Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer

Abstract

Purpose: To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.

Patients and methods: This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).

Results: PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.

Conclusion: Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

Fig 1.

CONSORT diagram. EMBRACE, Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers; PCa, prostate cancer; UKGCPS, United Kingdom Genetic Prostate Cancer Study.

Fig 2.

Kaplan-Meier survival curves: (A) overall survival (OS); (C) cause-specific survival (CSS); (E) CSS in early prostate cancer (PCa; CSS_M0); (G) CSS from metastatic disease; and (I) metastasis-free survival (MFS) in early PCa. Survival curves for noncarrier patients are represented in blue; BRCA1 and BRCA2 mutation carriers are illustrated in gold and gray, respectively. Diagrams illustrating the relative strength (hazard ratio [HR]) of each prognostic factor in the multivariate Cox regression: (B) OS; (D) CSS; (F) CSS_M0; (H) CSS from metastatic disease; and (J) MFS. The colored diamonds and the horizontal lines represent the estimated HR and their respective 95% CIs. The vertical discontinuous line represents no effect. If a CI overlaps this line, the effect of this factor did not significantly differ from no effect. PSA, prostate-specific antigen.

Fig 2.

Kaplan-Meier survival curves: (A) overall survival (OS); (C) cause-specific survival (CSS); (E) CSS in early prostate cancer (PCa; CSS_M0); (G) CSS from metastatic disease; and (I) metastasis-free survival (MFS) in early PCa. Survival curves for noncarrier patients are represented in blue; BRCA1 and BRCA2 mutation carriers are illustrated in gold and gray, respectively. Diagrams illustrating the relative strength (hazard ratio [HR]) of each prognostic factor in the multivariate Cox regression: (B) OS; (D) CSS; (F) CSS_M0; (H) CSS from metastatic disease; and (J) MFS. The colored diamonds and the horizontal lines represent the estimated HR and their respective 95% CIs. The vertical discontinuous line represents no effect. If a CI overlaps this line, the effect of this factor did not significantly differ from no effect. PSA, prostate-specific antigen.