Abstract 587P
Background
High-grade serous ovarian cancer (HGSOC) is now characterized by the status deficient (HRD) or proficient (HRP) of homologous recombination repair (HR). This status is currently determined by the screening of tumoral BRCA1/2 mutation and the Genomic Instability score (GIS) first developed by Myriad. Our goal is to test and develop other simpler and less expensive approach to determine the HR status with BRCA1 promoter methylation status and shallow whole genome sequencing (sWGS) profile.
Methods
BRCA1 methylation detection was performed by the bisulfite conversion and ddPCR (EpiTect Bisulfite Kits, QIAGEN and Stilla Technologies). The whole genome library was prepared by SureSelect XT HS kit (Agilent Technologies) on NextSeq (Illumina). HRD status on sWGS was visually analyzed or computed with ShallowHRD method [1]. 229 samples were reanalyzed Myriad HRD Score analyses in Gustave Roussy. We selected 101 FFPE samples from our internal cohort of 229 patients with Myriad HRD score to be tested for BRCA1 promoter methylation.
Results
Methylation was found in 27/101 samples (27%), with a complete methylation in 19/27 samples (70%) and a partial methylation in 8/27 samples (30%). All methylated samples were HRD except one among the complete methylation cohort. Two samples had very low methylation rate according to TP53/BRCA1/ LOH status. In the unmethylated samples, 27/74 were HRD (36%), 12 of which with BRCA1/2 pathogenic variants. According to these results, a sequential approach on 229 samples in GIS by Myriad and BRCA mutation and methylation status could be extrapolated leading to 40% samples that would not need a GI Score to determine HRD status. A sWGS approach can be proposed for the others. On the 18 non methylated and BRCA1/2 wild type status samples, 5 profiles were clearly HRP without any score computation (27%). Finally, the score is needed only for 33% based on sWGS profile.
Conclusions
BRCA1 promoter methylation combined with a visual interpretation of the sWGS or ShallowHRD method could be a useful test to determine HRD status, and help to identify the majority of HRD and HRP cases.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Integragen.
Disclosure
E. Rouleau: Financial Interests, Institutional, Invited Speaker: AstraZeneca, BMS, GSK. F. Blanc-Durand: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, GSK. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AZ, Clovis, Ability Pharma, MSD, Tesaro, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: Tesaro, AZ, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: Arcagy-Gineco, Sanofi, AZ; Financial Interests, Institutional, Funding, CI clinical trial: AZ; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AZ; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer. All other authors have declared no conflicts of interest.