768P - Reclassification and variant distribution in the GINECO GREAT study of ovarian cancer patients: Insights into HRD status

Background

From 2019 to 2022, 1507 patients, 90% with high-grade serous ovarian cancer (HGSOC), were enrolled in the GREAT study across 94 French centers to better describe the molecular background of this cancer.

Methods

Over a series of 15 meetings from 2020 to 2024, a 4-member expert committee reviewed 953 variants. The aim was to confirm variant nomenclature, classification, and distribution.

Results

Of the 436 variants corrected (46%), variable errors were identified: 162 in nucleotide and 317 in protein nomenclature, 53 in reference transcript and above all, 54 classification errors (mainly BRCA1/2): 10 variants were reclassified from pathogenic to uncertain significance (VUS), 15 from VUS to pathogenic and 29 from VUS to benign. Among the 1456 patients with molecular data, 616 had at least one tumor variant (42%) and 388 had at least 1 pathogenic or likely pathogenic variant of which 140 (9.6%) in BRCA1 and 121 (8.3%) in BRCA2. There were 313 pathogenic variants in HR (Homologous Recombination) core genes (mainly BRCA1/2-BRIP1-RAD51C/D) and 44 pathogenic variants in associated DNA repair genes (CDK12-ATM-CHEK2). For HGSOC, primary pathogenic variants were 136 BRCA1, 117 BRCA2, including 13 large rearrangements and 18 RAD51C/D. 34 pathogenic variants in oncogenes uncommonly observed in HGSOC (PIK3CA-ARID1A-BRAF) were identified. HR deficiency (HRD) status was available for 1031 tumors (68%) and 39% of HGSOC exhibit HRD. Among the latter, 38% have a pathogenic variant in BRCA1/2, RAD51C/D. 98% of BRCA1 pathogenic variants were associated with HRD, against 93% for BRCA2 and 100% for RAD51C and RAD51D. At the opposite, pathogenic variants in associated DNA repair genes showed HRD in less than 26% of the cases. Table: 768P

Gene mutation abnormalities depending on HRD status

Conclusions

Reclassification expert committee plays a crucial role in accurately describing GREAT cohort based on genomic data and confirms the significance of BRCA1/2-RAD51C/D in determining HRD status.

Clinical trial identification

NCT04027868.

Editorial acknowledgement

Legal entity responsible for the study

ARCAGY/ GINECO Group.

Funding

This study was partially funded by AstraZeneca.

Disclosure

E. Rouleau: Financial Interests, Personal and Institutional, Research Grant: AstaZeneca; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca, GSK, MSD, Clovis, Roche, BMS; Financial Interests, Personal and Institutional, Other, Spouse/partner: Thermofisher. I. Soubeyran: Financial Interests, Personal and Institutional, Research Grant: AstaZeneca; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Roche. V. Haddad: Financial Interests, Personal, Speaker, Consultant, Advisor: Brenus Pharma; Financial Interests, Personal, Other, Leadership role in any for-profit healthcare company: OncoDNA, Invitae. A. Buisson: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca, Sophia Genetics. R. Boidot: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim, Takeda, Oxford Nanopre Technologies, AstraZeneca; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca, MSD, GSK, SeqOne Genomics; Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca, GSK, Myriad Genetics; Financial Interests, Personal and Institutional, Other, Conference travel: Takeda, Oxford Nanopore Technologies, New England Biolabs, Agilent Technologies, SeqOne Genomics. L.M. Chevalier: Financial Interests, Personal and Institutional, Research Grant: MSD; Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca, Sophia Genetics. A. Lespagnol: Financial Interests, Personal and Institutional, Research Grant: AstaZeneca; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca, GSK, Amgen, Menarini, Stemlin Deciphera. C. Callens: Financial Interests, Institutional, Other: AstraZeneca, MSD, Pfizer. P.J. Lamy: Financial Interests, Personal and Institutional, Member of Board of Directors: AstaZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Personal and Institutional, Funding: AstaZeneca; Financial Interests, Personal and Institutional, Other, Trip: AstaZeneca. K. Leroy: Financial Interests, Personal, Other: Roche, AstraZeneca, Lilly, MSD, Janssen, GSK, BMS, Amgen. A. Tallet: Financial Interests, Personal, Advisory Board: AstraZeneca, Pierre Fabre Medicament; Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: AstaZeneca; Financial Interests, Personal and Institutional, Other, Hospitality (lunch or diner, hotel night and congress entry): AstraZeneca, Roche SAS, Pierre fabre medicament. O. Laghmari: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Amgen, MSD. J. Lehmann-Che: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD. A. Harlé: Financial Interests, Personal, Other, Hospitality, travels and honoraria: Amgen, Archer Invitae, AstraZeneca, Biocartis, BMS, GSK, Merck Serono, MSD, Novartis, Pfizer, Roche, Sophia Genetics, Tesaro ; Financial Interests, Personal, Officer, Honoraria: BioRad, HederaDX, Janssen, Pierre Fabre; Financial Interests, Institutional, Funding, Clinical Trials Funding: AstraZeneca, Merck Serono, Tesaro. E. Pujade-Lauraine: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Roche, GSK, Incyte, Agenus; Financial Interests, Personal and Institutional, Full or part-time Employment: Arcagy. T. De La Motte Rouge: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Clovis, Eisai, MSD, Natera, Pfizer, Roche, Sanofi, Seagen, GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Pfizer, Roche, GSK; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Clovis, MSD, Myriad, Pfizer, Roche, GSK; Financial Interests, Personal, Research Grant: MSD, Novartis, Pfizer; Financial Interests, Personal, Coordinating PI: AstraZeneca. D. Vaur: Financial Interests, Personal, Research Grant: AstaZeneca; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Speaker, Consultant, Advisor: AstraZeneca; Financial Interests, Institutional, Other, expert testimony, travel, accommodations, expenses: AstraZeneca. All other authors have declared no conflicts of interest.