PROREPAIR-A: Clinical and molecular characterization study of prostate cancer (PC) patients with and without previously known germline BRCA1/2 mutations.

Abstract

5511 Background: Germline BRCA1/2 (g BRCA1/2) mutations are associated with poor clinical outcomes in PC. Previous studies showed that g BRCA2 carriers present more CNV in several genes associated with more aggressive disease. These aberrations may explain the poor clinical outcomes of these patients, but larger studies are needed to confirm these findings. Methods: PROREPAIR-A is a multicenter case-control study in which g BRCA2 carriers with available diagnostic timor-tissue were matched 1:2 by Gleason and stage at diagnosis (M0 vs M1) with known non-carriers (NC). A minimum of 120 controls-60 cases were required to prove a 5yr Cause Specific Survival (CSS)-rate of 85% vs 60%. The primary endpoint was to confirm the independent prognostic value of g BRCA2 in PC CSS. In addition, we explored the prognostic role of g BRCA1 and somatic events in BRCA2, RB1, MYC, PTEN and TMPRSS2-ERG by FISH. Χ2, Kaplan-Meier, log-rank and cox-regression models were carried out to identify associations with baseline characteristics and outcomes: Metastases Free Survival (MFS), Time to Castration-Resistance (TTCR) and CSS. Results: A total of 80:160 matched cases-controls were initially included, but tumor tissue and clinical data were only available in 73 g BRCA2 and 127 NC. 14 g BRCA1 were also included. At diagnosis, g BRCA2 were younger (median 62.6 vs 64.5, p = 0.02) and had cT3-4 disease more often than NC (31.5% vs 9.4%, p < 0.01), but no other significant differences were found. Somatic BRCA2-RB1 codeletion (40.8% vs 11.8%, p < 0.01) and MYC amplification (51.4% vs 22.8%, p < 0.01) were more frequent in g BRCA2 compared to NC, but no significant differences in PTEN and TMPRSS2-ERG were observed. g BRCA2 mutations as well as somatic BRCA2-RB1 codel and MYC amplif were significantly associated with shorter CSS, MFS and TTCR (Table). MVA model confirmed the independent prognostic value of g BRCA2 (HR 1.94, p = 0.03), BRCA2-RB1 codel (HR 3.16, p < 0.01), MYC amplif (HR 2.36, p < 0.01), Gleason ≥8 (p < 0.01) and M1 at diagnosis (p < 0.01) for CSS. Conclusions: PROREPAIR-A confirmed the independent prognostic value of g BRCA2 for CSS. Somatic BRCA2, RB1 and MYC aberrations were more frequent in g BRCA2 carriers. Those alterations are associated with shorter CSS, MFS and TTCR, and may contribute to poor clinical outcomes in g BRCA2 and NC. [Table: see text]