D0816C00018
  • VIOLETTE: A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination with Olaparib versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-related Genes (including BRCA1/2). D5336C00001

Oncology Data Science (ODysSey) Group

Rodrigo Dienstmann
Principal Investigator
Biosketch
Principal Investigator Rodrigo Dienstmann Biostatistician Guillermo Villacampa Biomedical Engineer Anna Pedrola Data Curators Raquel Comas, Magdalena Guardiola, Fiorella Ruiz, Sara Torres, Cristina Viaplana

Summary

VHIO's ODysSey Group promotes translational research in precision oncology by integrating cancer molecular profiling data with clinical outcomes of oncology patients treated at the Vall d’Hebron University Hospital (HUVH).

To explore big and real-world data, we design and maintain comprehensive clinical-molecular databases and provide operational support to investigators interested in correlative analyses for hypothesis-generation and biomarker validation. We also assist investigators in sample size calculation, clinical trial design and downstream statistical analyses.

Our team also participates in international multi-omic data analyses projects and foster collaborative research in computational oncology. We are dedicated to connecting cancer researchers working on predictive and prognostic modelling, the identification of cancer drivers, molecular subtyping, primary-metastasis heterogeneity, microenvironment signatures and druggability in solid tumors.

Molecular Prescreening Program

In 2019, our group, together with Susana Aguilar and Jenifer Gonzalez, and in collaboration with VHIO's Cancer Genomics Group led by Ana Vivancos, and Molecular Oncology Group, directed by Paolo Nuciforo, have performed tumor molecular profiling in over 1,100 cancer patients as candidates for enrollment in clinical trials. In total, 151 patients were treated with biomarker-matched innovative therapies as a result of this effort.

Interpretation of next-generation sequencing tests and educating clinicians on emerging biomarkers is another of our priority areas. During our Molecular Tumor Board meetings, we promote precision oncology by providing guidance regarding inclusion in early clinical trials with biomarker-guided targeted agents or immunotherapies.



Strategic goals

Facilitate clinical-molecular correlative studies at VHIO:
  • Development and maintenance of clinical-molecular databases as a resource for clinicians, molecular pathologists and translational investigators.
  • Provide guidance to medical oncologists and cancer biologists during the design and interpretation of biomarker correlative studies, as well as development and validation of omics-based tests that have direct clinical application.
  • Promote evidence-based medicine:
  • Continued medical education with standardized reports of genomic alterations and weekly Molecular Tumor Boards. We facilitate data exchange among a wide range of experts for the review of patients’ medical histories and cancer molecular profiles in order to more precisely guide treatment decisions.
Collaborative research on Big and Real-World Data:
  • Encourage interactions among computational oncology scientists and preclinical-clinical researchers to promote the identification of cancer subtypes and druggable drivers.
  • Generate large databases that allow the study of complex associations between tumor omics, drug sensitivities and patient outcome.

Highlights

  • We have provided support to VHIO's investigators working on clinical and preclinical research. This has resulted in several impactful publications in the field, oral presentations at top oncology conferences and statistical leadership in multiple phase 2 and 3 trials.
  • We have developed and explored tools that help translate the strong biological dependencies of colorectal cancer subtypes into druggability opportunities. We have also studied the impact of driver genes, transcriptomic subtypes and microenvironment features on prognosis of colorectal cancer patients.
  • Active member of the AACR Genomics Evidence Neoplasia Information Exchange (GENIE) project, a multi-phase, multi-year, international study that catalyzes precision oncology through the development of a regulatory-grade registry aggregating and linking clinical-grade cancer genomic data with clinical outcomes from tens of thousands of cancer patients treated at the participating institutions.
  • Co-development of the Molecular Tumor Board portal (MTBP), a clinical decision support system to select the most appropriate treatment for cancer patients based on genomics data, including clinical trial opportunities. The portal employs a variety of state-of-the-art tools to interpret the biological and clinical significance of tumor and germline alterations. The MTBP is regularly used in the Cancer Core Europe (CCE) Consortium’s Basket of Basket (BoB) trial, which is the first European multi-modular academic clinical trial in Europe and set to significantly advance basket trial design to-date by integrating molecular prescreening, the development of novel diagnostic tests including ctDNA, and assessing targeted therapies matched to those patients who will be most likely to benefit from them.
An open access version of our MTBP technology, developed under CCE’s umbrella, is available at: http://mtbp.org.

Horizons

  • Work at the intersection of digital health and data science for research and clinical applications.
  • Closely collaborate with our Research Unit for Molecular Therapy of Cancer (UITM) - ”la Caixa”, Molecular Oncology and Radiomics Groups to accelerate the research and implementation of cutting-edge data science models and technology platforms in the healthcare domain for the personalization of patient care at VHIO.
  • Cross-training and education in computational oncology, development of digital health solutions and web-mobile applications for investigators, care providers and patients.

PI paper pick

  • Dienstmann R, Villacampa G, Sveen A, Mason MJ, Niedzwiecki D, Nesbakken A, Moreno V, Warren RS, Lothe RA, Guinney J. Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann Oncol. 2019 Oct 1;30(10):1622-1629.
  • Rodriguez-Freixinos V, Fariñas-Madrid L, Gil-Martin M, Barretina-Ginesta P, Romeo M, Villacampa G, Pardo B, Ahmed H, Recalde S, Piulats JM, Gómez-Plaza MC, Gil-Moreno A, Sala E, Martínez-Román S, Ponce J, Meléndez C, Carballas E, Dienstmann R, Oaknin A. Chemotherapy and PARP inhibitors in heavily pretreated BRCA1/2 mutation ovarian cancer patients. Gynecol Oncol. 2019 Feb;152(2):270-277.
  • Serna G, Ruiz-Pace F, Cecchi F, Fasani R, Jimenez J, Thyparambil S, Landolfi S, Elez ME, Vivancos A, Hembrough T, Tabernero J, Dienstmann R, Nuciforo P. Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer. Sci Rep. 2019 Sep 19;9(1):13568.

Projects

  • EUCANCan: a federated network of aligned and interoperable infrastructures for the homogeneous analysis, management and sharing of genomic oncology data for Personalized Medicine.
  • COLOSSUS: Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions.
  • LEGACy: improving gastric cancer outcomes by applying personalized medicine at the three levels of prevention in Europe and Latin America populations based on an “omics integrative epidemiology” conceptual model.
  • MoTriColor: Molecular guided Trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of Colorectal cancer.
  • Cancer Core Europe (CCE) Consortium’s Basket of Baskets (BoB).
  • American Association for Cancer Research’s (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE) project.
  • Variant Interpretation for Cancer Consortium.

Prostate Cancer Translational Research Group

Joaquin Mateo
Principal Investigator
Biosketch
Principal Investigator Joaquin Mateo Senior Investigator Nicolas Herranz Post-Doctoral Fellows Alejandro Athie, Irene Casanova PhD Student Sara Arce Technicians Teresa Casals, Sarai Cordoba

Summary

Over the last decade, we have witnessed a revolution in the treatment of metastatic castration-resistant prostate cancer (mCRPC) which is an advanced and lethal form of prostate cancer. A deeper understanding of its underlying biology has led to the development of compounds targeting the androgen signaling pathway and the immune system, as well as taxanes and radiopharmaceuticals.

Despite these advances in more effectively managing mCRPC, it remains a fatal disease resulting in significant morbidity and mortality globally. Arguably, the most critical need in drug development against CRPC is treatment molecular stratification. In parallel efforts must continue to center on identification of robust predictive biomarkers of response and the development of targeted anti-cancer therapies. The advent of these novel treatments has driven tumor evolution towards a shift in the genomic landscape observed in patients with advanced disease.

We embrace a purely comprehensive and integrative approach to research. As such, our group encompasses molecular biology, tumor genomics, clinical trials and computational sciences in order to develop precision medicine strategies to treat advanced prostate cancer based on predictive biomarkers of response.

Defects in DNA repair genes -particularly in double-strand breaks- are present in 20-25% of mCRPC cases, and allow us to study how we can deliver more precise cancer treatment and care. Some of these mutations have prognostic and predictive implications which are crucial in delivering on the promise of personalized medicine in oncology.

We use a range of tools (CRISPR gene editing, shRNA, siRNA and pharmacological inhibitors) to induce loss-of-function of key DNA repair genes in prostate cancer in-vitro models to establish how tumors adapt their DNA repair machinery, and how this is affected by modulation of oncogenic AR signaling. Our interest in cell cycle modulation by DNA damage has also led us to study the senescence-like phenotype observed after exposure to targeted agents, which we hypothesize is a mechanism of drug resistance, and how to target it therapeutically.

Aiming at translating our findings into benefits for patients as rapidly as possible, we study the same genomic and transcriptomic signatures in biopsies from patients with metastatic prostate cancer. In parallel, we collect longitudinal liquid biopsies to study how a tumor evolves during response and progression to targeted agents.

Our research focuses on optimal patient stratification strategies for clinical care, with particular emphasis on combining DNA repair targeting agents with those that inhibit androgen signaling.


Our comprehensive approach to prostate cancer research aims to encompass data from molecular biology assays in preclinical experiments with genomics, immunohistochemistry and immunofluorescence data in patient tumor biopsies and patient-derived laboratory models to optimize the development of precision medicine strategies to then be tested in clinical trials.

Strategic goals

  • To establish a clinically relevant re-classification of metastatic prostate cancer integrating genotypic and phenotypic data with functional assays.
  • Develop prostate cancer molecular stratification assays based on tumor tissue and circulating biomarkers.
  • Optimize the combination of DNA repair-targeting drugs with androgen receptor inhibitors.
  • Build a precision medicine core for prostate cancer patients treated at the Vall d'Hebron University Hospital (HUVH).

Highlights

  • Launch of the IRONMAN Registry in Spain. This project is driven by academic team-science and collects clinical data and biospecimens for correlative analysis from patients with advanced prostate cancer.
  • Participation in the PROfound study, the first-ever positive biomarker-driven clinical trial in prostate cancer, which has confirmed the efficacy of PARP inhibitors in DNA repair defective prostate cancer.
  • The setting up of our first investigator-initiated clinical trial co-targeting AR and PARP in metastatic hormone-naïve prostate cancer; the study will initiate recruitment in 2020.
  • We were granted the 2019 FERO Foundation Award, to develop liquid biopsy assays in advanced prostate cancer.

Horizons

  • To initiate an investigator-initiated phase II clinical trial combining AR and PARP inhibition in metastatic hormone-naïve prostate cancer.
  • Build a platform for collaborative research, integrating clinical and genomics data.
  • To develop genomics and transcriptomics assays, from both tumor tissue and liquid biopsies, to stratify prostate cancer accordingly to clinically-relevant signatures.
  • Validate genomic signatures of DDR defects in prostate cancer.

Awards and Recognition

  • The FERO Foundation 2019 Award.
  • Post-Doctoral Fellow Nicolas Herranz was awarded with an Instituto Salud Carlos III(ISCIII) - Miguel Servet Fellowship.
  • Sara Ace, PhD student of our group, received an Instituto Salud Carlos III(ISCIII) - PFIS Fellowship to Sara Arce (PhD student).
  • Post-Doctoral Fellow Irene Casanova-Salas received a Generalitat de Catalunya PERIS.
  • Joaquin Mateo served as Member of the ESMO 2019 Congress Scientific Program Committee.

PI paper pick

  • Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, Miranda S, Nava Rodrigues D, Gurel B, Clarke M, Atkin M, Chandler R, Messina C, Sumanasuriya S, Bianchini D, Barrero M, Petremolo A, Zafeiriou Z, Fontes MS, Perez-Lopez R, Tunariu N, Fulton BA, Jones R, McGovern UB, Ralph C, Varughese M, Parikh O, Jain S, Elliott T, Sandhu S, Porta N, Hall E, Yuan W, Carreira S, de Bono JS. Genomics of lethal prostate cancer at diagnosis and castration-resistance. J Clin Invest. 2019 Dec 24. pii: 132031.
  • Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, Syndikus I, Ralph C, Jain S, Varughese M, Parikh O, Crabb S, Robinson A, McLaren D, Birtle A, Tanguay J, Miranda S, Figueiredo I, Seed G, Bertan C, Flohr P, Ebbs B, Rescigno P, Fowler G, Ferreira A, Riisnaes R, Pereira R, Curcean A, Chandler R, Clarke M, Gurel B, Crespo M, Nava Rodrigues D, Sandhu S, Espinasse A, Chatfield P, Tunariu N, Yuan W, Hall E, Carreira S, de Bono JS. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Jan;21(1):162-174.
  • Athie A, Arce S, Gonzalez M, Morales R, Suarez C, Casals T, Hernandez G, Carles J, Mateo J. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Curr Oncol Rep. 2019 Mar 27;21(5):42.
  • Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, Cieslik M, Benelli M, Robinson D, Van Allen EM, Sboner A, Fedrizzi T, Mosquera JM, Robinson BD, De Sarkar N, Kunju LP, Tomlins S, Wu YM, Nava Rodrigues D, Loda M, Gopalan A, Reuter VE, Pritchard CC, Mateo J, Bianchini D, Miranda S, Carreira S, Rescigno P, Filipenko J, Vinson J, Montgomery RB, Beltran H, Heath EI, Scher HI, Kantoff PW, Taplin ME, Schultz N, deBono JS, Demichelis F, Nelson PS, Rubin MA, Chinnaiyan AM, Sawyers CL. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23): 11428-11436.

Full list of Publications

  1. Mateo J, Seed G. Bertan C, Rescigno P, Dolling D, Figueiredo I, et al. (2019)Genomics of lethal prostate cancer at diagnosis and castration-resistance. J Clin Inv., ePub ahead of print, Dec.; DOI 10.1172/JCI132031.
  2. Mateo J, Porta N, Bianchini D, McGovern U, Elliot T, Jones R et al. (2019) Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncology, ePub ahead of print, Dec 2019; DOI: 10.1016/S1470-2045(19)30684-9.
  3. Athie A, Arce S, Gonzalez M, Morales R, Suarez C, Casals T, Hernandez G, Carles J, Mateo J. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Curr Onc Rep. 2019. 1007/s11912-019-0790-6
  4. Abida, Wassim; Cyrta, Joanna; Heller, Glenn; Prandi, Davide; Armenia, Joshua; Coleman, Ilsa; Cieslik, Marcin; Benelli, Matteo; Robinson, Dan; Van Allen, Eliezer M; Sboner, Andrea; Fedrizzi, Tarcisio; Mosquera, Juan Miguel; Robinson, Brian D; De Sarkar, Navonil; Kunju, Lakshmi P; Tomlins, Scott; Wu, Yi Mi; Nava Rodrigues, Daniel; Loda, Massimo; Gopalan, Anuradha; Reuter, Victor E; Pritchard, Colin C; MATEO, JOAQUIN; Bianchini, Diletta; Miranda, Susana; Carreira, Suzanne; Rescigno, Pasquale; Filipenko, Julie; Vinson, Jacob; Montgomery, Robert B; Beltran, Himisha; Heath, Elisabeth I; Scher, Howard I; Kantoff, Philip W; Taplin, Mary-Ellen; Schultz, Nikolaus; deBono, Johann S; Demichelis, Francesca; Nelson, Peter S; Rubin, Mark A; Chinnaiyan, Arul M; Sawyers, Charles L. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Nat Acad Sci. 2019. 1073/pnas.1902651116
  5. Zafeiriou, Zafeiris; Bianchini, Diletta; Chandler, Robert; Rescigno, Pasquale; Yuan, Wei; Carreira, Suzanne; Barrero, Maialen; Petremolo, Antonella; Miranda, Susana; Riisnaes, Ruth; Rodrigues, Daniel Nava; Gurel, Bora; Sumanasuriya, Semini; Paschalis, Alec; Sharp, Adam; MATEO, JOAQUIN; Tunariu, Nina; Chinnaiyan, Arul M; Pritchard, Colin C; Kelly, Kevin; de Bono, Johann S. Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency. European Urology, 2019. 10.1016/j.eururo.2018.09.048
  6. Nava Rodrigues, Daniel; Casiraghi, Nicola; Romanel, Alessandro; Crespo, Mateus; Miranda, Susana; Rescigno, Pasquale; Figueiredo, Ines; Riisnaes, Ruth; Carreira, Suzanne; Sumanasuriya, Semini; Gasperini, Paola; Sharp, Adam; MATEO, JOAQUIN; Makay, Alan; McNair, Christopher; Schiewer, Matthew; Knudsen, Karen; Boysen, Gunther; Demichelis, Francesca; de Bono, Johann S. Clin Cancer Res, 2019. 10.1158/1078-0432.CCR-18-2068
  7. MATEO, JOAQUIN; Fizazi, Karim; Gillessen, Silke; Heidenreich, Axel; PEREZ LOPEZ, RAQUEL; Oyen, Wim J G; Shore, Neal; Smith, Matthew; Sweeney, Christopher; Tombal, Bertrand; Tomlins, Scott A; de Bono, Johann S. Managing Nonmetastatic Castration-resistant Prostate Cancer. European Urology, 2019. 10.1016/j.eururo.2018.07.035
  8. MATEO, JOAQUIN; Lord, C J; SERRA, VIOLETA; Tutt, A; BALMAÑA, JUDITH; CASTROVIEJO, CRISTINA; CRUZ, CRISTINA; OAKNIN, ANA; Kaye, S B; de Bono, J S. A decade of clinical development of PARP inhibitors in perspective. Ann Onc, 2019. 10.1093/annonc/mdz192
  9. Sharp, Adam; Welti, Jon C; Lambros, Maryou B K; Dolling, David; Rodrigues, Daniel Nava; Pope, Lorna; Aversa, Caterina; Figueiredo, Ines; Fraser, Jennifer; Ahmad, Zai; Lu, Changxue; Rescigno, Pasquale; Kolinsky, Michael; Bertan, Claudia; Seed, George; Riisnaes, Ruth; Miranda, Susana; Crespo, Mateus; Pereira, Rita; Ferreira, Ana; Fowler, Gemma; Ebbs, Berni; Flohr, Penny; Neeb, Antje; Bianchini, Diletta; Petremolo, Antonella; Sumanasuriya, Semini; Paschalis, Alec; MATEO, JOAQUIN; Tunariu, Nina; Yuan, Wei; Carreira, Suzanne; Plymate, Stephen R; Luo, Jun; de Bono, Johann S. Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. European Urology. 10.1016/j.eururo.2019.04.006

Projects

  • Defining the Landscape and Clinical Relevance of ATM Defects in Lethal Prostate Cancer.
    Grantor: Prostate Cancer Foundation.
  • Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays.
    Grantor: US Department of Defense Congressionally-Directed Medical Research Program.
  • Co-targeting androgen receptor signalling and DNA damage repair for precision therapy in advanced prostate.
    Grantor: European Commission H2020 Program.
  • Novel approaches to liquid biopsy in prostate cancer to inform precision medicine.
    Grantor: FERO Foundation.

Clinical Trials

  • IRONMAN-ES: Estudio prospectivo observacional de parámetros clinicos y biomarcadores en cáncer de próstata avanzado en hospitales de España.
  • ZZ-First: A Biomarker–Discovery Phase II Trial of Enzalutamide and Talazoparib (BMN 673) for the Treatment of Metastatic Hormone–Naïve Prostate Cancer.

Radiation Oncology Group

Jordi Giralt
Principal Investigator
Biosketch
Principal Investigator Jordi Giralt Radiation Oncologists Manel Altabas, Sergio Benavente, Alexandra Giraldo, Raquel Granado, Beatriz Gutierrez, Begoña Navalpotro, Maria Magdalena Marti, Xavier Maldonado, Soraya Mico, Monica Ramos, Victoria Reyes

Summary

VHIO’s Radiation Oncology Group is integrated within the Radiation Oncology Department of the Vall d’Hebron University Hospital (HUVH), and is actively involved in the multidisciplinary treatment of patients with malignant tumors. We also participate either as Principal Investigators or research collaborators in a number of pioneering clinical trials, translational research projects, as well as technology development programs.

In 2019 we have renewed three linacs thanks to a donation received from the Amancio Ortega Foundation. The machines incorporate all the very latest technology and the implementation of these highly complex techniques requires additional expertise from our service, special trainings in order to establish the indications, administration procedures, quality control methods, as well as the implementation of the necessary tools for the measurement of results. These include:

  • Breathing control for the treatment of tumors that are located in moving body regions such as the lungs and liver. Therapy is synchronized with respiratory rhythm. This technique is especially indicated in stereotactic body radiotherapy (SBRT).
  • Deep inspiration breath hold (DIBH) is a radiation therapy technique where patients take a deep breath during treatment. The patient is asked to take a deep breath and hold this breath while the radiation is delivered. Deep breathing ensures that the heart moves away from the chest and thus receives a lower dose.
  • Real-Time Tumor-Tracking Radiotherapy is used in the hypofractionated treatment of prostate cancer. Markers are placed on the prostate and during therapy the system recognizes them. If the prostate moves (e.g. bladder or rectum), the technique can detect this and indicates the correction.
  • Adaptive radiotherapy is used for the treatment of gynecological and bladder tumors, which move and can change position. A three-dimensional image is taken before therapy is administered and indicates where the organ requires therapy, with a treatment plan that best adapts to the position of the organ at that precise moment.
  • Radiosurgery of small lesions is applied for the treatment of small brain tumors and/or metastases, and for some non-oncological conditions such as trigeminal neuralgia that no longer responds to standard therapy, and some Parkinsonism conditions. A very high dose is administered in very small volume (5-10 mm in diameter), requiring extremely precise techniques.

A patient being treated with the ‘Breast hold’ technique. The upper image shows the patient's CT scan. The orange line marks the contour of the heart, which moves away from the breast (in red). The light green line is the left lung, and the pink, the tumor bed. The lower part of the figure shows breathing control. When the black line (volume of the lung), is between the orange and blue lines the treatment is on, if it goes out of this line the beam is off. The yellow area is when treatment is administered.

Strategic goals

  • Technology development: acquisition of new equipment to implement cutting edge clinical techniques such as rotational radiotherapy - with intensity modulated arc therapy (VMAT), adaptive radiotherapy, respiratory control radiotherapy (RT4D), and image-guided radiotherapy (IGRT).
  • Translational research: application of insights into cancer biology as well as healthy tissue in order to personalize therapy matched to the characteristics and specificities of each patient, each individual tumor.
  • Quality. Continue to obtain the ISO 9001/2008 recertification in the field of radiation oncology.
  • Clinical research. To accelerate and advance clinical research into combined radio-immunotherapy therapy.

Highlights

  • Over 90% of our patients treated with radical radiotherapy have received highly complex techniques.
  • We now started therapy using our Halcyon linac - the first ever to be installed in Spain.
  • Our group has initiated a project for combined radiotherapy and nanoparticles in head and neck cancer.
  • We have implemented the `breath hold’ technique, with the first of our patients having already received this treatment approach.
  • We participate as national heads of radiotherapy quality control procedures in the International Society of Paediatric Oncology (SIOP) trials for medulloblastoma (PNET5), ependymoma (EP2), and Wilms (umbrella).

PI paper pick

  • Giralt J, Tao Y, Kortmann RD, Zasadny X, Contreras-Martinez J, Ceruse P, Arias de la Vega F, Lalla RV, Ozsahin EM, Pajkos G, Mazar A, Attali P, Bossi P, Vasseur B, Sonis S, Henke M, Bensadoun RJ. Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2019 Oct 25. pii: S0360-3016(19)33905-7.
  • de Rojas T, Clementel E, Giralt J, Cruz O, Boterberg T, Kortmann RD, Gaze MN, Moreno L, Janssens GO; SIOP-Europe QUARTET Project and of the EORTC. Radiotherapy practice for paediatric brain tumors across Europe and quality assurance initiatives: Current situation, international survey and future perspectives. Eur J Cancer. 2019 Jun; 114:36-46.
  • Seibold P, Webb A, Aguado-Barrera ME, Azria D, Bourgier C, Brengues M, Briers E, Bultijnck R, Calvo-Crespo P, Carballo A, Choudhury A, Cicchetti A, Claßen J, Delmastro E, Dunning AM, Elliott RM, Fachal L, Farcy-Jacquet MP, Gabriele P, Garibaldi E, Gómez-Caamaño A, Gutiérrez-Enríquez S, Higginson DS, Johnson K, Lobato-Busto R, Mollà M, Müller A, Payne D, Peleteiro P, Post G, Rancati T, Rattay T, Reyes V, Rosenstein BS, De Ruysscher D, De Santis MC, Schäfer J, Schnabel T, Sperk E, Symonds RP, Stobart H, Taboada-Valladares B, Talbot CJ, Valdagni R, Vega A, Veldeman L, Ward T, Weißenberger C, West CML, Chang-Claude J; REQUITE consortium. REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer. Radiother Oncol. 2019 Sep;138:59-67.
  • Bonvalot S, Rutkowski PL, Thariat J, Carrère S, Ducassou A, Sunyach MP, Agoston P, Hong A, Mervoyer A, Rastrelli M, Moreno V, Li RK, Tiangco B, Herraez AC, Gronchi A, Mangel L, Sy-Ortin T, Hohenberger P, de Baère T, Le Cesne A, Helfre S, Saada-Bouzid E, Borkowska A, Anghel R, Co A, Gebhart M, Kantor G, Montero A, Loong HH, Vergés R, Lapeire L, Dema S, Kacso G, Austen L, Moureau-Zabotto L, Servois V, Wardelmann E, Terrier P, Lazar AJ, Bovée JVMG, Le Péchoux C, Papai Z. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol. 2019 Aug;20(8):1148-1159.

Full list of Publications

  1. Giralt J, Tao Y, Kortmann RD, Zasadny X, Contreras-Martinez J, Ceruse P, Arias de la Vega F, Lalla RV, Ozsahin EM, Pajkos G, Mazar A, Attali P, Bossi P, Vasseur B, Sonis S, Henke M, Bensadoun RJ. Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2019 Oct 25. pii: S0360-3016(19)33905-7. doi: 10.1016/j.ijrobp.2019.10.023.
  2. de Rojas T, Clementel E, Giralt J, Cruz O, Boterberg T, Kortmann RD, Gaze MN, Moreno L, Janssens GO; SIOP-Europe QUARTET Project and of the EORTC. Radiotherapy practice for paediatric brain tumors across Europe and quality assurance initiatives: Current situation, international survey and future perspectives.Eur J Cancer. 2019 Jun;114:36-46. doi: 10.1016/j.ejca. 2019.03.018. Epub 2019 Apr 28.
  3. Biau J, Lapeyre M, Troussier I, Budach W, Giralt J, Grau C, Kazmierska J, Langendijk JA, Ozsahin M, O'Sullivan B, Bourhis J, Grégoire V. Selection of lymph node target volumes for definitive head and neck radiation therapy: a 2019 Update.Radiother Oncol. 2019 May;134:1-9. doi: 10.1016/j.radonc.2019.01.018. Epub 2019 Jan 30.
  4. Rodríguez A, Arenas M, Lara PC, López-Torrecilla J, Algara M, Conde A, Pérez-Montero H, Muñoz JL, Peleteiro P, Pérez-Calatayud MJ, Contreras J, Ferrer C; Spanish Society of Oncology and Radiotherapy (SEOR) Analysis Group. Are there enough radiation oncologists to lead the new Spanish radiotherapy?Clin Transl Oncol. 2019 Apr 3. doi: 10.1007/s12094-019-02095-x.
  5. Seibold P, Webb A, Aguado-Barrera ME, Azria D, Bourgier C, Brengues M, Briers E, Bultijnck R, Calvo-Crespo P, Carballo A, Choudhury A, Cicchetti A, Claßen J, Delmastro E, Dunning AM, Elliott RM, Fachal L, Farcy-Jacquet MP, Gabriele P, Garibaldi E, Gómez-Caamaño A, Gutiérrez-Enríquez S, Higginson DS, Johnson K, Lobato-Busto R, Mollà M, Müller A, Payne D, Peleteiro P, Post G, Rancati T, Rattay T, Reyes V, Rosenstein BS, De Ruysscher D, De Santis MC, Schäfer J, Schnabel T, Sperk E, Symonds RP, Stobart H, Taboada-Valladares B, Talbot CJ, Valdagni R, Vega A, Veldeman L, Ward T, Weißenberger C, West CML, Chang-Claude J; REQUITE consortium.REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapyfor breast, lung or prostate cancer.Radiother Oncol. 2019 Sep;138:59-67.
  6. Cambra MJ, Moreno F, Sanz X, Anglada L, Mollà M, Reyes V, Arenas M, Pedro A, Ballester R, García V, Casals J, Cusidó M, Jimenez C, Escribà JM, Macià M, Solé JM, Arcusa A, Seguí MA, Gonzalez S, Farrús B, Biete A. Role of boost radiotherapy for local control of pure ductal carcinoma in situ after breast-conserving surgery: a multicenter, retrospective study of 622 patients.Clin Transl Oncol. 2019 Jul 1.
  7. Bellet M, Ahmad F, Villanueva R, Valdivia C, Palomino-Doza J, Ruiz A, Gonzàlez X, Adrover E, Azaro A, Valls-Margarit M, Parra JL, Aguilar J, Vidal M, Martín A, Gavilá J, Escrivá-de-Romaní S, Perelló A, Hernando C, Lahuerta A, Zamora P, Reyes V, Alcalde M, Masanas H, Céliz P, Ruíz I, Gil M, Seguí MÀ, de la Peña L. Palbociclib and ribociclib in breastcancer: consensus workshop on the management of concomitant medication.Ther Adv Med Oncol. 2019 May 10.
  8. Garcia-Mayea Y, Mir C, Muñoz L, Benavente S, Castellvi J, Temprana J, Maggio V, Lorente J, Paciucci R, LLeonart ME. Autophagy inhibition as a promising therapeutic target for laryngeal cancer. Carcinogenesis.2019 May 3. pii: bgz080. doi: 10.1093/carcin/bgz080.
  9. Guillem V., Algaba F., Arranz JA., Cassinello J., Climent MA., Duran I., Gómez de Liaño A., Maldonado X., Puente J., Rubio J. NCCN Clinical Practice Gudelines in Oncology(NCCN Guidelines). European edition: Spain. Version 2.2019-August 6, 2019.
  10. Font A., Luque R., Villa JC., Domenech M., Vázquez S., Gallardo E., Virizuela JA., Beato C., Morales-Barrera R., Gelabert A., Macià S., Puente J., Rubio G., Maldonado X.,Pérez Valderrama B., Pinto A., Fernández Calv o O., Grande E., Garde Noguera J., Fernández Parra E., Arranz Ja. The Challenge of Managing Bladder Cancer and Upper Tract Urothelial Carcinoma: A Review with treatment recommendations from the Spanish Oncology GenitoUrinary Group (SOGUG). Targeted Oncology
  11. Carles, E.Gallardo, M.Doménech, A.Font, J.Bellmeunt, M.Fígols, B.Mellado, MI Sáez, C.Suárez, MJ Mémdez, P.Maroto, R.Luque, T.Portugal, R.Aldabó, T.bonfill, R.Morales-Barrera, J.García, S.Macía,X.Maldonado, P.Foro. Phase 2 Randomized Study of Radiation Therapy and 3 Year Androgen Deprivation with or without concurrent weekly Docetaxel in High-Risk localized Prostate Cancer Patients. Int J. Radiat Oncol Biol Phys. 2019 Vol. 103, Issue 2, 344–352.
  12. Gil-Moreno A, Carbonell-Socias M, Salicrú S, Bradbury M, García Á, Vergés R, Puig OP, Sánchez-Iglesias JL, Cabrera-Díaz S, de la Torre J, Gómez-Hidalgo NR, Pérez-Benavente A, Díaz-Feijoo B. Nerve-sparing versus non-nerve-sparing radical hysterectomy: surgical and long-term oncological outcomes. Oncotarget. 2019 Jul 16;10(44):4598-4608,
  13. Bonvalot S, Rutkowski PL, Thariat J, Carrère S, Ducassou A, Sunyach MP, Agoston P, Hong A, Mervoyer A, Rastrelli M, Moreno V, Li RK, Tiangco B, Herraez AC, Gronchi A, Mangel L, Sy-Ortin T, Hohenberger P, de Baère T, Le Cesne A, Helfre S, Saada-Bouzid E, Borkowska A, Anghel R, Co A, Gebhart M, Kantor G, Montero A, Loong HH, Vergés R, Lapeire L, Dema S, Kacso G, Austen L, Moureau-Zabotto L, Servois V, Wardelmann E, Terrier P, Lazar AJ, Bovée JVMG, Le Péchoux C, Papai Z. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol. 2019 Aug;20(8):1148-1159.

Projects

Funded Projects
  • Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE).
  • Supported through a European grant of the EU 7th Framework Programme (FP7), this project aims to optimize the delivery of (chemo) radiotherapy and/or surgery to cancer patients. Participating centers: The Netherlands Cancer Institute, Karolinska Institutet, Institut Gustave Roussy, Maastro Clinic, the Vall d’Hebron University Hospital, Christie Hospital, European Society for Radiotherapy & Oncology (ESTRO), Maastro innovations, and RaySearch. This study explores dose escalation strategies using adaptive radiotherapy and metabolic and biological markers. We participate in the study of patients with head and neck tumors.
  • Adiogenomics Biorepository and Databank (RBD) PAR-11-167 Core Infrastructure and Methodological Research for Cancer Epidemiology Cohorts (UM1).
  • In addition to DNA isolated from blood collected epidemiological data / records of patient outcomes related to the treatment.
  • The main aim will be normal tissue toxicity data from patients and electronic data capture. A unique element of this project is the centralized storage of radiotherapy treatment plans.
  • Evaluation of the efficacy and effectiveness of new treatments for localized prostate cancer at low risk (FIS)
  • A multicenter randomized trial in patients diagnosed with low-risk prostate cancer controlled clinical trial design. Patients will be treated with laparoscopic radical prostatectomy, robotic surgery, brachytherapy or IMRT. Main endpoints are performance parameters and quality of life. To evaluate the probability of nonadherence to external radiotherapy and its associated factors in patients treated for cancer in Catalonia (FIS).
  • Patient non adherence to external radiotherapy and the frequency of retreatment are two parameters with very few studies available. There are currently none from a population based perspective. Retreatments are increasing due to the improvements in technology and progression in survival. Both are key factors in the planning of radiotherapy planning resources. This project has two complementary objectives: 1. to analyze the probability of non adherence to external radiotherapy treatment, its associated factors and its association with one year survival; and 2. assess the frequency of retreatments during the five years following initial therapy for the same primary tumor, and its relationship with the tumor site, intention for treatment and time from the initial therapy.
  • COGNITO: Evaluation of long-term cognitive effects in childhood cancer survivors. Reference: PR(AMI)389/2017.
    PI: Monica Ramos.
    EU project 899995 – EURAMED.
Non-Funded Projects
  • Adaptive radiation therapy based on PET functional imaging for H&N cancer patients.
  • Breast irradiation, comparisons and analysis of dose distribution and reproducibility in supine versus prone position.
  • Phase II clinical Essay extracranial stereotactic radiotherapy in the treatment of locally advanced prostate cancer.
  • Instrumentation radiotherapy of the spine and paraspinal tumors and metastases.
  • Extracranial stereotactic radiotherapy in pancreatic cancer, commissioning and validation of the technique.
  • Techniques for reducing toxicity: radiotherapy treatment in the pediatric patients with brain tumors.
  • Radiation treatment planning of gynecological tumors. Monitoring compliance in filling the urinary bladder.
  • Total marrow irradiation program for bone marrow transplantation in patients with multiple myeloma; dosimetric studies.
  • A feasibility trial evaluating anti-PD1 nivolumab consolidation after standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC.
  • REQUITE project. Inclusion and monitoring of lung cancer patients.
  • Adaptive radiotherapy in the treatment of patients with non-small cell lung neoplasia in stages IIA and IIB.(AG) 288/216.
  • Extracranial stereotactic radiotherapy (SBRT) as a treatment for unresectable liver metastases.

Clinical Trials

  • A multicenter randomized, open-label phase II/III study, to compare the efficacy of NBTXR3, implanted as intratumor injection and activated by radiotherapy, versus radiotherapy alone in patients with locally advanced soft tissue sarcoma of the extremity and trunk wall. Reference: NBTXR3-301 PI: RamonaVergés
  • A phase III randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with Retroperitoneal sarcoma (RPS). Reference: EORTC 62092-22092 (STRASS) PI: Ramona Vergés
  • A prospective randomised phase III study of androgen deprivation therapy with docetaxel with or without local radiotherapy with or without abiraterone acetate and prednisone in patients with metastatic hormone-naïve prostate cancer (PEACE-1). Reference: UC-0160/1105 GETUG AFU-21 PI: Xavier Maldonado
  • Estudio clínico fase II aleatorizado de radioterapia y quimioterapia con docetaxel verus radioterapia y hormonoterapia en cáncer de próstata de alto riesgo. Reference: GETUG AFU-23 PI: Xavier Maldonado
  • Ensayo clínico fase IB-II de gel de melatonina oral para la prevención y tratamiento de la mucositis oral en pacientes con cáncer de cabeza y cuello tratados con quimioradioterapia. Reference: JAN13004-30 PI: Jordi Giralt
  • Trial of preoperative therapy for gastric and esophagogastric junction adenocarcinoma. A randomized phase II/III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer (TOP GEAR). Reference: 22114-40111 PI: Begoña Navalpotro
  • Phase I-II prospective trial, multicenter, open label, exploring the combination of Trabectedin plus Radiotherapy in Soft Tissue Sarcoma patients. Reference: GEIS 37 TRAST PI: Ramona Vergés
  • A feasibility trial evaluating anti-PD1 nivolumab consolidation after standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC. Reference: CL1-49076-003 PI: Jordi Giralt
  • Tratamiento Preoperatorio de Inducción con 12 semanas de Panitumumab combinado con FOLFOX 6m en una población enriquecida (Quádruple Wild-Type) de pacientes con cáncer de recto de tercio medio mrT3 y fascia mesorrectal no invadida. Reference: GEMCAD 1601 Collaborating Researcher: Begoña Navalpotro
  • Estudio aleatorizado multicéntrico en fase III de radioterapia de corta duración seguida de quimioterapia preoperatoria de larga duración y cirugía en el cáncer rectal primario de alto riesgo. Reference: RAPIDO Collaborating Researcher: Begoña Navalpotro
  • Tratamiento de inducción con FOLFOX +/- aflibercept seguido de QT-RT en cáncer de recto localmente avanzado de alto riesgo. Estudio fase II randomizado, multicéntrico, abierto. Reference: GEMCAD 1402 Collaborating Researcher: Begoña Navalpotro
  • Ensayo clínico multicéntrico prospectivo controlado y aleatorizado de no inferioridad del tratamiento del cáncer de recto T2-T3s (superficial) N0m0 mediante quimiorradioterapia preoperatoria y microcirugía endoscópica transanal (TEM versus excisión total del mesorrecto. Reference: ETM
  • Estudio de fase 3 aleatorizado, doble ciego y controlado con placebo de JNJ-56021927 en sujetos con cáncer de próstata de alto riesgo localizado o localmente avanzado que están recibiendo tratamiento con radioterapia primaria. Reference: AC/R(AG)250/2015(4685) Collaborating Researcher: Begoña Navalpotro
  • Estudio fase III, alestorizado, abierto de nivolumab frente a temozolamida, cada uno en combinación con radioterapia en pacientes con recién diagnóstico de glioblastoma multiforme. Reference: CA-209-498-030 Collaborating Researcher: Xavi Maldonado
  • Fase II, ensayo multicéntrico, randomizado, doble ciego, controlado por placebo que compara la eficacia y la tolerancia de Clonidine Lauriad R 50 mcg y 100 mcg comprimido bucal mucoadhesivo administrado una vez por día a un placebo en la prevención y tratamiento de la mucositis oral inducida por quimioterapia y radioterapia en pacientes con cáncer de cabeza y cuello. Reference: BA-2009-28-01 PI: Jordi Giralt
  • Tratamiento radioterápico adaptativo e innovador para mejorar el resultado del tratamiento del cáncer. Estudio aleatorizado con cisplatino o cetuximab y radioterapia estandar o adaptativa a alta dosis en cáncer localmente avanzado de cabeza y cuello. Reference: ARTFORCE PI: Jordi Giralt
  • Ensayo clínico fase II para evaluar la eficacia del anticuerpo anti-PD-L1 atezolizumab (MPDL3280A) administrado con radioterapia ablativa estereotáctica. Reference: SABR-PDL1 PI: Jordi Giralt
  • Estudio europeo, multicéntrico, abierto, del dolor oncológico irruptivo: Evaluación del ajuste de la dosis y del tratamiento con comprimidos bucales de fentanilo en pacientes que están recibiendo opioides. Reference: C25608/4027/BP/EU PI: Sergi Benavente
  • Primer estudio en el ser humano de la administración repetida de REGN2810, un anticuerpo monoclonal, totalmente humano frente a la proteína de muerte celular programada 1 (PD-1), en monoterapia y en combinación con otros tratamientos antineoplásicos, en pacientes con tumores malignos avanzados. Reference: R2810-ONC-1423 Collaborating Researcher: Jordi Giralt

Radiomics Group

Raquel Perez-Lopez
Principal Investigator
Biosketch
Principal Investigator Raquel Perez-Lopez Post-Doctoral Fellows Kinga Bernatowicz-Goma, Iñaki Rabanillo PhD Students Alonso Garcia, Marta Ligero Students Touria Ahaouari, Eric Delgado, Maria Vittoria Raciti, Samantha Elizabeth Toinga

Summary

Our Radiomics Group keeps growing; in 2019 Alonso Garcia and Marta Ligero started their PhD programs and Samantha Toinga joined us to carry out her MsC research project on imaging habitats towards evaluating tumor heterogeneity. Kinga Bernatowicz also joined the group as our new Post-Doctoral Scientist. We are also pleased to announce that we are currently recruiting for additional new talents and will soon incorporate another post-doctoral researcher to the group.

Over the last year, we have fostered further collaborations with additional leading imaging research groups including the Computing Vision Centre (CVC–Universitat Autónoma de Barcelona), and cutting-edge centres such as the Bellvitge Institute for Biomedical Research (IDIBELL), in Barcelona, the Institute of Cancer Research (ICR), London, UK, the Netherlands Cancer Institute (NKI), Amsterdam, and the Cancer Research UK (CRUK) Cambridge Institute. In partnership, we have designed various projects for which we have applied for funding through national and international grants.

Continuing our collaboration with VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa” led by Elena Garralda, we have developed a CT-radiomics signature towards better characterizing immunotherapy response (selected as an Oral Presentation at the ESMO Congress 2019, 27 September – 01 October, Barcelona; paper currently under review). Thanks to the support received through an AstraZeneca Proof of Concept Award, we will soon initiate the first prospective study of CT and multiparametric MRI-radiomics to quantify changes in tumor cellularity and vascularization as a biomarker of response to immune checkpoint inhibitors.

We are also delighted to report that the CRIS Cancer Foundation has recently awarded Raquel Perez-Lopez with a Research Talent Award. This will fuel her research aimed at improving cancer patient selection for immunotherapy and better understanding differential responses to immune-checkpoint inhibitors.

Thanks to the support of received from the Carlos III Institute of Health (ISCIII) and the Prostate Cancer Foundation Young Investigator Award, we have started a multi-center prospective study of whole-body diffusion-weighted MRI as a response biomarker of bone metastasis in prostate cancer patients. This study will soon be expanded to include breast cancer patients thanks to funding from La Fundació La Marato de TV3 (PreciMet study).

We have also established interdisciplinary partnerships with various VHIO groups to work together on several translational research projects. Our ethos of team science is key for optimizing imaging and accelerating translational research against cancer.

Focused on applying imaging biomarkers and radiomics to cancer discovery, our efforts center on advancing precision imaging in personalized medicine towards ultimately improving outcomes for cancer patients.


Unravelling tumor heterogeneity using advanced computational analysis of medical images.

Strategic goals

  • Provide expertise in engineering and bioinformatics for the development and clinical qualification of quantitative imaging biomarkers for precision medicine to improve outcomes for cancer patients.
  • Use functional imaging for optimizing drug development through clinical trials.
  • Integrate radiomics and genomics in translational studies towards a deeper understanding of tumor evolution and mechanisms of resistance to anti-cancer therapies.
  • Optimize and standardize imaging acquisition protocols.
  • Develop and implement computational models for advanced image processing.

Highlights

  • Our group was awarded with a Fundació La Marato de TV3 Grant and Raquel Perez-Lopez has just been granted a CRIS Foundation Research Talent Award.
  • We have developed and validated a combined CT-radiomics and clinical signature with predictive value of response to immunotherapy. The preliminary results of this study were presented at the European Society for Medical Oncology (ESMO) Congress 2019 (manuscript currently under review).
  • We have also developed a pipeline for semi-automatic robust quantification of residual tumor on the post-surgery MRI in patients with brain glioblastoma (manuscript under review).
  • The continued expansion of existing partnerships with other groups as well as new collaborative projects in order to increase the incorporation of imaging studies within translational research lines.

Horizons

  • Build a team with talented radiologists, physicists and engineers to develop cutting-edge imaging research.
  • Incorporate imaging biomarkers in translational research projects at VHIO as well as other leading research centers.
  • Develop novel imaging processing algorithms for advanced imaging analysis.

Awards and Recognition

  • Personalized REsponse Imaging biomarker for Cancer immunotherapy. CRIS Research Talent Program from the CRIS Cancer Foundation. PI: Raquel Perez-Lopez. 
  • PrecIMet: precision imaging for bone metastases. Fundació La Marató de TV3. PI: Raquel Perez-Lopez. 
  • Detection of genetic abnormalities using persistent homology in radiomics. Horizon 2020-Attract Project. Co-PI: Raquel Perez-Lopez.

PI paper pick

  • Deroose CM, Gheysens O, Perez-Lopez R. PET or MRI to improve evaluation of response in clinical trials? Lancet Oncol. 2019 Aug;20(8):1060-1062.
  • Perez-Lopez R, Tunariu N, Padhani A, Oyen W, Fanti S, Vargas HA, Omlin A, Morris MJ, De Bono J, Koh DM. Imaging diagnosis and follow-up of advanced prostate cancer: Clinical perspectives and state-of-the-art. Radiology. 2019 Aug;292(2):273-286.
  • Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, Miranda S, Nava Rodrigues D, Gurel B, Clarke M, Atkin M, Chandler R, Messina C, Sumanasuriya S, Bianchini D, Barrero M, Petremolo A, Zafeiriou Z, Fontes MS, Perez-Lopez R, Tunariu N, Fulton BA, Jones R, McGovern UB, Ralph C, Varughese M, Parikh O, Jain S, Elliott T, Sandhu S, Porta N, Hall E, Yuan W, Carreira S, de Bono JS. Genomics of lethal prostate cancer at diagnosis and castration-resistance. J Clin Invest. 2019 Dec 24. pii: 132031.
  • Matos I, Martin-Liberal J, Garcia-Ruiz A, Hierro C, Ochoa de Olza M, Viaplana C, Azaro A, Vieito M, Brana I, Mur G, Ros J, Mateos J, Villacampa G, Berché R, Oliveira M, Alsina M, Élez E, Oaknin A, Muñoz-Couselo E, Carles J, Felip E, Rodon J, Tabernero J, Dienstmann R, Perez-Lopez R, Garralda E. Capturing Hyperprogressive disease with immune checkpoint inhibitors using RECIST 1.1 criteria. Clin Cancer Res. 2019 Nov 22. pii: clincanres.2226.2019.

Projects

  • PREdICT: Personalized REsponse Imaging biomarker for Cancer immunotherapy.
    CRIS Cancer Research Talent Program from the CRIS Foundation, AstraZeneca PoC Award.
  • PrecIMet: precision imaging for bone metastases.
    Fundació La Marató de TV3.
  • TOPiomics: Detection of genetic abnormalities using persistent homology in radiomics.
    Horizon 2020-Attract Project.
  • Immune-Image: Specific Imaging of Immune Cell Dynamics Using Novel Tracer Strategies.
    Horizon 2020-Innovative Medicine Initiatives (IMI2-Call4; 831514).
  • Validaciónclínica de la resonancia de cuerpo completo con difusión en pacientes con cáncer de próstata resistente a la castración y metástasis óseas.
    Instituto de Salud Carlos III-Investigación en Salud (PI18/01395).
  • A two-stage study to clinically qualify whole-body diffusion-weighted MRI in patients with metastatic castration resistant prostate carcinoma with bone metastases.
    Prostate Cancer Foundation (PCF)-Young Investigator Award.
  • BevaThings: Moving liquid biopsy beyond current applications: study of prognostic and predictive values of circulating tumour DNA in metastatic colorectal cancer.
    Spanish Association Against Cancer (AECC).
  • Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays.
    Department of Defense (DoD) from the USA Impact Award.

Sarcoma Translational Research Group

César Serrano
Principal Investigator
Biosketch
Principal Investigator César Serrano Pre-Doctoral Fellows Alfonso García Valverde, Daniel Pilco Janeta Student Carlos Ramírez Vázquez

Summary

Sarcoma encompasses >70 entities of mesenchymal origin, constituting 1-2% of all cancers. From a biological perspective sarcomas can be classified into two broad categories: genomically simple sarcomas driven by simple genetic alterations, such as translocations or specific activating mutations; and tumors with complex and unbalanced genomic aberrations. Each of these categories includes diverse sarcomas subtypes showing often profound differences in their molecular makeup, course of disease and therapeutic approach.

Our group focuses on the study of sarcomas with oncogenic dependency on specific drivers of disease. Among them, gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal neoplasm and constitutes a paradigmatic model to study oncogene addiction and identify structural and functional mechanisms for drug response and drug resistance.

Ongoing aim efforts aim at a deeper biological understanding of GIST and other sarcomas in order to advance drug development. One of the major hurdles with a direct impact on patients’ outcomes, concerns the heterogeneity of mechanisms of resistance. Our overarching goal is therefore to identify crucial molecules and signaling mechanisms in GIST biology that can serve as therapeutic vulnerabilities.

We also continue to validate a core set of molecules co-regulated by KIT downstream pathways and identified through extensive whole transcriptome studies across several clinically representative human GIST models. Our group is particularly interested in those with pro-survival function to better understand cellular adaptation to driver inhibition, which may eventually be novel therapeutic targets.

We are as equally interested in performing high-throughput genomic and transcriptomic studies in order to decipher the evolving patterns of resistance in GIST throughout the course of disease, as well as researching liquid biopsy in sarcoma to provide robust evidence that will help to more precisely guide treatment decisions through plasma sequencing.

Our goal is to have a true impact clinically by improving the daily treatment and care of our sarcoma patients. We are proud to report that our Sarcoma Multidisciplinary Unit has been designated as an Expert National Sarcoma Center by the Spanish Ministry of Health, and thus constitutes an optimal setting to translate cancer discovery into true clinical outcomes.


Gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal tumor and a successful and paradigmatic model to dissect mechanisms of response and resistance to molecularly targeted agents. Our group has recently discovered that small molecule KIT-inhibitor monotherapies have a drug-specific activity profile against a subset of the KIT secondary mutational spectrum, which constitutes the molecular basis for the modest clinical benefit observed with successive lines of treatment in imatinib-resistant GIST. This finding has a direct impact on the future of drug development in GIST and other diseases (Figure from Serrano & Fletcher, Oncotarget 2019; 10: 6286-6287.).

Strategic goals

  • Identification of critical molecular mediators of oncogenic signaling in sarcomas.
  • Characterization of response and resistance mechanisms to targeted therapies in sarcomas.
  • Preclinical modelling and validation of therapeutic strategies to translate at the clinical level.

Highlights

  • We have recently determined the molecular basis for the limited clinical benefit of TKIs in imatinib-resistant GIST.
  • Our group has led high-level studies towards the clinical implementation of liquid biopsy in GIST patients.
  • We have been awarded by the Spanish Ministry of Science and Innovation (FIS Program) to study the evolutionary landscape of resistance in GIST.
  • César Serrano organized the first national symposium for sarcoma patients and advocacy groups.

Horizons

  • To develop E3 Ubiquitin ligase inhibitors as a salvage mechanism to boost TKI-induced apoptosis.
  • Decipher novel patterns of resistance in TKI-refractory GIST.
  • Pursue ctDNA implementation in GIST to guide clinical decisions.
  • Preclinical and clinical drug development of novel compounds and/or combinations to transfer to the clinic.

Awards and Recognition

  • Spanish Sarcoma Group (GEIS): steering committee.
  • Co-coordinator for the national GIST guidelines.
  • Spanish Association of Sarcoma patients: scientific advisor.

PI paper pick

  • Serrano C, Leal A, Kuang Y, Morgan JA, Barysauskas CM, Phallen J, Triplett O, Mariño-Enríquez A, Wagner AJ, Demetri GD, Velculescu VE, Paweletz CP, Fletcher JA, George S. Phase I Study of Rapid Alternation of Sunitinib and Regorafenib for the Treatment of Tyrosine Kinase Inhibitor Refractory Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Dec 15;25(24):7287-7293.
  • Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu MJ, Yu C, Mannan AM, Rubin BP, Demetri GD, Raut CP, Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary KIT mutations in imatinib-resistant gastrointestinal stromal tumors. Br J Cancer. 2019 Mar;120(6):612-620.
  • Serrano C, García-Del-Muro X, Valverde C, Sebio A, Durán J, Manzano A, Pajares I, Hindi N, Landolfi S, Jiménez L, Rubió-Casadevall J, Estival A, Lavernia J, Safont MJ, Pericay C, Díaz-Beveridge R, Martínez-Marín V, Vicente-Baz D, Vivancos A, Hernández-Losa J, Arribas J, Carles J. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib. Oncologist. 2019 May;24(5):680-687.

Projects

  • Relevancia biológica y clínica de estudios transcriptómicos en GIST
    Funding agency: SENSCYT
    PI: César Serrano
    2018 – 2022 
  • Caracterización del potencial predictivo y terapéutico de FBXO32 como mediador crítico de la señalización oncogénica de KIT/PDGFRA en tumores del estroma gastrointestinal
    Funding agency: Fundación MPJC
    2018 - 2020
  • KIT-independent oncogenic activation of KIT-downstream pathways as a novel mechanism for resistance: biologic, clinical and therapeutic relevance
    Funding agencies: Spanish Research Council (FIS ISCIII) and PERIS Research Grant
    2017- 2020

Clinical Trials

  • NAVIGATOR: A phase 1 Study of BLU-285 in Patients with Gastrointestinal Stromal Tumors (GIST) and other Relapsed and Refractory Solid Tumors Role: PI; Advisory Board Member
  • INVICTUS: A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of DCC-2618 In Patients with AdvanCed Gastrointestinal Stromal TUmorS who have Received Treatment with Prior Anticancer Therapies Role: National PI; Advisory Board Member
  • CRENOGIST: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Trial of Crenolanib in Subjects with Advanced or Metastatic Gastrointestinal Stromal Tumors with a D842V Mutation in the PDGFRA Gene Role: National PI
  • VOYAGER: An International, Multicenter, Open-label, Randomized, Phase 3 Study of BLU-285 vs Regorafenib in Patients with Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) Role: National PI; Advisory Board Member
  • INTRIGUE: A Phase 3, Interventional, Randomized, Multicenter, Open-Label Study of DCC-2618 vs Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumors after Treatment with Imatinib. Role: National PI; Advisory Board Member
  • SELIGIST: A multicenter, phase Ib/II trial of Selinexor in combination with Imatinib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) Role: Global Trial Coordinator

Thoracic Tumors & Head and Neck Cancer Group

Enriqueta Felip
Principal Investigator
Biosketch
Principal Investigator Enriqueta Felip Medical Oncologists and Clinical Fellows Irene Braña, Ana Callejo, Susana Cedres, Francisco Grau, Alberto Hernando, Patricia Iranzo, Alexandre Martinez, Alejandro Navarro, Nuria Pardo Associate Researcher Ramon Amat Bioinformatician Joan Frigola Post-Doctoral Fellow Caterina Carbonell Clinical Nurse Specialists Victor Monton, Gisela Rodriguez

Summary

VHIO’s Thoracic Tumors & Head and Neck Cancer Group is dedicated to advancing cancer treatment and care for patients suffering from thoracic malignancies, including lung cancer, mesothelioma and thymic malignancies, and head and neck cancers. We focus on disease prevention, early detection and the more precise diagnosis and staging of disease toward improving clinical outcomes.

Our group strives to match currently available targeted therapies with specific molecular alterations identified in patients, identify molecular mechanisms of acquired resistance, and optimize novel immunotherapy strategies.

For our patients with early-stage thoracic malignancies, we collaborate closely with a multidisciplinary team incorporating thoracic surgeons, radiation therapists, radiologists, pulmonologists, pathologists and biologists. In so doing, we are potentiating several treatment approaches and modalities. Given that our patients can suffer from severe symptoms we are also deeply committed to ameliorating clinical outcomes by working in tight connectivity with professionals across other disciplines.

Precision medicine for the treatment advanced lung cancer is no longer an ambition. It is a guiding principle. We establish molecular determinants of disease in individual tumors and circulating-free DNA (cfDNA) by liquid biopsy, to more effectively tailor therapies to the specificities of each patient’s disease.

For patients with head and neck tumors we work alongside expert surgeons, radiotherapists, radiologists, pathologists, and nutritionists, and also lead a clinical trial program to assess novel immunotherapeutics and targeted agents in this particular setting.

Immune-based strategies have a role in the treatment algorithm for the management of non-small cell lung cancer; a number of protocols are now ongoing at our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”. We contribute to VHIO’s early clinical drug development efforts, led by Elena Garralda, and also manage other less common thoracic malignancies including head and neck cancer, small-cell lung cancer, mesothelioma, thymoma and neuroendocrine tumors.


Strategic goals

  • Consolidation of our translational thoracic cancer program in non-small-cell lung cancer, small-cell lung cancer and mestothelioma.
  • Implementation of liquid biopsy determinations.
  • Contribute to early drug development, targeted therapies and immunotherapy strategies for the treatment of thoracic and head and neck tumors.
  • Advance precision medicine for lung cancer patients through translational research and the application of cutting-edge technologies and novel approaches.
  • Potentiate new therapies including immunotherapeutics and targeted agents for the management of patients with thoracic and head and neck malignancies.
  • Further strengthen multidisciplinarity for optimal patient care.

Highlights

  • Consolidation of our translational thoracic cancer genomics unit, which counts on the expertise of Ramon Amat, Senior Scientist, Post-Doctoral Fellow, Caterina Carbonell, and a Bioinformatician, Joan Frigola. By integrating genomics, molecular biology and clinical data, this team collaborates closely with our clinical investigators to better understand lung cancer physiology and response to therapy.

Horizons

  • Identification with massive sequencing technologies of new genetic alterations for targeted therapies against lung cancer.
  • Wnt/beta-catenin pathway activation in advanced non-small cell lung cancer: implications in resistance to immunotherapy and novel therapeutic strategies.
  • Non-invasive prognostic markers for resected early-STage NSCLC: role of circulating and exosomal miRNAs and free circulating DNA.
  • Study intratumoral heterogeneity in chromosomal alterations and immune infiltrationin primary lung tumors, and their implication in
  • Decipher the molecular determinants of response to immunotherapy and their subsequent use as biomarkers of response and sustained benefit.
  • Characterize cell free DNA of metastatic patients to predict response to therapy,
  • Characterize cell free DNA of early stage patients to understand/predictdiseaserelapse

Awards and Recognition

  • The Web of Science Group announced its who’s who on the annual and global Highly Cited Researchers list for 2019, curated by the Institute for Scientific Information. Featuring among the 6216 top drawer leading researchers across the main 21 fields of the sciences and social sciences covered by the Essential Science Indicator (ESI), Enriqueta Felip, Principal Investigator of our Thoracic Tumors & Head and Neck Cancer Group, was selected for her exceptional advancements in cancer science under the category of Clinical Medicine that lists a total of 436 named leaders for 2019.

PI paper pick

  • Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin CC, Soo RA, Riely GJ, Ou SI, Clancy JS, Li S, Abbattista A, Thurm H, Satouchi M, Camidge DR, Kao S, Chiari R, Gadgeel SM, Felip E, Martini JF. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2019 Jun 1;37(16):1370-1379.
  • Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Felip E, Goldman JW, Scalzo C, Jensen E, Kush DA, Hui R. Five-Year Overall Survival for Patients With Advanced Non-Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol. 2019 Oct 1;37(28):2518-2527.
  • Subbiah V, Gervais R, Riely G, Hollebecque A, Blay JY, Felip E, Schuler M, Gonçalves A, Italiano A, Keedy V, Chau I, Puzanov I, Raje NS, Meric-Bernstam F, Makrutzki M, Riehl T, Pitcher B, Baselga J, Hyman DM. Efficacy of Vemurafenib in Patients With Non-Small-Cell Lung Cancer With BRAF V600 Mutation: An Open-Label, Single-Arm Cohort of the Histology-Independent VE-BASKET Study. JCO Precis Oncol. 2019 Jun 27;3:PO.18.00266.
  • Dziadziuszko R, Smit EF, Dafni U, Wolf J, Wasąg B, Biernat W, Finn SP, Kammler R, Tsourti Z, Rabaglio M, Ruepp B, Roschitzki-Voser H, Stahel RA, Felip E, Peters SJ. Afatinib in NSCLC With HER2 Mutations: Results of the Prospective, Open-Label Phase II NICHE Trial of European Thoracic Oncology Platform (ETOP). Thorac Oncol. 2019 Jun;14(6):1086-1094.

Full list of Publications

  1. Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Felip E, Goldman JW, Scalzo C, Jensen E, Kush DA, Hui R.J Clin Oncol. 2019 Oct 1;37(28):2518-2527. doi: 10.1200/JCO.19.00934. Epub 2019 Jun 2.PMID:
  2. Clinical Management of Adverse Events Associated with Lorlatinib. Bauer TM, Felip E, Solomon BJ, Thurm H, Peltz G, Chioda MD, Shaw AT. Oncologist. 2019 Aug;24(8):1103-1110. doi: 10.1634/theoncologist.2018-0380. Epub 2019 Mar 19.PMID: 30890623
  3. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin CC, Soo RA, Riely GJ, Ou SI, Clancy JS, Li S, Abbattista A, Thurm H, Satouchi M, Camidge DR, Kao S, Chiari R, Gadgeel SM, Felip E, Martini JF. J Clin Oncol. 2019 Jun 1;37(16):1370-1379. doi: 10.1200/JCO.18.02236. Epub 2019 Mar 20.PMID: 30892989
  4. Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies. Nosaki K, Saka H, Hosomi Y, Baas P, de Castro G Jr, Reck M, Wu YL, Brahmer JR, Felip E, Sawada T, Noguchi K, Han SR, Piperdi B, Kush DA, Lopes G. Lung Cancer. 2019 Sep;135:188-195. doi: 10.1016/j.lungcan.2019.07.004. Epub 2019 Jul 8.PMID: 31446994
  5. Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study. Leighl NB, Hellmann MD, Hui R, Carcereny E, Felip E, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Lubiniecki GM, Zhang J, Piperdi B, Garon EB. Lancet Respir Med. 2019 Apr;7(4):347-357. doi: 10.1016/S2213-2600(18)30500-9. Epub 2019 Mar 12.PMID: 30876831 Clinical Trial.
  6. Capturing Hyperprogressive Disease with Immune-Checkpoint Inhibitors Using RECIST 1.1 Criteria. Matos I, Martin-Liberal J, García-Ruiz A, Hierro C, Ochoa de Olza M, Viaplana C, Azaro A, Vieito M, Braña I, Mur G, Ros J, Mateos J, Villacampa G, Berché R, Oliveira M, Alsina M, Elez E, Oaknin A, Muñoz-Couselo E, Carles J, Felip E, Rodón J, Tabernero J, Dienstmann R, Perez-Lopez R, Garralda E. Clin Cancer Res. 2020 Apr 15;26(8):1846-1855. doi: 10.1158/1078-0432.CCR-19-2226. Epub 2019 Nov 22.PMID: 31757877
  7. Position of a panel of international lung cancer experts on the approval decision for use of durvalumab in stage III non-small-cell lung cancer (NSCLC) by the Committee for Medicinal Products for Human Use (CHMP). Peters S, Dafni U, Boyer M, De Ruysscher D, Faivre-Finn C, Felip E, Garrido P, Girard N, Guckenberger M, Haanen J, Le Pechoux C, Mornex F, Ozsahin M, Paz-Ares L, Planchard D, Raben D, Ramalingam S, Reck M, Smit E, Stahel R, Stenzinger A, Swanton C, Vallone S, Garassino MC. Ann Oncol. 2019 Feb 1;30(2):161-165. doi: 10.1093/annonc/mdy553.PMID: 30624547
  8. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Peters S, Felip E, Dafni U, Belka C, Guckenberger M, Irigoyen A, Nadal E, Becker A, Vees H, Pless M, Martinez-Marti A, Tufman A, Lambrecht M, Andratschke N, Piguet AC, Kassapian M, Roschitzki-Voser H, Rabaglio-Poretti M, Stahel RA, Vansteenkiste J, De Ruysscher D. Lung Cancer. 2019 Jul;133:83-87
  9. YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib. Garmendia I, Pajares MJ, Hermida-Prado F, Ajona D, Bértolo C, Sainz C, Lavín A, Remírez AB, Valencia K, Moreno H, Ferrer I, Behrens C, Cuadrado M, Paz-Ares L, Bustelo XR, Gil-Bazo I, Alameda D, Lecanda F, Calvo A, Felip E, Sánchez-Céspedes M, Wistuba II, Granda-Diaz R, Rodrigo JP, García-Pedrero JM, Pio R, Montuenga LM, Agorreta J. Am J Respir Crit Care Med. 2019 Oct 1;200(7):888-899.
  10. Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. Herbst RS, Baas P, Perez-Gracia JL, Felip E, Kim DW, Han JY, Molina JR, Kim JH, Dubos Arvis C, Ahn MJ, Majem M, Fidler MJ, Surmont V, de Castro G Jr, Garrido M, Shentu Y, Emancipator K, Samkari A, Jensen EH, Lubiniecki GM, Garon EB. Ann Oncol. 2019 Feb 1;30(2):281-289.
  11. Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study. Conde E, Hernandez S, Martinez R, Angulo B, De Castro J, Collazo-Lorduy A, Jimenez B, Muriel A, Mate JL, Moran T, Aranda I, Massuti B, Rojo F, Domine M, Sansano I, Garcia F, Felip E, Mancheño N, Juan O, Sanz J, Gonzalez-Larriba JL, Atienza-Cuevas L, Arriola-Arellano E, Abdulkader I, Garcia-Gonzalez J, Camacho C, Rodriguez-Abreu D, Teixido C, Reguart N, Gonzalez-Piñeiro A, Lazaro-Quintela M, Lozano MD, Gurpide A, Gomez-Roman J, Lopez-Brea M, Pijuan L, Salido M, Arriola E, Company A, Insa A, Esteban-Rodriguez I, Saiz M, Azkona E, Alvarez R, Artal A, Plaza ML, Aguiar D, Enguita AB, Benito A, Paz-Ares L, Garrido P, Lopez-Rios F. J Thorac Oncol. 2019 Dec;14(12):2120-2132
  12. Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer. Gerber DE, Infante JR, Gordon MS, Goldberg SB, Martín M, Felip E, Martinez Garcia M, Schiller JH, Spigel DR, Cordova J, Westcott V, Wang Y, Shames DS, Choi Y, Kahn R, Dere RC, Samineni D, Xu J, Lin K, Wood K, Royer-Joo S, Lemahieu V, Schuth E, Vaze A, Maslyar D, Humke EW, Burris HA 3rd. Clin Cancer Res. 2020 Jan 15;26(2):364-372. doi: 10.1158/1078-0432.CCR-18-3965. Epub 2019 Sep 20.PMID: 31540980
  13. Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC. Barlesi F, Garon EB, Kim DW, Felip E, Han JY, Kim JH, Ahn MJ, Fidler MJ, Gubens MA, de Castro G Jr, Surmont V, Li Q, Deitz AC, Lubiniecki GM, Herbst RS. J Thorac Oncol. 2019 May;14(5):793-801. doi: 10.1016/j.jtho.2019.01.016. Epub 2019 Jan 31.PMID: 30711649 Clinical Trial.
  14. Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial. Michels S, Massutí B, Schildhaus HU, Franklin J, Sebastian M, Felip E, Grohé C, Rodriguez-Abreu D, Abdulla DSY, Bischoff H, Brandts C, Carcereny E, Corral J, Dingemans AC, Pereira E, Fassunke J, Fischer RN, Gardizi M, Heukamp L, Insa A, Kron A, Menon R, Persigehl T, Reck M, Riedel R, Rothschild SI, Scheel AH, Scheffler M, Schmalz P, Smit EF, Limburg M, Provencio M, Karachaliou N, Merkelbach-Bruse S, Hellmich M, Nogova L, Büttner R, Rosell R, Wolf J. J Thorac Oncol. 2019 Jul;14(7):1266-1276.
  15. Afatinib in NSCLC With HER2 Mutations: Results of the Prospective, Open-Label Phase II NICHE Trial of European Thoracic Oncology Platform (ETOP). Dziadziuszko R, Smit EF, Dafni U, Wolf J, Wasąg B, Biernat W, Finn SP, Kammler R, Tsourti Z, Rabaglio M, Ruepp B, Roschitzki-Voser H, Stahel RA, Felip E, Peters S. J Thorac Oncol. 2019 Jun;14(6):1086-1094.
  16. Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors. Nadal E, Massuti B, Dómine M, García-Campelo R, Cobo M, Felip E. Cancer Immunol Immunother. 2019 Mar;68(3):341-352.
  17. Epidermal growth factor receptor first generation tyrosine-kinase inhibitors. Martinez-Marti A, Navarro A, Felip E. Transl Lung Cancer Res. 2019 Nov;8(Suppl 3):S235-S246. doi: 10.21037/tlcr.2019.04.20.PMID: 31857948
  18. Lung cancer in Spanish women: The WORLD07 project. Garrido P, Viñolas N, Isla D, Provencio M, Majem M, Artal A, Carcereny E, Garcia Campelo R, Lianes P, De La Peñas R, Felip E. Eur J Cancer Care (Engl). 2019 Jan;28(1):e12941. doi: 10.1111/ecc.12941. Epub 2018 Oct 2.
  19. Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance. Zugazagoitia J, Gómez-Rueda A, Jantus-Lewintre E, Isla D, Camps C, Ramos I, Trigo JM, Bernabé R, Juan-Vidal O, Sanchez-Torres JM, García-Campelo R, Provencio M, Felip E, de Castro J, Faull I, Lanman RB, Ponce-Aix S, Paz-Ares L, Garrido P. Lung Cancer. 2019 Aug;134:72-78.
  20. Afatinib With Pembrolizumab for Treatment of Patients With Locally Advanced/Metastatic Squamous Cell Carcinoma of the Lung: The LUX-Lung IO/KEYNOTE 497 Study Protocol. Levy B, Paz-Ares L, Bennouna J, Felip E, Abreu DR, Isla D, Barlesi F, Molinier O, Madelaine J, Audigier-Valette C, Kim SW, Kim HR, Ozguroglu M, Erman M, Badin FB, Mekhail TM, Scheff R, Chisamore MJ, Sadrolhefazi B, Riess JW. Clin Lung Cancer. 2019 May;20(3):e407-e412.
  21. An open-label phase IB study to evaluate GSK3052230 in combination with paclitaxel and carboplatin, or docetaxel, in FGFR1-amplified non-small cell lung cancer. Morgensztern D, Karaseva N, Felip E, Delgado I, Burdaeva O, Dómine M, Lara P, Paik PK, Lassen U, Orlov S, Trigo J, Shomova M, Baker-Neblett K, Vasquez J, Wang X, Yan L, Mitrica I, DeYoung MP, Garrido P. Lung Cancer. 2019 Oct;136:74-
  22. Consolidative thoracic radiotherapy in stage IV small cell lung cancer: Selection of patients amongst European IASLC and ESTRO experts. Putora PM, Glatzer M, De Ruysscher D, Faivre-Finn C, Belderbos J, Besse B, Blackhall F, Califano R, Cappuzzo F, de Marinis F, Dziadiuszko R, Felip E, Früh M, Garrido P, Le Pechoux C, McDonald F, Nestle U, Novello S, Brien MO, Paz Ares L, Peeters S, Pöttgen C, Ramella S, Reck M, Troost EGC, Van Houtte P, Westeel V, Widder J, Mornex F, Slotman BJ. Radiother Oncol. 2019 Jun;135:74-77.
  23. Prophylactic cranial irradiation in stage IV small cell lung cancer: Selection of patients amongst European IASLC and ESTRO experts. Putora PM, Glatzer M, Belderbos J, Besse B, Blackhall F, Califano R, Cappuzzo F, de Marinis F, Dziadziuszko R, Felip E, Faivre-Finn C, Früh M, Garrido P, Le Pechoux C, McDonald F, Nestle U, Novello S, O'Brien M, Paz Ares L, Peeters S, Pöttgen C, Ramella S, Reck M, Slotman B, Troost EGC, Van Houtte P, Westeel V, Widder J, Mornex F, De Ruysscher D. Radiother Oncol. 2019 Apr;133:163-166.
  24. Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping. Zugazagoitia J, Ramos I, Trigo JM, Palka M, Gómez-Rueda A, Jantus-Lewintre E, Camps C, Isla D, Iranzo P, Ponce-Aix S, García-Campelo R, Provencio M, Franco F, Bernabé R, Juan-Vidal O, Felip E, de Castro J, Sanchez-Torres JM, Faul I, Lanman RB, Garrido P, Paz-Ares L. Ann Oncol. 2019 Feb 1;30(2):290-296.
  25. Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer. Sequist LV, Gray JE, Harb WA, Lopez-Chavez A, Doebele RC, Modiano MR, Jackman DM, Baggstrom MQ, Atmaca A, Felip E, Provencio M, Cobo M, Adiwijaya B, Kuesters G, Kamoun WS, Andreas K, Pipas JM, Santillana S, Cho BC, Park K, Shepherd FA. Oncologist. 2019 Aug;24(8):1095-1102. doi: 10.1634/theoncologist.2018-0695. Epub 2019 Apr 11
  26. A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer. Cejalvo JM, Jacob W, Fleitas Kanonnikoff T, Felip E, Navarro Mendivil A, Martinez Garcia M, Taus Garcia A, Leighl N, Lassen U, Mau-Soerensen M, Adessi C, Michielin F, James I, Ceppi M, Hasmann M, Weisser M, Cervantes A. ESMO Open. 2019 Jul 22;4(4):e000532.
  27. Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. Levy BP, Giaccone G, Besse B, Felip E, Garassino MC, Domine Gomez M, Garrido P, Piperdi B, Ponce-Aix S, Menezes D, MacBeth KJ, Risueño A, Slepetis R, Wu X, Fandi A, Paz-Ares L. Eur J Cancer. 2019 Feb;108:120-128.
  28. 5 protein-based signature for resectable lung squamous cell carcinoma improves the prognostic performance of the TNM staging. Martínez-Terroba E, Behrens C, Agorreta J, Monsó E, Millares L, Felip E, Rosell R, Ramirez JL, Remirez A, Torre W, Gil-Bazo I, Idoate MA, de-Torres JP, Pio R, Wistuba II, Pajares MJ, Montuenga LM. Thorax. 2019 Apr;74(4):371-379. doi: 10.1136/thoraxjnl-2018-212194. Epub 2018 Nov 24.
  29. Efficacy of Vemurafenib in Patients With Non-Small-Cell Lung Cancer With BRAF V600 Mutation: An Open-Label, Single-Arm Cohort of the Histology-Independent VE-BASKET Study. Subbiah V, Gervais R, Riely G, Hollebecque A, Blay JY, Felip E, Schuler M, Gonçalves A, Italiano A, Keedy V, Chau I, Puzanov I, Raje NS, Meric-Bernstam F, Makrutzki M, Riehl T, Pitcher B, Baselga J, Hyman DM. JCO Precis Oncol. 2019 Jun 27;
  30. Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer. Michels S, Heydt C, van Veggel B, Deschler-Baier B, Pardo N, Monkhorst K, Rüsseler V, Stratmann J, Griesinger F, Steinhauser S, Kostenko A, Diebold J, Fassunke J, Fischer R, Engel-Riedel W, Gautschi O, Geissinger E, Haneder S, Ihle MA, Kopp HG, de Langen AJ, Martinez-Marti A, Nogova L, Persigehl T, Plenker D, Puesken M, Rodermann E, Rosenwald A, Scheel AH, Scheffler M, Spengler W, Seggewiss-Bernhardt R, Brägelmann J, Sebastian M, Vrugt B, Hellmich M, Sos ML, Heukamp LC, Felip E, Merkelbach-Bruse S, Smit EF, Büttner R, Wolf J. JCO Precis Oncol. 2019 Mar 27;3:PO.18.00210.
  31. Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial. Ceresoli GL, Aerts JG, Dziadziuszko R, Ramlau R, Cedres S, van Meerbeeck JP, Mencoboni M, Planchard D, Chella A, Crinò L, Krzakowski M, Rüssel J, Maconi A, Gianoncelli L, Grosso F. Lancet Oncol. 2019 Dec;20(12):1702-1709. doi: 10.1016/S1470-2045(19)30532-7. Epub 2019 Oct 15.PMID: 31628016 Clinical Trial.
  32. Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial. Scagliotti GV, Gaafar R, Nowak AK, Nakano T, van Meerbeeck J, Popat S, Vogelzang NJ, Grosso F, Aboelhassan R, Jakopovic M, Ceresoli GL, Taylor P, Orlandi F, Fennell DA, Novello S, Scherpereel A, Kuribayashi K, Cedres S, Sørensen JB, Pavlakis N, Reck M, Velema D, von Wangenheim U, Kim M, Barrueco J, Tsao AS. Lancet Respir Med. 2019 Jul;7(7):569-580. doi: 10.1016/S2213-2600(19)30139-0. Epub 2019 May 15.PMID: 31103412 Clinical Trial.
  33. Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study. Fennell DA, Baas P, Taylor P, Nowak AK, Gilligan D, Nakano T, Pachter JA, Weaver DT, Scherpereel A, Pavlakis N, van Meerbeeck JP, Cedrés S, Nolan L, Kindler H, Aerts JGJV. J Clin Oncol. 2019 Apr 1;37(10):790-798. doi: 10.1200/JCO.2018.79.0543. Epub 2019 Feb 20.PMID: 30785827 Clinical Trial.
  34. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, Thai AA, Mascaux C, Couraud S, Veillon R, Van den Heuvel M, Neal J, Peled N, Früh M, Ng TL, Gounant V, Popat S, Diebold J, Sabari J, Zhu VW, Rothschild SI, Bironzo P, Martinez-Marti A, Curioni-Fontecedro A, Rosell R, Lattuca-Truc M, Wiesweg M, Besse B, Solomon B, Barlesi F, Schouten RD, Wakelee H, Camidge DR, Zalcman G, Novello S, Ou SI, Milia J, Gautschi O. Ann Oncol. 2019 Aug 1;30(8):1321-1328.
  35. Chronic pulmonary aspergillosis in a tertiary care centre in Spain: A retrospective, observational study. Aguilar-Company J, Martín MT, Goterris-Bonet L, Martinez-Marti A, Sampol J, Roldán E, Almirante B, Ruiz-Camps I. Mycoses. 2019 Sep;62(9):765-772. doi: 10.1111/myc.12950. Epub 2019 Jun 25.PMID: 31162731 Clinical Trial.
  36. Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC. Bauer TM, Besse B, Martinez-Marti A, Trigo JM, Moreno V, Garrido P, Ferron-Brady G, Wu Y, Park J, Collingwood T, Kruger RG, Mohammad HP, Ballas MS, Dhar A, Govindan R. J Thorac Oncol. 2019 Oct;14(10):1828-1838. doi: 10.1016/j.jtho.2019.06.021. Epub 2019 Jun 28.PMID: 31260835 Free article. Clinical Trial.
  37. Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis. Aasen T, Sansano I, Montero MÁ, Romagosa C, Temprana-Salvador J, Martínez-Marti A, Moliné T, Hernández-Losa J, Ramón y Cajal S. Cancers (Basel). 2019 Mar 6;11(3):320. doi: 10.3390/cancers11030320.PMID: 30845770
  38. Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study. Schuler M, Cho BC, Sayehli CM, Navarro A, Soo RA, Richly H, Cassier PA, Tai D, Penel N, Nogova L, Park SH, Schostak M, Gajate P, Cathomas R, Rajagopalan P, Grevel J, Bender S, Boix O, Nogai H, Ocker M, Ellinghaus P, Joerger M. Lancet Oncol. 2019 Oct;20(10):1454-1466. doi: 10.1016/S1470-2045(19)30412-7. Epub 2019 Aug 9.PMID: 31405822 Clinical Trial.

Projects

  • Grantor: AECC Scientific Foundation Ref: GCB14-2170.
    Title: Use of next-generation sequencing technologies for the identification of new therapeutic targets and prognostic markers in lung carcinoma poorly characterized.
    Coordinator: Luis Montuenga – CIMA (University of Navarra) Partner 3: Vall d’Hebron Institute of Oncology (VHIO).
    Principal Investigator: Enriqueta Felip
    2014 – 2019.
  • Grantor: Grant for Oncology Innovation - Merck
    Title: New technologies for new treatments: liquid biopsy meets immunotherapy.
    Principal Investigator: Enriqueta Felip.
    2016 – 2020.
  • Grantor: Instituto de Salud Carlos III Ref: PI17/00938.
    Title: Wnt/beta-catenin pathway activation in advanced non-small cell lung cancer: implications in resistance to immunotherapy and novel therapeutic strategies.
    2018 – 2020.
  • Grantor: ERA-NET Transcan 2017 Ref:TRANSCAN-084 Title: Non-invasive prognostic markers for Resected Early-STage NSCLC: role of circulatING and exosomal miRNAs and free circulating DNA (RESTING).
    Coordinator: Paola Ulivi– IRST-IRCCS Partner 2: Vall d’Hebron Institute of Oncology (VHIO)
    Principal Investigator: Enriqueta Felip.
    2018 – 2020.
  • Grantor: Cancer Research UK (CRUK) / AECC Scientific Foundation. Title: PREDICT-Meso: PRE-malignant Drivers Combined with Target-Drug validation in Mesothelioma”
    Coordinator: Kevin Blyth – University of Glasgow.
    Partner: Vall d’Hebron Institute of Oncology (VHIO).
    Principal Investigator: Susana Cedrés.
    2019 – 2022.

Tumor Immunology & Immunotherapy Group

Alena Gros
Principal Investigator
Biosketch
Principal Investigator Alena Gros Post-Doctoral Fellows Ricky Fong, Jara Palomero Graduate Students Judit Díaz, Andrea García, María Lozano, Anna Yuste Technicians Immaculada Creus, Albert Marín Students Roc Farriol, Carla Panisello

Summary

The immune system can recognize, hone in on and eliminate cancer. Through multiple mechanisms however, tumors can evade and dodge the immune response. Immunotherapies against cancer exploit the immune system to more effectively attack disease. Clinical studies have shown that immune checkpoint inhibitors and T cell-based therapies can mediate tumor regression in cancer patients with metastatic disease. Thus, in addition to surgery, radiation therapy and chemotherapy, immunotherapy is increasingly representing the fourth pillar of anti-cancer therapy across a variety of tumor types.

Despite encouraging antitumor responses, currently only a fraction of patients treated with immune-based therapies respond and some unfortunately report autoimmune-related adverse events. There is therefore a critical need to develop and personalize these promising treatments.

To do so, and thanks to the support received from the BBVA Foundation's Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) at VHIO, we study mechanisms of response, toxicity and resistance to cancer immunotherapeutics in patients at the Vall d’Hebron University Hospital (HUVH). We aim to identify biomarkers of response in liquid biopsies.

One correlative biomarker described to-date is mutation burden. Tumor-specific somatic mutations are optimal targets for cancer immunotherapy and render tumors immunogenic; some of these can bind to the patients’ human leukocyte antigen (HLA) molecules and elicit T-cell responses.

We adopt a highly personalized approach to screen for T-cell mediated recognition of mutated antigens as well as shared antigens using autologous antigen presenting cells that can process and present in all the potential HLA restriction elements.

Following this strategy, we aim to establish whether the presence of lymphocytes recognizing these antigens is associated with response. In parallel, we plan to advance personalized T-cell therapies to treat metastatic colorectal cancer, which is largely resistant to current anti-cancer strategies. We plan to file an IND to the Spanish Regulatory Agency in October 2020 that will enable us to treat patients with metastatic epithelial cancers with neoantigen-reactive TILs using this personalized approach. By enriching for neoantigen-reactive lymphocytes, we hope to enhance the efficacy of TIL therapy in epithelial cancers.

In summary, our group focuses on better understanding the naturally occurring T-cell response to cancer and establishing ways to exploit these antitumor responses to develop more effective, powerful, and precise immunotherapies against cancer.


Personalized approach to identify tumor and neoantigen-specific TILs. a) We sequence normal and tumor DNA to identify all the non-synonymous mutations. b) In parallel we attempt to generate a tumor cell line. When generated, we isolate the peptide-MHCI complexes and we identify the peptides presented by MHCI by the tumor cell line by Mass spectrometry. c) Finally, we screen the TILs expanded from the tumor cell line for recognition of the candidate neoantigen peptides identified in a) or elluted from MHCI in b).

Strategic goals

  • Characterize the personalized anti-tumor T-cell response in cancer patients.
  • Mine the personalized repertoire of tumor-reactive lymphocytes for potential biomarkers of response to cancer immunotherapy.
  • Investigate novel strategies to more swiftly identify tumor-reactive lymphocytes as well as the target antigens driving this response.
  • Study the tumor cell intrinsic mechanisms of resistance to T cell mediated cytotoxicity
  • Develop personalized T-cell-based cancer immunotherapies for patients with solid tumors.

Highlights

  • We have performed the clinical grade validations of TIL expansion for the treatment of patients in collaboration with our hospital’s Blood and Tissue Bank, and thanks to funding received from the BBVA Foundation and its Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) at VHIO Elena Garralda, Principal Investigator of VHIO’s Early Clinical Drug Development and Director of our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”, is designing the clinical protocol to treat patients with epithelial cancers with TILs enriched for neoantigen recognition. We estimate that we will submit the investigational new drug application (IND) and clinical protocol to the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) by October 2020. Our aim is to treat patients by mid-2021.
  • Our group is now collaborating with Holger Heyn, Team Leader at the National Center for Genomic Analysis (CNAG-CRG), Barcelona, to study the T cells infiltrating endometrial cancers with unprecedented detail, at the single cell level. These studies will guide the identification of T cells with superior traits for adoptive cell transfer.

Horizons

  • Use proteogenomics to identify neoantigen-specific and tumor-reactive cells.
  • Characterize the phenotype of circulating lymphocytes and changes following treatment with immune checkpoint inhibitors.
  • Develop non-invasive personalized T-cell based therapies for patients with solid cancers.

PI paper pick

  • Gros A, Tran E, Parkhurst MR, Ilyas S, Pasetto A, Groh EM, Robbins PF, Yossef R, Garcia-Garijo A, Fajardo CA, Prickett TD, Jia L, Gartner JJ, Ray S, Ngo L, Wunderllich JR, Yang JC, Rosenberg SA. Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes. J Clin Invest. 2019 Nov 1;129(11):4992-5004.
  • Garcia-Garijo A, Fajardo CA, Gros A. Determinants for Neoantigen Identification. Front Immunol. 2019 Jun 24;10:1392.

Projects

  • Grantor: Miguel Servet (Type 1).
    Title: Characterization of neoantigen-specific T cells and identification of predictive biomarkers of response in patients with MSI and MSI-like CRC treated with anti-PDL1.
  • Grantor: Instituto de Salud Carlos III.
    Title: Identificación de antígenos tumorales no canónicos y análisis de su relevancia en la inmunoterapia del cáncer.
  • Grantor: Asociación Española Contra el Cáncer – AECC (Lab AECC).
    Title: Identification of biomarkers of response to cancer immunotherapy in liquid biopsies.
  • Grantor: Asociación Española Contra el Cáncer – AECC (Ideas Semilla).
    Title: Identification of the personalized repertoire of immunogenic tumor rejection epitopes.
  • Grantor: EMD Serono (Grant for Oncology Innovation).
    Title: Personalized non-invasive T-cell therapies targeting the mutanome
  • Grantor: Fundación Fero (Beca Fero)
    Title: Non-invasive personalized T-cell therapies targeting recurrent hot spot driver mutations in cancer.
  • Grantor: Fundación BBVA.
    Alena Gros is a member of our VHIO-BBVA Foundation’s Immunotherapy & Immunology Program (CAIMI).