Abstract 64P
Background
The presence of a BRCA mutation (BRCAm) is the only biomarker of response to treatment with platinum and PARP inhibitors (PARPi) validated in HGSOC. However, the location of the BRCAm and whether it is germline (gBRCAm) or somatic (sBRCAm) can affect the response to treatment and progression-free survival (PFS). Determining the influence of these factors is necessary to optimize treatment strategies.
Methods
Retrospective observational study of stage III-IV BRCAm or HRD+ HGSOC patients (pts) diagnosed in our institution from 01/2015 to 06/2023. Functional domains (FD) of BRCA1 were defined as RING, DNA-BD or BRCA1 C terminus (BRCT) and FD of BRCA2 were PALB2, RAD51-BD and DNA-BD. Presence of BRCA1/2 mutation was determined using NGS.
Results
Eighty-one pts were included: 32 BRCA1m (21 germline), 29 BRCA2m (12 germline) and 20 BRCAwt/HRD+ (7 germline: 2 PALB2m, 2 RAD51Cm, 2 RAD51Dm, 1 BRIP1m). 42 pts received first-line PARPi (24 olaparib, 8 niraparib and 10 bevacizumab/olaparib). Of the pts who received olaparib, 11 had disease progression/relapse (2 after the end of treatment, 2 after stopping treatment due to toxicity and 7 during it). Pts with a shortest time to progression (3-11 months (m)) had sBRCA1m and/or mutations in the RING or BRCT domains of BRCA1, and they achieved lower overall survival (OS) than expected in BRCAm pts due to poor response to successive treatments. Four pts who received niraparib progressed to treatment, all of them during it (1 BRCAwt/HRD+), and sBRCA1m pts showed worse prognosis. Statistical analysis indicates a positive trend in OS for pts with a missense BRCAm. 12 pts received olaparib in second line of treatment, and 5 of them showed disease progression (2 pts during treatment: 1 with BRCA1 nonsense mutation showed PFS of 3 m). Pts in response reached a median treatment time of 81’5 m. 1 of 3 pts who received niraparib progressed during treatment (showing mutation in the RING domain of BRCA1). Median follow-up was 32’5 m (1-123).
Conclusions
In our study, mutation on BRCA1 RING or BRCT showed a poor response to PARPi and lower survival consistenly with previous reports, highlighting among them somatic mutations.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
I. Miras Rodriguez: Financial Interests, Personal, Other, Travel grant: MSD, Lilly, Gilead. P. Estevez Garcia: Financial Interests, Personal, Advisory Role: GSK, AstraZeneca, Clovis, MSD; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Personal, Other, Travel grant: MSD, AstraZeneca, GSK, PharmaMar, Clovis.