Joaquín Arribas
Preclinical & Translational Research
Co-Program Director

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Joan Seoane
Preclinical & Translational Research
Co-Program Director

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Josep Tabernero
Clinical Research
Program Director

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Preclinical & Translational Research

From the Co-Program Director

Joaquín Arribas
Preclinical & Translational Research
Co-Program Director

Preclinical research at VHIO focuses on establishing new ways to halt and revert the progression of highly aggressive tumors, including those affecting the breast, pancreas, colon, lung, and brain.

Considering the extensive inter- and intra-tumoral heterogeneity of human cancers, this is a complex challenge. To achieve this, we investigate novel anti-cancer therapeutic approaches tailored to each tumor type. We apply these therapies in increasingly faithful experimental models. Using these predictive models, we also anticipate the resistance of tumors to anti-cancer drugs.

As I reflect on just some of the many research highlights reported by our program this year, 2019 has been a particularly fruitful one. These advances have undoubtedly been driven by our purely collaborative approach to cancer science and teamwork with other VHIO groups and leading institutes in oncology. As Co-Program Director it is a pleasure and privilege to update on few important developments in 2019:

Tumor Biomarkers Group

VHIO’s Tumor Biomarkers Group, headed by Josep Villanueva, has continued to pursue their studies to demonstrate the potential of HMGA1 as a biomarker and drug target in breast cancer. Notably, his team has focused on the development of monoclonal antibodies against HMGA1 that could be used in the near future in cancer diagnostics and therapeutics.

Their expertise in this field led to a review article this year exploring the future clinical implications of the unexpected secretion of HMGA1 in triple-negative breast cancer (Méndez et al. Int J. Mol. Sci. 2019), and has also resulted in several collaborations with academic groups and the pharmaceutical industry. As an example, they have recently participated in a project led by Arkaitz Carracedo at the CIC BioGUNE (Bizkaia, Spain), that studied the induction of senescence by the gene PML (Revandkar et al. Cell Death Differ. 2019).

Experimental Therapeutics Group

Our Experimental Therapeutics Group, directed by Violeta Serra, has made important progress this past year. Crucially, they initiated the clinical validation of the RAD51predict test, an immune-based assay performed on FFPE tumor sections, to predict response to PARP inhibitors across multiple tumor types. This is an international project funded by the ERA PerMed program - an ERA-Net Cofund, supported by 32 partners from 23 countries, and co-funded by the European Commission (Coordinator: Instituto de Salud Carlos III - ISCIII).

Thanks also to the support received this year from the CaixaImpulse Consolidate program ("la Caixa" Foundation and Caixa Capital Risk), this test will be further developed towards its implementation as a diagnostic test.

Additionally, her group has unveiled novel mechanisms of resistance to targeted therapies in hereditary BRCA1/2 breast cancer and in estrogen receptor (ER)-positive breast cancer. These findings have been reported as publications in renowned journals including Nature Communications and Molecular Cancer Therapeutics. Finally, with funding received from the Breast Cancer Now Foundation, a novel strategy to treat ER+ tumors based on targeting the androgen receptor will be widely tested in patient-derived tumor models. Again, the close collaboration and connectivity with other VHIO groups are key to these important achievements.

Mouse Models of Cancer Therapies Group

Laura Soucek’s Mouse Models of Cancer Therapies Group, has continued to contribute to groundbreaking science by reporting definitive advances in bringing the Myc inhibitor mini-protein, Omomyc, closer to the clinic (Beaulieu et al. Sci Transl Med. 2019). The relevance of this publication was attested by a comment in Nature Reviews Cancer, and Nature Reviews Drug Discovery by the journal’s Editor, Teresa Villanueva.

Laura’s group has also collaborated with Rajeev Vibhakar, the University of Colorado Health Sciences Center (USA), to demonstrate the therapeutic potential of Myc inhibition in childhood rhabdoid tumors. As a result of another collaboration with Esther Vázquez and Antonio Villaverde, Universitat Autònoma de Barcelona (UAB), and Ibane Abasolo, Vall d'Hebron Research Institute (VHIR), Barcelona, her group has shown the therapeutic potential of therapeutic proteins delivered in the form of inclusion bodies to treat breast cancer.

Finally, alongside Jordi Alcaraz, University of Barcelona (UB), Laura’s team has also evidenced that epigenetic SMAD3 repression in tumor-associated fibroblasts reduces fibrosis and sensitivity to the antifibrotic drug nintedanib in lung squamous cell carcinoma.

Growth Factors Group

My own Growth Factors Group, has embarked on a novel line of research to generate novel CARs (chimeric antigen receptors) as the state-of-the-art strategy to use the immune system of patients to eradicate tumors.

With the insights gained during the development and characterization of bispecific antibodies, we have been able to develop our CARs in a highly efficient manner. They are directed against a protein, named p95HER2, which is only found in some mammary and gastric tumors and completely absent in normal tissues. Of note, this project has been funded by the Spanish Association Against Cancer (AECC), for the next five years.

Our expanding platform of breast and pancreatic cancer patient-derived experimental models has allowed us to establish a series of fruitful collaborations with several national and international groups. These partnerships have enabled us to identify novel mechanisms of resistance to anti-tumor therapies (Lambies et al., Diaz-Rodriguez et al., and Gomez-Miragaya et al.) and biomarkers of sensitivity to precision therapies (Kang et al., Blasco-Benito et al.).

We have also contributed to characterizing a novel antibody drug conjugate that has proven effective against some pancreatic tumors and triple negative breast cancers (Merlino et al.). In addition, we have helped to identify drugs targeting senescent cells which, under certain circumstances, have an important role in tumor progression. Within VHIO, we have joined forces with Sandra Peiró’s Chromatin Dynamics in Cancer Group, to unveil mechanisms that govern gene expression in triple negative breast cancer (Cebria Costa et al.).

In 2019 Veronica Rodilla was awarded with a Stop Fuga de Cerebros grant from Roche aimed at retaining talent ‘at home’, and Irene Rius and Faiz Bilal both defended their PhDs on novel therapies against breast and pancreatic cancers, respectively.

Lastly, it has been an extremely productive year for the Centro de Investigación Biomédica en Red (CIBERONC- Instituto de Salud Carlos III (ISCIII): Center for the Biomedical Research Network in Oncology), under the expert leadership of Anna Bigas, Hospital del Mar Medical Research Institute - IMIM (Barcelona).

This network, which I had the pleasure of leading from 2016-2019, comprises several of the most active cancer research groups across Spain, including my own group, VHIO's Gene Expression, and Gastrointestinal & Endocrine Tumors Groups (PI: Teresa Macarulla), directed by Joan Seoane and Josep Tabernero, respectively.

Preclinical & Translational Research

From the Co-Program Director

Joan Seoane
Preclinical & Translational Research
Co-Program Director

To develop and enhance anti-cancer therapies targeting all cell types within a tumor, we must achieve a deeper understanding of intratumoral heterogeneity. Among the different cell types forming this complex landscape, cancer stem cells (CSCs) have been characterized by their self-renewing capacity, multi-lineage differentiation properties, high oncogenic potential, and ability to replicate the heterogeneity of original human tumors in mouse models.

They are also responsible for the initiation, recurrence and chemo- and radio-resistance of tumors, indicating that more effective therapies could be identified via strategies targeting the stem-cell-like component of tumors. To-date, few pharmacological compounds have proven successful.

VHIO’s preclinical and translational researchers investigate cancer as closely as possible to the actual tumor and generate patient-derived in vitro and in vivo cancer models. Tumor specimens are obtained shortly upon surgical resection and we then study their respective tumor cells and cancer stem cells. Mouse models are then developed to recapitulate the characteristics of patients’ tumors as faithfully as possible.

Both VHIO’s Stem Cells & Cancer Group, led by Héctor G. Palmer, and my own Gene Expression & Cancer Group, have helped to develop these models for brain cancer as well as CRC, neuroendocrine, hepatic tumors, and peritoneal pseudomyxoma, respectively.

Stem Cells & Cancer Group

In 2019, Héctor G. Palmer's Group has also continued to explore novel strategies to combat cancer cell dormancy and discover new therapeutic targets. Building on their previous findings (Puig et al. J Clin Invest. 2018), evidencing TET2 as a controller of chemo-resistant slow-cycling cancer cell survival and tumor recurrence, his group is now investigating the function of TET2, DPPA3, and other epigenetic factors governing dormancy in further depth.

They are making important progress in developing therapies that modulate these dormancy drivers and defining biomarkers to detect chemo-resistant dormant tumor cells (DTCs).

His team explores molecular mechanisms conferring sensitivity or resistance to therapies in order to more precisely stratify patients for enrollment in clinical trials. As an example, in collaboration with other Spanish groups and VHIO teams including Gastrointestinal & Endocrine Tumors (PI: Teresa Macarulla), Cancer Genomics (PI: Ana Vivancos), Molecular Oncology (PI: Paolo Nuciforo), Early Clinical Drug Development (PI: Elena Garralda), they have studied epigenetic EGFR gene repression and the conferrence of sensitivity to therapeutic BRAFV600E blockade in colon neuroendocrine carcinomas; results of which were published this year (Capdevila et al. Clin Cancer Res. 2020. Epub 2019).

Cellular Plasticity & Cancer Group

VHIO’s Cellular Plasticity & Cancer Group headed by Maria Abad, continues to mark important progress in identifying and characterizing novel cancer micropeptides involved in cancer cell plasticity that could represent novel actors in carcinogenesis. Not only could these tumor-micropeptides be crucial in advancing insights into cancer physiopathology, but they could also serve as novel cancer biomarkers for early detection of disease.

To-date Maria’s team have discovered six new cancer micropeptides and shown evidence in vitro and in vivo that four of them act as novel tumor suppressors, triggering cell cycle arrest, differentiation, or inhibition of mesenchymal traits in cancer cells. During 2019 her group’s research has expanded to identify novel secreted micropeptides that act as crucial cellular messengers for pancreatic metastasis. Watch this space!

Chromatin Dynamics in Cancer Group

Research carried out by Sandra Peiró’s Chromatin Dynamics in Cancer Group, continues to advance insights in deciphering the 3D chromatin structure and dynamics in cancer, as well as identify biomarkers and epigenetic mechanisms of drug resistance in ER+ breast cancer, cholangiocarcinomas, and NUT-midline carcinomas.

Alongside other groups including VHIO’s Growth Factors Group (PI: Joaquín Arribas), her group has recently reported findings (Cebrià-Costa el al. Oncogene 2020. Epub 2019), that could represent a forward step in more effectively combating cancer drug resistance in triple-negative breast cancer (TNBC).

When compared to other breast cancer subtypes, they have discovered that the DNA of TNBC cells is much more compacted which renders it resistant to therapy. Their results indicate that chromatin decompaction could potentiate current therapies.

They have also shown that LOXL2 inhibition could prevent chromatin compaction from occurring. This is particularly relevant since it seems to frequently occur in TNBC, which hinders therapies from accessing the nucleus of cancer cells. In patients with the triple-negative subtype who show most resistance to conventional therapies, LOXL2 is present in high levels. This finding points to its role as a mechanism of resistance.

Gene Expression & Cancer Group

My group has continued to pioneer and develop liquid biopsy to disentangle the complexity and heterogeneity of brain tumors. Our analysis of ctDNA in cerebrospinal fluid has opened up new avenues for research aimed at achieving a better understanding of central nervous system cancers.

Reflective of our expertise in this field, we recently analyzed various studies on the use of liquid biopsy in primary and metastatic brain tumors for diagnosis and follow-up of disease as well as the identification of mechanisms or resistance or susceptible mutations (Seoane et al. Ann Oncol. 2019). Not yet ready for ‘prime time’, our group will continue to lead research in liquid biopsy to bring this novel approach closer to the clinic.

We are as equally committed to exploring the tumor microenvironment which, in the case of brain tumors, plays a key role in cancer progression. Importantly, we have reported that the cytokine LIF assumes an essential role in the tumor microenvironment and is thus a promising therapeutic target.

Building on our previous research, where we established a link between LIF and cancer as well as showed that its blockade eliminates cancer stem cells and prevents disease progression and recurrence, our group has now evidenced that LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8 + T cell tumor-inflation impairing anti-PD1 therapy (Pascual-García et al. Nat Commun. 2019).

Finally, we have embarked on two new multidisciplinary projects in 2019. First, in collaboration with Enriqueta Felip, PI of VHIO’s Thoracic Tumors and Head and Neck Cancer Group, and Eva Muñoz, Clinical Investigator of our Breast Cancer & Melanoma Group (PI: Cristina Saura, we will analyze patients’ brain metastases and compare them with respective primary tumors to identify ‘governers’ of clinical response to immune checkpoint blockade.

Secondly, in partnership with Francesc Bosch, PI of VHIO´s Experimental Hematology Group, our research in liquid biopsy will extend to CNS lymphoma patients for the early and real-time detection of disease recurrence and brain metastases.

It is thanks to such a strong VHIO ethos of teamwork and purely multidisciplinary approach to cancer science that preclinical and clinical research at our Institute are tightly connected. Our teams collectively strive to accelerate the transformative, robust science that can translate into clinical benefits for our patients.

Clinical Research

From the Program Director

Josep Tabernero
Clinical Research
Program Director

VHIO’s multidisciplinary and translational approach to team science tightly connects its cancer scientists with our clinical investigators. From the very outset, this model has enabled our program to spearhead cooperative preclinical, early phase studies aimed at developing novel anti-cancer therapies, as well as new or redefined prognostic/diagnostic tools and techniques to better detect disease, track progression and more accurately predict response to treatments.

As our Institute goes from strength to strength, and further develop its research lines and projects based on defined strategic directions, we continue to expand our scientific faculty as well as scientific support units and teams. As an example in 2019, César Serrano, Medical Oncologist and Clinical Investigator of our Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group (directed by Joan Carles), set up our Sarcoma Translational Research Group.

His group aims to identify the critical molecular mediators of oncogenic signaling sarcomas, characterize response and resistance mechanisms to targeted therapies against these tumor types, as well as preclinically model and validate therapeutic strategies toward improving outcomes for patients in the clinic.

Many research lines at VHIO are fueled thanks to our three institutional programs; the VHIO-FERO Foundation’s Advanced Molecular Diagnostics Program (DIAMAV), VHIO- ”la Caixa” Foundation Advanced Oncology Research Program, and the VHIO-BBVA Foundation Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI). We also continue to advance cancer science and medicine thanks to the tremendous support that we receive from all of our Institutional Supporters, international and national funding bodies, associations and entities, as well as companies, patient advocay groups, charities, and individual donors.

Concerning clinical trial design in the era of precision oncology, our program pioneers novel study design including Baskets and first-in-human trials. As an example, results from the WINTHER clinical trial, Genomic and transcriptomic profiling expands precision medicine, co-authored by Jordi Rodón, Clinical Investigator at the MD Anderson Cancer Center (Texas, USA), and Associate Investigator of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM), and Irene Braña, Phase I Investigator of the same Unit, published in 2019 (Rodon J et al. Nat Med. 2019).

Led by VHIO’s Early Clinical Drug Development Group directed by Elena Garralda, and carried out in collaboration with other leading members of the WIN Consortium, findings showed that RNA profiling together with DNA testing matches more patients with advanced cancer to personalized anti-cancer therapies than DNA profiling for tumor mutations alone. For more information please see my Foreword.

Additionally, our Basket of Baskets (BoB) two-stage clinical trial study that promises a more flexible and adaptive model in order to significantly accelerate patients’ access to an array of novel therapeutics, officially launched in 2019. Endorsed by the Cancer Core Europe Consortium – CCE, BoB is the first European multi-modular academic trial that integrates molecular prescreening, the development of novel diagnostic tests including ctDNA, with the assessment of targeted therapies matched to those patients who will be most likely to benefit from them.

This novel trial is being carried out at our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”, directed by Elena Garralda, and counts on the expertise of several VHIO investigators including Rodrigo Dienstmann, PI of VHIO’s Oncology Data Science Group (ODysSey), and Ana Vivancos who leads our Cancer Genomics Group. For more updates on BoB please also see my Foreword.

In addition to our participation in the WIN Consortium and Cancer Core Europe, we also belong to several other important cross-border collaborations. Covered in detail in my Foreword to this report, 2019 celebrated the launch of an additional five pioneering projects.

In addition to my pick of additional practice changing studies highlighted in my Foreword, I also take this opportunity to mention a few more that made the headlines in 2019:

Good news for the treatment landscape of HER2+ refractory metastatic breast cancer

Data from a phase II study, that were presented on the ground at the 2019 San Antonio Breast Cancer Symposium – SABCS (10-14 December, San Antonio, USA), driven in collaboration with VHIO, promise new hope for the treatment of metastatic HER2-postive breast cancer.

The phase II DESTINY-Breast01 study (Modi S et al. N Engl J Med. 2019), co-authored by VHIO’s Cristina Saura, Principal Investigator of our Breast Cancer Group, also in collaboration with Javier Cortés, Translational Investigator of the same group this study built on findings from the phase I safety results (Tamura K et al. Lancet Oncol. 2019) of this second generation antibody drug conjugate; trastuzumab deruxtecan against advanced HER2 positive breast cancer previously treated with trastuzumab emtansine.

Findings showed that 60.9% of those patients treated with this novel therapy had an objective response, with progression free survival at more than 16 months. These results are particularly important considering that these patients had progressed after an average of 6 other previous lines of therapy. Importantly, the investigators showed that trastuzumab deruxtecan achieves lasting results and significant anti-cancer activity. As such, this novel approach could provide fresh hope for those patients with refractory disease who have limited treatment options.

Gene-targeted olaparib delivers powerful blows against BRCA1/2 mutated prostate cancer

First authored by Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research Group, results from the TOPARP-B multi-center phase II trial, published ahead of print in 2019 (Mateo J et al. Lancet Oncol. 2020), confirmed the anti-tumor activity of single agent PARP inhibitor, olaparib, against metastatic castration-resistant prostate cancer (mCRPC).

Designed as an open-label single arm study, the second in this two part adaptive trial sought to establish the efficacy of treating mCRPC patients with DNA-damage repair (DDR) alterations, who had previously received chemotherapy and were no longer responding to standard treatments. TOPARP-B drew on the promising results reported from TOPARP-A where the association between DNA repair defects and response to olaparib in 49 molecularly unselected patients was first described.

The investigators performed targeted screening and identified those patients whose prostate cancers had faulty DNA repair genes. 98 patients from across a total of 17 UK hospitals were randomly assigned and treated in the study. Results showed that overall, 47% of patients with these DNA repair defects responded to olaparib, putting the brakes on disease progression for an average of 5.5 months. The most common defects were BRCA mutations, although various others were also identified in other genes including PALB2 and ATM, among others.

Importantly, those men with BRCA1/2 mutated disease responded the best, with 80% responding and 40% free of cancer progression for over a year. The high and durable responses observed in the subpopulation of patients with mCRPC support the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice based on tumor sequencing. This gene-targeted approach could help guide treatment decisions as well as match more effective therapies to the molecular make up of individual patients’ tumors.

Encouraging responses were also observed in patients carrying PALB2 mutations, ATM mutations, and other DNA repair gene alterations – totaling at 50, 37, and 20% respectively. These findings might also point to PARPi having a role as monotherapy or in combination to more effectively tackle other subtypes of metastatic prostate cancer.

Driving the development of pioneering cell therapies for non-responders to current immunotherapies

Research led by Alena Gros, Principal Investigator of our Tumor Immunology & Immunotherapy Group signposts a new, less invasive approach to identify killer T lymphocytes in patients with gastrointestinal tumors with low mutational burden who are refractory to approved immune-based treatments. Importantly, killer T cells identified in blood that can hone in on mutations uniquely expressed in cancer cells pave the way for an alternative and personalized therapeutic avenue.

More specifically, those patients with gastrointestinal tumors with low mutational burden, so-called ‘cold’ tumors, constitute a current challenge for immunotherapy. Novel cell therapies based on the administration of killer T cells that can recognize neoantigens, have shown promising antitumor activity in a small number of patients with cold tumors.

Findings reported by Alena’s Group (Gros A et al. J Clin Invest. 2019), in collaboration with colleagues at the National Cancer Institute (NCI-NIH) and other leading institutes, break new ground within the field by promoting the development of these treatments towards ultimately providing new hope for patients with metastatic disease who do not respond to treatment with approved cancer immunotherapies. Additionally, the investigators described a less invasive, blood-based method to identify, measure and track lymphocytes against neoantigens expressed in advanced gastrointestinal cancers including pancreas, gastroesophageal, bile duct, colon and rectum.

While the investigators did not initially expect to find killer T lymphocytes in the blood of these patients with cold tumors, with low mutational burden, they showed that these cells can be identified and selected in blood. This study will promote the identification of neoantigen-specific T lymphocytes derived from blood towards ultimately offering a new array of personalized and more promising anti-cancer immunotherapeutic for these patients.

Screening BRCA1/2 deep intronic regions to reveal the missing links in HBOC susceptibility

Dedicated to unmasking variants toward improved genetic diagnosis, research spearhead by Judith Balmaña’s Hereditary Cancer Genetics Group, first co-authored by Gemma Montalban (former Graduate Student of the group), and Senior Scientists, Sara Gutiérrez-Enríquez and Orland Díez (Montalban G. J Med Genet. 2019), builds on their efforts to more precisely explore the genetic epidemiology of hereditary breast and ovarian cancer (HBOC).

This 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.

Genetic analysis of BRCA1 and BRCA2 for the diagnosis of hereditary breast and ovarian cancer (HBOC) generally focuses on coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain around 20% of HBOC cases, there is still an important fraction that remains undiagnosed.

Aimed at identifying potential spliceogenic variants that could explain part of the missing HBOC susceptibility, the investigators screened BRCA1/2 deep intronic regions by targeted gene sequencing in 192 high-risk HBOC families testing negative for BRCA1/2 during conventional analysis.

This research identified the first BRCA1 deep intronic variant associated with HBOC by pseudoexon activation. While the frequency of deleterious variants in these regions appeared to be low, their study highlights the importance of studying non-coding regions and performing comprehensive RNA assays to both complement and improve genetic diagnosis.

lorlatinib and the more precise treatment of non-small-cell lung cancer

Research co-authored by Enriqueta Felip, Principal Investigator of our Thoracic Tumors & Head and Neck Cancer Group, represents an important advance in more effectively treating patients suffering from anaplastic lymphocyte kinase (ALK) -positive non-small-cell lung cancer who have failed therapy with one or more second-generation ALK tyrosine kinase inhibitors – TKIs (Shaw AT et al. J Clin Oncol. 2019).

Considering the body of preclinical data that suggest ALK resistance mutations may represent a biomarker of response in previously treated patients, the investigators sought to advance insights into the molecular determinants of response to lorlatinib, a third-generation ALK-TKI, to more effectively identify those patients who are more likely to derive clinical benefit.

Plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer. The researchers analyzed plasma DNA for ALK mutations and studied tumor tissue DNA using an ALK mutation-focused next-generation sequencing assay. Results showed that lorlatinib is more effective in patients with ALK mutations compared with those without.

Tumor genotyping for ALK mutations after failure of a second-generation TKIs may more precisely identify patients who are most likely respond to this therapy.

BRCA reversion mutations: key players in resistance to PARP inhibitors

Ana Oaknin, Principal Investigator of VHIO’s Gynecological Malignancies Group, has co-authored research evidencing that BRCA reversion mutations in circulating tumor DNA (ctDNA) predict primary and acquired resistance to the PARP Inhibitor (PARPi) rucaparib in high-grade ovarian carcinoma – HGOC (Lin KK et al. Cancer Discov. 2019).

A key resistance mechanism to platinum-based chemotherapies and PARPi in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in HGOC, the authors of this study performed deep liquid biopsy analysis on patients’ blood samples collected during their participation in the ARIEL2 international, multicenter, two-part, phase II study.

By targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with PARPi rucaparib, BRCA reversion mutations were identified in pretreatment cfDNA from 18% of platinum-refractory and 13% of platinum-resistant cancers, compared with 2% of platinum-sensitive cancers.

Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations. To study acquired resistance, they sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA.

Adding to our increasing insights into PARPi and mechanisms of resistance, results show that BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC, and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, demonstrating the capture of multiclonal heterogeneity.

Seeking out more effective and less toxic treatment approaches against prostate cancer

First authored by Joan Carles, Principal Investigator of our Genitourinary, CNS Tumors, Sarcoma and Cancer of Unknown Primary Site Group, in collaboration with Jordi Giralt’s Radiation Oncology Group, a phase II randomized study (Carles J et al. Int J Radiat Oncol Biol Phys. 2019) assessed the activity of radiation therapy and 3-year androgen deprivation with or without chemotherapy in patients with high-risk localized prostate cancer.

Chemotherapy with docetaxel improves survival in patients with metastatic prostate cancer. The investigators aimed to establish the efficacy of combining docetaxel with radiation therapy (RT) plus androgen deprivation in this patient population by examining the benefit of 9 weekly docetaxel administrations to RT plus three years of luteinizing hormone-releasing hormone analogues.

A total of 132 patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT + 9 weekly cycles of docetaxel + 3 years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5 years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity.

Results showed that concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. While no statistically significant differences for 5-year BRFS, PFS, and OS were observed when docetaxel was added to conventional treatment, long-term follow-up has not yet been enough to meet median PFS and OS.

Predicting risk of distant dissemination in early-stage colorectal cancer

Led by Rodrigo Dienstmann, Principal Investigator of VHIO’s Oncology Data Science – ODysSey Group, results from a study (Dienstmann R et al. Ann Oncol. 2019) assessing the relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer, confirm tumor microenvironment infiltration patterns as powerful predictors of the risk for distant dissemination in early-stage colorectal cancer (CRC).

The investigators sought to establish whether consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns can better predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage CRC.

Results showed that in multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores and the poor prognosis linked to high CAF scores was limited to stage III disease.

These findings show that tumor microenvironment infiltration patterns represent potent determinants of the risk of cancer cell spread in patients with early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

In addition to the many original research articles published this year, our investigators have also authored several reviews, commentaries, opinion pieces, and invited perspectives.

As an example, Francesc Bosch, Principal Investigator our Experimental Hematology Group, co-authored a superb review (Bosch F, Dalla-Favera R. Nat Rev Clin Oncol. 2019), exploring novel insights into the genetic lesions involved in the pathogenesis of chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in adults, and how these discoveries are influencing the clinical management and the development of new therapeutic strategies against this disease.

Importantly, my selection of the clinical science that has shaped our year offers a mere snapshot of the many contributions driven by VHIO talents. These accomplishments have only been possible in collaboration with other VHIO groups, and thanks to strong cross-border partnerships.

Together, we can and will do better.