Currently little is known about correlations between the type and the location of the BReast CAncer genes (BRCA) 1/2 mutations and response to Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer (OC). Clinical data from PAOLA1 study suggest that patients with mutations in DNA binding domain (DNA-BD) of BRCA1 are more sensitive to the combination olaparib/bevacizumab and those in the DNA-BD of BRCA2 confer excellent outcomes. We investigated if the type and the location of the BRCA 1/2 mutations are related with PARPi sensitivity.
This multicenter and retrospective study evaluated the efficacy of PARPi according to the mutation type and location in the functional domain (FD) of BRCA1 (RING, DNA-BD or BRCA1 C terminus [BRCT]) and BRCA2 (PALB2, RAD51-BD; DNA-BD). BRCA1/2 germline mutated OC patients receiving PARPi as maintenance, after a response to platinum-based first line chemotherapy were enrolled. Baseline characteristics and survival data were collected from 3 academic centers.
Of 202 patients treated between December 2008 and October 2021, 122 (60.4%) received PARPi in the first-line setting and 80 (39.6%) at recurrence. Among the first group, 73 (60%) and 49 (40%) harbored BRCA1 and BRCA2 mutations, respectively. BRCA1 mutations in FDs of RING, DNA-BD and BRCT were found in 3 (2.5%), 8 (6.6%) and 21 (17.2%) patients, respectively. BRCA2 mutation were detected in FDs of RAD51-BD and DNA-BD in 25 (20.5%) and 5 (4.1%) patients, respectively. Median follow-up was of 20 (4-100) months. In patients with DNA-BD mutation of BRCA1/2, 2-yr Progression Free Survival PFS was 100%, compared with 80% in mutation in the other domains (log rank p= 0.079). With regard to the mutation type, patients harboring a missense BRCA1 mutation had a longer PFS (2-yr PFS 100%), compared with 50% of those with a splicing mutation (log rank p= 0.021) and 75% of those with a nonsense mutation (log rank p= 0.049). Mutation types in BRCA2 were not analyzed due to the small numbers.
The results confirmed that mutations in the DNA-BD region in the BRCA 1/2 genes confer longer PFS respect to other location of mutation. Besides, missense mutation has the best prognosis, compared with splicing and nonsense mutation.