- Université Claude Bernard Lyon 1, Research on Healthcare Performance (RESHAPE), Inserm U1290
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, Belgique.
- Université Libre de Bruxelles, Bruxelles, Belgique
Theme : Sciences Médicales, Oncologie
Title of thesis : Caractérisation moléculaire de l'hétérogénéité intra-tumorale et du microenvironnement des carcinomes ovarien séreux de haut grade et des cancers du sein mutés BRCA1/2 par la transcriptomique spatiale
Year of registration : 2022
Co-directeurs : Prof Isabelle Ray-Coquard, Prof Christos Sotiriou
Abstract :
High grade serous ovarian cancer (HGSOC) and breast cancers (BC) share clinical and molecular features such as BRCA1/2 mutations, platinum- and PARP inhibitors (PARPi) sensitivity. Recent data showed the role of intra-tumor heterogeneity (ITH) in treatment resistance and prognosis. However, most of them were based on bulk tumor analysis ignoring tumor spatiale organization and cell-to-cell interaction. The main goal of this study is to assess the ITH of HGSOC and germline BRCA1/2 mutant BC by combining spatial transcriptomics and proteomics. We aim to characterize tumor cell transcriptomes and copy number profiles, their surrounding TME including immune component, clonality, cell-to-cell interactions and assess how these impact clinical outcome and response to platinum-based chemotherapy with or without PARPi and immunotherapy. Three cohorts already identified will be used: 2 cohorts of HGSOC samples from 1) PAOLA-1 clinical trial testing the combination of olaparib and bevacizumab as first line maintenance after a platinum based chemotherapy, 2) samples from NEOPEMBROV trial assessing the use of pembrolizumab in peri-operative first line setting. The third cohort include 20 BRCA mutant BC samples treated with PARPi in metastatic setting from the Institut Jules Bordet. ST will allow to deconvolute the clonal architecture and the ITH including TME characterizing ovarian and BRCA1/2 mutant BC at an unprecedented level, providing novel insight into mechanisms of resistance to therapies. BRCA1/2 mutant BC and HSGOC will be compared to find shared tumor subclones, cell-to-cell interaction and biological pathways including TME to extend the use of PARPi and provide novel insights for innovative combination of PARPi.
Recently graduated as medical ongologist, I have spent my internship in the « Hospices Civils de Lyon » in France. During my intership, I had the opportunity to work in close contact with the Professor Ray-Coquard and to gain experience on gyneacological cancers, especially in ovarian cancers. For my medical thesis, I also worked with the Professor Benoit You on NIRAPK (NCT04861181) clinical trial aiming at studying the relationships between clinical, biological and pharmacokinetic metrics and toxicities when niraparib is used as maintenance treatment for ovarian cancer patients. This work gave me the opportunity to acquire skills in clinical and translational research.
Simultaneously, with the goal to pursue a long-term career in research, I apply for a master in medical science entitled “Omics technologies�? at the University Claude Bernard Lyon 1. I acquired knowledges in molecular biology and bioinformatics. I also had the opportunity to work for one year in the Breast Cancer Translational Research (BCTL) Laboratory at the Institut Jules Bordet, headed by Prof Christos Sotiriou. I was deeply involved in the set-up of spatial transcriptomics both in the wet-lab and in bio-informatics pipeline working on the project entitled « characterizing intra-tumor heterogeneity including tumor microenvironment in invasive lobular breast cancer using spatial transcriptomics ». The results were presented in international congresses such as « San Antonio Breast Cancer Symposium » and publication is pending.
Therefore, in order to pursue an academic career, I apply for a PhD thesis. For this purpose, I aimed to bridge together my experience in gynecologic oncology and my experiences in molecular biology and translational research. I built a scientific project in co-supervision, bridging the molecular biology experience of the BCTL with the experience of Prof Ray-Coquard in ovarian cancer to characterize the intratumor heterogeneity and tumor microenvironment in high grade serous ovarian cancer and BRCA1/2 mutant breast cancers using spatial transcriptomics. This PhD will give me the opportunity to be fully involve in translational research and to increase my knowledges on molecular biology and gynecological tumours. Besides, this purpose is enhancing an international collaboration.
1. Efficacy of second-line chemotherapy or immune checkpoint inhibitors for patients with a prolonged objective response (≥ 6 months) after first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma: a retrospective study. Vienne A, Collet L, Chevalier T, Borel C, Tardy M, Huguet F, Richard S, Salas S, Saada-Bouzid E, Fayette J, Daste A. BMC Cancer. 2023, PMID: 37452287
2. Predictive Biomarkers for Response to Immunotherapy in Triple Negative Breast Cancer: Promises and Challenges, Xiaoxiao Wang, Laetitia Collet, Mattia Rediti, Véronique Debien, Alex De Caluwé, David Venet, Emanuela Romano, Françoise Rothé, Christos Sotiriou, Laurence Buisseret, Journal of Clinical Medicine, January 2023 PMID: 36769602
3. Clinical outcome of patients with isolated central nervous system progression on first-line pertuzumab and trastuzumab treatment for HER2-positive metastatic breast cancer in a real-life cohort, Laetitia Collet, Lauriane Eberst, Gauthier Ludovic, Marc Debled, Loana Hrab, Marie-Ange Mouret-Reynier, Isabelle Desmoulins, Anthony Goncalves, Mario Campone, Jean-Marc Ferrero, Etienne Brain, Lionel Uwer, Jean-Christophe Eymard, Veronique Dieras14, Gaetane Simon, Marianne Leheurteur, Florence Dalenc, Laurence Vanlemmens, Amelie Darlix, Monica Arnedos, Thomas Bachelot, Breast Cancer, January 2023 PMID: 36630013
4. Predominance of BRCA2 Mutation and Estrogen Receptor Positivity in Unselected Breast Cancer with BRCA1 or BRCA2 Mutation. Pascal Pujol, Kevin Yauy, Amandine Coffy, Nicolas Duforet-Frebourg, Sana Gabteni, Jean-Pierre Daurès, Frédérique Penault Llorca, Frédéric Thomas, Kevin Hughes, Clare Turnbull, Virginie Galibert, Chloé Rideau, Carole Corsini, Laetitia Collet, Benoit You, David Geneviève and Nicolas Philippe, Cancers July 2022 PMID: 35805038
PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers, Laetitia Collet, Julien Péron, Frédérique Penault-Llorca, Pascal Pujol, Jonathan Lopez, Gilles Freyer and Benoît You, Cancers, January 2022 PMID: 35158866
6. Analyses of the rationale and implementation of research biopsies in oncology clinical trials at a tertiary cancer center, L. Collet, N. Olympios, M. Paesmans, C. Jungels, N. Kotecki, A. Awada, P. Aftimos, The Oncologists, July 2021
7. Biological and clinical features of triple negative Invasive Lobular Carcinomas of the breast. Clinical outcome and actionable molecular alterations, F. Conforti, L. Pala, E. Pagan, E. Guerini Rocco, V. Bagnardi, E. Montagna, G. Peruzzotti, T. De Pas, C. Fumagalli, S. Pileggi, C. Pesenti, S. Marchini, G. Corso, C. Marchio’, A. Sapino, R. Graffeo, L. Collet, P. Aftimos, C. Sotiriou, M. Piccart, R. D. Gelber, G. Viale, M. Colleoni, A. Goldhirsch, The Breast, June 2021 PMID: 34217971
8. Association between Body Mass Index and Survival Outcome in Metastatic Cancer Patients Treated by Immunotherapy: Analysis of a French Retrospective Cohort, Laetitia Collet, Lidia Delrieu, Amine Bouhamama, Hugo Crochet, Aurélie Swalduz, Alexandre Nerot, Timothée Marchal, Sylvie Chabaud, Pierre Etienne Heudel, Cancers, May 2021 Association between Body Mass Index and Survival Outcome in Metastatic Cancer Patients Treated by Immunotherapy: Analysis of a French Retrospective Cohort, Laetitia Collet, Lidia Delrieu, Amine Bouhamama, Hugo Crochet, Aur√©lie Swalduz, Alexandre Nerot, Timoth√©e Marchal, Sylvie Chabaud, Pierre Etienne Heudel, Cancers, May 2021
