BRCA functional domains associated with high risk of multiple primary tumors and domain-related sensitivity to olaparib: the Prometheus Study.

Abstract

Background: Germline pathogenic variants (gPVs) in the breast cancer susceptibility gene 1/2 (BRCA1/2) genes confer high-penetrance susceptibility to breast cancer (BC) and ovarian cancer (OC). Although most female BRCA carriers develop only a single BRCA-associated tumor in their lifetime, a smaller subpopulation is diagnosed with multiple primary tumors (MPTs). The genetic factors influencing this risk remain unclear. Further, in patients with BRCA-mutated tumors, there appears to be a variability in the effectiveness of olaparib treatment.

Patients and methods: This real-world, multicenter, observational study aimed to determine whether the location of BRCA gPVs within functional domains (FDs) is associated with the development of MPTs and the magnitude of olaparib benefit. The study population comprised consecutive patients with OC who underwent hereditary cancer genetic testing between May 2015 and March 2023. MPT history was assessed based on mutated genes (BRCA1 or BRCA2) and the location of the PVs within the FDs. Clinical outcomes of olaparib first-line maintenance therapy were evaluated according to BRCA1/2 FD location.

Results: The frequency of MPT history in the overall population was 13.3% (118/882), and 20.4% in the BRCA-mutated subpopulation (68/333; P < 0.001). We observed a significant association between the DNA-binding domain (DBD) FD of BRCA2 and MPT. Specifically, 55.6% of BRCA2-mutated patients with PVs in the DBD had a history of BC as a second tumor. At a median follow-up of 48.5 months (95% confidence interval 10-70 months), the 48-month progression-free survival rates were 100.0% for patients with PVs in DBD, 91.7% for those with PVs in other FDs, and 36.4% for those with PVs in the RAD51-binding domain (RAD51-BD) of BRCA2 (P = 0.01). Results in the BRCA1 cohort were not statistically significant.

Conclusions: The results suggest that the location of PVs within BRCA FDs may influence the onset of multiple tumors and the benefit of olaparib in patients with BRCA-mutated OC. These findings could be relevant for cancer prevention efforts, particularly given the increasing number of cancer survivors. However, further understanding is needed before these results can inform clinical decisions.