Molecular analysis for refractory rare cancers: Sequencing battle continues – learnings for the MOSCATO-01 study

ElsevierVolume 181, January 2023, 103888Critical Reviews in Oncology/HematologyAuthor links open overlay panelAbstractBackground

For patients with metastatic rare cancers, treatments are limited. How systematic tumor sequencing can improve therapeutic possibilities in this population?

Patients and methods

Patients with rare cancer were identified in the MOSCATO-01 trial. Patients’ outcome was measured by progression-free survival (PFS) and overall survival (OS).

Results

The most frequently identified histologic subypes were ovarian adenocarcinoma (N = 13), carcinoma of unknown primary (N = 11), and leiomyosarcoma (N = 10). Ninety-nine (39%) of them had at least one targetable cancer molecular alteration Forty-nine patients (50%) received the therapy proposed by the molecular tumor board, and 13 patients (26%, 95%CI 15–41%) achieved a PFS2/PFS1 > 1.3. The median PFS2 on matched treatment subgroup was 2.3 months (95% CI 1.8–3.6) and the median OS was 11.4 months (95% CI 9–15.5).

Conclusions

The molecular screening of patients with refractory, metastatic rare cancers might increase the therapeutic options. Facilitating access strategy to molecular-driven clinical trials or agnostic-approved treatment is crucial.

Introduction

The definition of rare cancer varies across institutions: for the NCI the cut-off is an annual incidence lower than 15 cases per 100,000 persons whereas the RARECAREnet and ESMO define rare cancers for an annual incidence lower than six per 100,000 people (Definition of rare cancer - NCI Dictionary of Cancer Terms - National Cancer Institute, 2011, Gatta et al., 2011). Overall, rare cancers encompass more than 200 histologic types. The cumulative frequency of patients with rare cancers in the US ranges between 20% and 25% of all cancers (DeSantis et al., 2017, Gatta et al., 2017, Gatta et al., 2011, Greenlee et al., 2010).

Rare cancers are more often diagnosed at the metastatic stage (59%) compared to non-rare cancer types (45%) (DeSantis et al., 2017). These patients have poorer outcomes compared to patients affected by the most frequent cancer types (respective 5-year overall survival (OS) of 49% versus 63%) (DeSantis et al., 2017). This observation could be explained by the limited number of standard treatments for rare cancers, mainly because of the lack of data from large randomized trials, particularly beyond the first line in the metastatic setting. Trials dedicated to specific rare tumor types are limited by poor recruitment, thus tumor-agnostic approaches can compensate this limitation.

Conventional therapeutic strategies for patients with rare cancer at the metastatic stage are best supportive care and/or systemic therapy, mostly chemotherapy, often without strong evidence for efficacy but used out of label by analogy with other tumor types. In the case of identifiable molecular targets, there are tumor-agnostic approved drugs in some rare situations but few registration trials exist (for example larotrectinib for tumors harboring NTRK fusion or immune checkpoint inhibitors for patients with mismatch repair deficient tumors, or with high tumor mutational burden) (Lemery et al., 2017, Drilon et al., 2018, Marabelle et al., 2020). Finally, in case of a lack of any therapeutic alternative, the type of clinical trials offered to patients with rare cancers could be 1) specific to their tumor type, rare by nature, 2) pan-tumor - mostly phase I dose-escalation clinical trials, or 3) studies enriched on molecular alteration(s) (Adashek et al., 2019, Groisberg et al., 2018, Mandrekar and Sargent, 2011). We propose a rational approach to promote access to molecularly driven trials and therefore to increase the therapeutic possibilities for patients with a metastatic rare cancer. To support this hypothesis, we performed on-purpose tumor molecular analysis of patients with metastatic or locally advanced rare cancers refractory to recommended treatments in a Comprehensive Cancer Center within the MOSCATO-01 trial cohort. The purpose of this analysis is to investigate the feasibility of molecular-driven therapy in the challenging setting of metastatic rare cancers and to present preliminary data on the impact on progression-free survival of this strategy (according to MOSCATO-1 protocol criteria). The discussion on this data provides an insight into initiatives aiming to improve diagnosis and treatment for rare cancer patients.

Section snippetsMolecular analysis

The prospective evaluation of the MOlecular Screening for Cancer Treatment Optimization trial (MOSCATO, NCT01566019) was conducted in Institut Gustave Roussy, Villejuif, France, between December 2011 and March 2016. New freshly frozen biopsies from the metastatic sites were collected and analyzed by high throughput genomic analysis. A dedicated pathologist revised the tumor tissue to guarantee the sample quality. In the case of more than 30% of tumor cells on biopsy, a CGH and targeted

Patients characteristics

Among a total cohort of 948 patients prospectively enrolled in the MOSCATO-1 trial between December 2011 and March 2016, with advanced cancers and successful biopsies, 252 patients had rare cancer type. The median age at diagnosis was 51 years old (range, 19–84), with a majority of females (53%), and 64% of patients had one to two metastatic sites (Supplementary Table 1). In this cohort, 99 patients had at least one actionable alteration (39%) (Fig. 1, Table 1). The median age at inclusion was

Discussion

Here we report the analysis of patients with rare cancers as defined by the ESMO and RARECAREnet, who participated in a treatment personalization program. We identified a targetable molecular alteration for 39.3% and administered a recommended targeted treatment for 19% of patients with rare cancers. These numbers are slightly below the whole MOSCATO-01 cohort where 49% of patients who consented had a targetable molecular alteration and 24% received the recommended therapy (Massard et al., 2017

Véronique Debien, MD, MSc: She has a medical degree obtained at University of Strasbourg, France, as well as a Master of Science degree in research in Biomedicine. She performed her medical oncology specialization in University Hospital of Strasbourg, Institut de Cancérologie Strasbourg, and at Institut Gustave Roussy (Villejuif, France). She is currently a postdoctoral research fellow at Institut Jules Bordet (Brussels, Belgium.) The clinical research with the emphasis on the academic promoted

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Véronique Debien, MD, MSc: She has a medical degree obtained at University of Strasbourg, France, as well as a Master of Science degree in research in Biomedicine. She performed her medical oncology specialization in University Hospital of Strasbourg, Institut de Cancérologie Strasbourg, and at Institut Gustave Roussy (Villejuif, France). She is currently a postdoctoral research fellow at Institut Jules Bordet (Brussels, Belgium.) The clinical research with the emphasis on the academic promoted studies is the core of her research work. She is actively involved in conducting phase II clinical trials in breast and bladder cancer, as well as leading research projects. Her clinical activity is focused on the breast cancer and early drug development. She is an author and co-author of around ten peer-reviewed publications, and has presented her work at different poster sessions at San Antonio Breast cancer Symposium, ASCO, ESMO annual congresses. She is a PhD candidate in Biomedicine at Université Libre de Bruxelles. She is a member of ESMO, ASCO, AACR, and young investigator in Breast and Genito-Urinary Groups at EORTC.

Stéphane Vignot, MD, PhD: He is a medical oncologist, former Assistant Professor and hospital practitioner at the Assistance Publique - Hôpitaux de Paris (France). He received his medical degree from Paris Diderot University, a PhD in Science from Paris Sud University and holds a diploma in Pedagogy. He joined the ANSM (the French National Agency for the Safety of Medicines and Health Products) as medical advisor in 2018. His activity is focused on access to innovation (clinical trials, early access) and the management of health crises, in connection with the Europe and Innovation Directorate and the Scientific Delegation of the ANSM. He is actually head of the Medical Oncology Department at the Godinot Institute in Reims (France) and works on immunoregulation and cancer in a translational research unit at the University of Reims (France). He has contributed to over 115 peer-reviewed publications, including publications in Journal of Clinical Oncology, Annals of Oncology, European Journal of Cancer, and Critical Reviews in Oncology/Hematology.

Christophe Massard, MD, PhD: He is a medical oncologist at Institut Eugène Marquis, Rennes, France, he was a Head of the Drug Development Department (DITEP), Gustave Roussy, (Villejuif, France) for almost 5 years. He is primarily involved in translational cancer research and the designing and running of early-phase biomarker-driven clinical trials, with a special interest in genitourinary cancer and the central nervous system. He received his medical degree from ParisS XI University, and later obtained an MSc and PhD also from ParisS XI University. He completed his residency training in Paris Hospital, followed by a fellowship in medical oncology at Gustave Roussy. He is board certified in Medical Oncology and did a post-doctoral fellowship in Prof DeBono’s lab at the Royal Marsden Hospital of London and Institute of Cancer Research (London, United Kingdom). He is a member of ESMO, ASCO, and AACR. Over the last 5 years, he has been one of the principal investigators of 15 phase I trials, 1 phase II trial (prostate cancer), and sub investigator of more than 80 clinical trials (phase 1 trials and GU cancers). He is also involved in translational research aspects related to precision medicine (MOSCATO, MATCH-R and PETRUS program). He has contributed to more than 180 peer-reviewed publications, including publications in European Urology, Annals of Oncology and Journal of Clinical Oncology. He is also a member of the editorial boards of Bulletin du Cancer, Investigational New Drugs, European Journal of Cancer, and Critical Reviews in Oncology/Hematology.

Gabriel Malouf, MD, PhD: He is a medical oncology, physician-scientist, consultant in genitourinary medical oncology at the Institut de Cancérologie de Strasbourg, France, and researcher at the Institute of Genetics and Molecular and Cellular Biology (Illkirch, France). He obtained a PhD in cancer epigenetics. After a postdoctoral fellowship in MD Anderson Cancer Center (Houston, USA), he was appointed as Chef de Clinique at the Sorbonne University (Paris, France) before undertaking a full professor position at Strasbourg University (France) in 2018. Gabriel Malouf leadership, training, clinical, translational and basic science expertise are mainly dedicated to studying the molecular underpinnings of rare cancers. During last decade, he generated the most extensive integrative profiling of several rare cancers such as fibrolamellar carcinomas, medullary carcinomas, translocation renal cell carcinomas, esthesioneuroblastomas and upper-tract urothelial carcinomas. He reported seminal works on the role of long-non coding RNA and epigenetic alterations in these cancers. He is currently developing a dedicated translational research program focusing on precision medicine for rare cancers patients, including the generation of genetically engineered mice and investigating tumor heterogeneity using single-cell sequencing approaches. He has a proven publication records in top-tier cancer journals (i.e. Cancer Cell, Genome Biology, Cancer Research, European Urology…) while maintaining clinical care allowing him to be at the intersection of clinic and biology.

Antoine Hollebecque, MD, PhD: He is a senior medical physician at Institut Gustave Roussy (Villejuif, France). He received his medical degree from Lille2 University (France) in 2008. He completed his residency training followed by his fellowship in hepato-gastroenterology at Lille2 University. He spent 2 years as an Assistant Professor in the Drug Development Department at Institut Gustave Roussy in 2012–2013. He completed his training with a one-year post-doctoral fellowship in the Clinical and Experimental Pharmacology (CEP) (Pr C. Dive), Manchester Institute, Cancer Research (Manchester, United Kingdom) where he worked on cell-free DNA. Over the last 5 years, he was the principal investigator of 20 phase I trials and sub-investigator of more than 100 phase I. He has contributed to over 64 peer-reviewed publications, including publications in New England Journal of Medicine, Journal of Clinical Oncology, European Journal of Cancer, Gastroenterology, Hepatology. He is a member of ESMO, ASCO, and AACR.

Jean-Yves Scoazec, MD, PhD: He is a pathologist, head of the Department of Medical Biology and Pathology at Institut Gustave Roussy (Villejuif, France), and director of the Inserm US 23 and CNRS UMS 3655 Unit "Molecular Analysis, Imaging and Modeling of Cancer Disease" (AMMICA). He is a university professor and hospital practitioner at the University of Paris-Sud (France). He is the author of more than 450 scientific publications and has contributed to several WHO classifications of tumors. His main research interests are the cellular and molecular mechanisms involved in neuroendocrine tumors and the mechanisms of neuroendocrine differentiation in carcinomas. He in charge of the management of Institut Gustave Roussy's ten research platforms which include: preclinical evaluation, transgenic models, biological resources, experimental pathology, genomics, imaging and cytometry, metabolomics, bioinformatics, rare circulating cells, immuno-monitoring and hematology Former member of the Scientific Council of the European Neuroendocrine Tumor Society (ENETS), chair of the Endocrine Working Group of the European Society of Pathology (ESP), he was president of the French Society of Pathology and is currently president of the French National Professional Council of Pathologists.

Stefan Michiels, PhD: He is Head of the Oncostat Team of CESP, INSERM U1018, University Paris-Saclay, University Paris-Sud, Institut Gustave Roussy (Villejuif, France). His areas of expertise are clinical trials, meta-analyses, analysis of biomarkers and prediction models in oncology. He holds a PhD in Biostatistics from the School of Public Health at the University Paris-Sud and Master Degrees in Statistics and in Applied Mathematics from the University of Leuven. His previous positions include the Université Libre de Bruxelles- Institut Jules Bordet (FNRS researcher, Belgium), the National Cancer Institute (France) and the University of Leuven (Belgium). He has authored above 170 peer-reviewed publications. He is currently member of the editorial board of JNCI, Annals of Oncology, NPJ Breast Cancer and Cancer Prevention Research.

Loïc Verlingue, MD, PhD: He is a young medical oncologist, working in early phase drug development unit at Centre Léon Bérard (Lyon, France). He spent 2 years as Assistant Professor in the Drug Development Department at Institut Gustave Roussy in 2019–2021. He holds a PhD in Bioinformatics. With the Pôle Data at Centre Léon Bérard, the Centre de Recherche en Cancérologie of Lyon and U1030, he works at developing ways to translate methods from Bioinformatics, Systems Biology and Deep Learning, in the clinic.

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