BLOOD-REPARP: Circulating biomarkers of resistance to PARP inhibitors in HER2-negative metastatic breast cancer.
PARP inhibitors improve progression free survival compared to standard chemotherapy ofHER2-negativemetastaticbreast cancer (mBC) patients bearing germline mutations in the homologous recombination (HR) repair genes such as BRCA1/2. However, these patients present different level of sensitivity to PARPi and, despite an initial response, the development of acquired resistance is inevitable. Today, little is known about the resistance (primary or acquired) mechanisms and biomarkers predictive for therapeutic response are an urgent but still unmet clinical need.
The most common mechanism of PARPi resistance occurs through somatic reversion mutations of BRCA1/2 or other HR pathway genes rendering tumors partially HR proficient. Moreover, the loss of 53BP1 or Shielding complex (REV7, SHLD1-3) factors known to repress HR together with Polθ over-expression, acting as an alternative end-joining pathway directly competing with HR, might also confer resistance to PARPi of BRCA deficient tumor cells.
We propose, in this prospective translational research program, to evaluate on liquid biopsy biomarkers (circulating tumor DNA, ctDNA and circulating tumor cells, CTC), less invasive than tumoral biopsies, if biological mechanisms that we have above listed may be biomarkers of PARPi resistance. These liquid biopsies will be collected within the frame of a multicenter prospective trial (REPARP) enrolling HER2-negative mBC patients eligible to PARPi sponsored by IUCT-Oncopole, with the first inclusion starting in July 2022.
Our comprehensive approach combining ctDNA and CTCs characterization will lead to the identification of minimally-invasive biomarkers that could be use repeatedly to monitor tumor evolution and may enable an earlier detection of the therapeutic escape. Moreover, with the recent advent of new Polq inhibitors in pre-clinical studies, these biomarkers might also become useful companion diagnostics biomarkers in future clinical trials.
The REPARP study is open at IUCT-Oncopole since July 2022, and we are in the process of opening it in 20 other centers in France that also have a high recruitment potential, including most of the « Centres de Lutte Conte le Cancer ». The Coordinating investigator of this trial is Pr Florence Dalenc. Camille Franchet and Jean-Sébastien Hoffmann are the scientific coordinators. The primary objective of REPARP trial is to evaluate the discriminatory capacity of baseline POLQ expression, measured by RNAscope® (and other suitable techniques if available) in tumor biopsies, to identify patients with HER2-negative locally advanced or metastatic BC presenting a progression or death up to 6 months after PARPi stand-alone therapy (= primary resistance).
CRCT and IUCT-Oncopole Partners :
Anne Pradines and Laura Keller
This project will be conducted in collaboration with the team of Christine Toulas (Department of Oncogenetics of IUCT-Oncopole)
Start date of inclusions: 01/07/2022
Ending date of inclusions: 30/06/2024
Duration of the project 36 months
This research program is part of the iNCA call for basic and translational research accepted in 2022.