Etude de recherche translationnelle visant à comprendre comment les gènes BRCA1 et BRCA2 peuvent influencer la réponse au traitement des patientes incluses dans l'étude clinique PAOLA-1

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

The objectives of this project are to :
1. Test the hypothesis that patients with pathogenic mutations highly likely to revert have a poorer response to maintenance olaparib + bevacizumab than those who have pathogenic mutations less likely to revert.
2. Test the value of a classifier that uses the rules that govern the revertability of BRCA1/2 pathogenic mutation to predict response to olaparib + bevacizumab.
3. Assess the frequency and type of reversion mutations that emerge in PAOLA-1. (this third objective is optional: we can help with reversion sequencing and analysis using an in-house developed pipeline2 if this is not already underway).

For that, about 806 patientes clinical and biological data will be analyzed from the PAOLA-1 clinical trial "Randomized, Double-Blind, Phase III Trial of Olaparib vs. Placebo in Patients with Advanced FIGO Stage IIIB – IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer treated with standard First-Line Treatment, Combining Platinum-Taxane Chemotherapy and Bevacizumab Concurrent with Chemotherapy and in Maintenance".

ICR team will classify mutations into groups based on the above hypotheses, for grouped survival analysis following the methods in Labidi-Galy et al (2023). Kaplan-Meier analysis and Cox proportional hazards models will be employed to compare OS and PFS across specific mutation-based subgroups of interest. Our hypothesis testing will include pair-group comparisons, assessing whether patients in groups predicted to be at higher risk of reversion experience shorter PFS than those less likely to revert.