Germline BRCA2 mutations (gBRCA2) are associated with poor clinical outcomes in prostate cancer (PC), however, the molecular origin of this clinical aggressiveness have not been fully elucidated.
In this multicentre case-control study, gBRCA2 carriers were matched 1:2 to known non-carriers (NC) by Gleason score and stage at diagnosis (M0 vs M1). A minimum of 60 cases-120 controls were required to prove a 5yrs cause-specific survival (CSS) rate of 60% vs 85%. The primary aim was to confirm the independent prognostic role of gBRCA2 in PC CSS. Secondary aims included to explore the clinical impact of somatic events in BRCA2, RB1, MYC, PTEN and TMPRSS2-ERG by FISH. Kaplan Meier and Cox-regression models were used to identify associations between molecular characteristics and outcomes.
A total of 73 gBRCA2 carriers and 127 NC were eligible. gBRCA2 carriers were younger at diagnosis (p=0.02) and had more often T3/4 (p<0.001) than NC, but no other significant differences were found. gBRCA2 carriers presented more somatic alterations than NC (p<0.001), including BRCA2 loss, RB1 loss and MYC amplification. BRCA2 were frequently co-deleted with RB1 (Pearson correlation 0.96; p=0.001). gBRCA2 mutations were independently associated with CSS (HR 3.70; p=0.008). CSS were shorter in gBRCA2 carriers who also present somatic BRCA2-RB1 codel or MYC amplification compared with gBRCA2 without such alterations. SImilar results were observed in NC (Table). MVA model confirmed the independent prognostic value of somatic BRCA2-RB1 codel (HR 4.13; p=0.004) and MYC amplif (HR 2.27; p=0.033) for CSS. Table: 612MO
|Median CSS (96%CI), yrs||p-value|
|gBRCA2 gBRCA2 + BRCA2-RB1 codeletion||11.3 (7-2-15.4) 6.3 (2.1-10.6)||0.041|
|gBRCA2 gBRCA2 + MYC amplification||13.4 (10-16.8) 6 (4.1-7.9)||<0.001|
|NC NC + BRCA2-RB1 codeletion||17.6 (NR) 9.8 (5.9-13.8)||<0.001|
|NC NC + MYC amplification||17.6 (NR) 4.8 (0-10.8)||<0.001|
PROREPAIR-A is the largest series of gBRCA2 tumors assembled to date to explore associations between somatic alterations and clinical outcomes in PC. Our results suggest that somatic BRCA2-RB1 codel and MYC amplification define an aggressive subtype of PC with poor clinical outcomes in both gBRCA2 and NC.
Clinical trial identification
Legal entity responsible for the study
Spanish National Cancer Research Centre (CNIO).
CRIS Foundation, Prostate Cancer Foundation PCF Foundation.
R. Lozano Mejorada: Speaker Bureau/Expert testimony: Roche, Janssen-Cilag, Sanofi; Travel/Accommodation/Expenses: Roche, Janssen-Cilag, Astellas Pharma. E. Castro Marcos: Honoraria (self): Astellas Pharma, AstraZeneca, Bayer, Janssen-Cilag, Pfizer; Advisory/Consultancy: AstraZeneca, Bayer, Janssen; Research grant/Funding (institution): AstraZeneca, Bayer, Janssen; Travel/Accommodation/Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. F. Lopez Campos: Advisory/Consultancy: Astellas Pharma; Speaker Bureau/Expert testimony: Janssen, Astellas Pharma; Travel/Accommodation/Expenses: Astellas Pharma, Janssen; Research grant/Funding (self): Astellas Pharma. U. Anido: Honoraria (self): Pfizer, Novartis, Bayer, Bristol-Myers-Squbb, EUSA Pharma, Eisai, Astellas Pharma, Jassen-Oncology, Sanofi; Advisory/Consultancy: Bayer, Pfizer, Novartis, Ipsen, Eisai, EUSA Pharma, Sanofi; Research grant/Funding (self): Pierre Fabre; Travel/Accommodation/Expenses: Astellas Pharma, Novartis, Roche, Pfizer, Ipsen, Sanofi. M.J. Juan Fita: Advisory/Consultancy: Janssen; Speaker Bureau/Expert testimony: Sanofi, Astellas, Janssen, BMS, Bayer; Travel/Accommodation/Expenses: Janssen. N. Romero Laorden: Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Janssen, IPSEN, Astellas, Astra-Zeneca, MSD, Bayer, Tesaro, Sanofi. J. Rubio Briones: Advisory/Consultancy: Janssen, Astellas, Bayer; Research grant/Funding (self): HealthMDx. C.C. Pritchard: Advisory/Consultancy: AstraZeneca, Promega. D. Olmos Hidalgo: Honoraria (self): Bayer, Janssen, Sanofi; Advisory/Consultancy: AstraZeneca, Bayer, Clovis Oncology, Daiichi-Sankyo, Janssen, MSD, Roche ; Research grant/Funding (institution): Astellas, AstraZeneca, Bayer, Genentech, Janssen, Medication, MSD, Pfizer, Roche, Tokai Pahrmaceutics; Travel/Accommodation/Expenses: Bayer, Ipsen, Janssen, Roche. All other authors have declared no conflicts of interest.