Randomised phase 3 trials have demonstrated that poly (ADP-ribose) polymerase (PARP) inhibitors significantly improve progression-free survival in BRCA-mutant high-grade serous and endometrioid ovarian carcinoma. Consequently, the demand for germline and tumour BRCA1/2testing has increased significantly throughout the UK. We report results from a tumour BRCA1/2testing service available to cancer centres across England, Wales and Northern Ireland from July 2017 to February 2019.
DNA extracted from formalin fixed, paraffin-embedded tumour samples underwent next generation sequencing for BRCA1/2 variants. Eligibility criteria included relapsed, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer with germline BRCA1/2wild-type or unknown germline. Patients also had to have received ≥2 prior lines of platinum-based chemotherapy. A confirmatory histopathology report was requested as part of the tumour BRCA1/2testing service.
Two hundred and ninety-three histologically-confirmed high-grade serous and/or endometrioid ovarian cancer tumour samples underwent tumour BRCA1/2testing. The prevalence of pathogenic (class 5) or likely pathogenic (class 4) variants was 17.7% (52/293). The germline BRCA1/2was wild-type for 185/293 (63.1%) of patients, with the remaining 36.9% (108/293) with germline BRCA1/2unknown. There were at least 36 (12.3%) pathogenic/likely pathogenic somatic BRCA1/2variants detected. The allele fraction for somatic BRCA1/2pathogenic variants ranged from 0.06 to 0.98, with 50% (18/36) reported with an allele fraction of ≥ 0.5 (50%), in keeping with putative biallelic loss-of-function.
Prospective evaluation of paired germline and tumour BRCA1/2testing in all women who are diagnosed with platinum-sensitive high-grade serous and/or endometrioid ovarian cancer in the UK is now required to validate these findings.
AstraZeneca.
AstraZeneca.
All authors have declared no conflicts of interest.