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.

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

“…However, the clinical relevance of germline and somatic defects in DDR genes remains largely unclear at present-the exception being germline BRCA2 mutations, which have been shown to be an independent prognostic factor for prostate cancer outcomes in different settings. 13,15,25,26 For non-metastatic prostate cancer patients A range of management options, including active surveillance, radical prostatectomy and/or radiotherapy with or without hormonal deprivation, is currently available to treat patients with localised prostate cancer. Data regarding the implications of germline and somatic DDR defects in early prostate cancer come from retrospective analyses, most of them focused on germline BRCA mutation carriers.…”

Current progress and questions in germline genetics of prostate cancer

“…It is becoming apparent that stratification of men at all risk levels is possible using germline genetic markers: Men undiagnosed for PCa can benefit from knowing their risk of any PCa diagnosis as determined by common genetic variants, as well as their risk of aggressive/lethal disease, as conferred by rare pathogenic mutations in genes like BRCA2 and ATM . Men diagnosed with low risk PCa can be informed of their suitability for treatment by active surveillance [80] , and men diagnosed with high risk disease can benefit by identification of optimal treatment regimens. Using a combination of common and rare genetic variants, a personalized program of disease screening before diagnosis, and disease management and treatment after diagnosis can be designed.…”

Germline and Somatic Mutations in Prostate Cancer: Focus on Defective DNA Repair, PARP Inhibitors and Immunotherapy

“…It is worth mentioning in this setting that the risk for breast cancer in men is increased to approximately 8% with mutation of the BRCA2 gene, being only 1% with a BRCA1 mutation. Breast cancer in men is quite rare in the population, the lifetime risk being of 0.1% [14]. There is scant knowledge on the clinical and pathological characteristics and features of male BRCA1/2 mutation carriers and breast cancer.…”