779P - Testing unselected women with newly diagnosed high-grade serous ovarian cancer (HGSOC) for germline pathogenic variants (PVs) in mismatch repair (MMR) genes is unnecessary

Background

The NHS Genomic Medicine Service in England allows all women diagnosed with epithelial ovarian cancer (EOC) to be tested for germline PVs (R207 panel) in homologous recombination repair (HRR) genes (BRCA1/2, PALB2, BRIP1, RAD51C/D) and MMR genes (MSH2/6 and MLH1, but not PMS2). We investigated the prevalence of germline PVs in HRR and MMR genes in consecutive, unselected cases of newly diagnosed EOC treated at The Christie Hospital between April 2022 and April 2024.

Methods

All histological subtypes of epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible for inclusion. R207 panel testing was performed in the North West Genomic Laboratory Hub using DNA extracted from peripheral blood lymphocytes. Next-generation sequencing was used to detect small sequencing variants (SSVs) ≤40bps to a 5% variant allele fraction. Multiplex ligation-dependent probe amplification and Detection of Exon Copy Number variants were used to identify copy-number variants (CNVs).

Results

401 women were tested (median age 65, range 38-90). 342 tests (85%) were completed in a turnaround time of ≤42 days. 315 women (79%) had HGSOC and 331 (83%) had FIGO stage III or IV disease. 43 germline PVs (11%) were detected in HRR genes (BRCA1=15, BRCA2=12, PALB2=4, BRIP1=7, RAD51C=2, RAD51D=3). There were 37 SSVs and 6 CNVs. In women with a germline PV in a HRR gene, 90% had HGSOC and 52% had a family history of breast, ovarian, pancreatic and/or prostate cancer. No germline PVs were detected in MMR genes (MSH2=0, MSH6=0, MLH1=0) in all 401 women tested.

Conclusions

The prevalence of germline PVs in MMR genes in women with newly diagnosed HGSOC is at least <0.32%, indicating unselected germline testing of these genes is unnecessary in this disease. Instead, mainstream germline testing in women with HGSOC should include core HRR genes only.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Christie NHS Foundation Trust.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.