Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer

Abstract

Background: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa).

Objective: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS).

Design, setting, and participants: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively.

Outcome measurements and statistical analysis: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis.

Results and limitations: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point.

Conclusions: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS.

Patient summary: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.

Keywords: ATM; Active surveillance; BRCA1; BRCA2; Germline mutations.

Fig. 1 -

Cumulative incidence of upgrading on biopsies after the diagnostic biopsy in (A) carriers and noncarriers of mutations in BRCA1/2 and/or ATM; (B) carriers and noncarriers of mutations in BRCA2 only. Cumulative incidence based on competing risk analysis. Upgrading refers to any grade group (GG) or Gleason score higher than diagnostic biopsy GG irrespective of initial grade at biopsy.

Fig. 2 -

Cumulative incidence of upgrading after diagnostic biopsy among carriers and noncarriers of mutations in BRCA1/2 and/or ATM who were initially diagnosed with grade group (GG) 1 (Gleason score 3 + 3) (A) upgrading after diagnostic biopsy to GG 2 or above (Gleason score 3 + 4 or above); (B) upgrading after diagnostic biopsy to GG 3 or above (Gleason score 4 + 3 or above). Cumulative incidence based on competing risk analysis.

Fig. 3 -

Cumulative incidence of upgrading after diagnostic biopsy among carriers and noncarriers of mutations in BRCA2 only who were initially diagnosed with grade group (GG) 1 (Gleason score 3 + 3) (A) upgrading after diagnostic biopsy to GG 2 or above (Gleason score 3 + 4 or above); (B) upgrading after diagnostic biopsy to GG 3 or above (Gleason score 4 + 3 or above). Cumulative incidence based on competing risk analysis.