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.
Introduction
Active surveillance (AS) is the recommended management strategy for men with favorable-risk prostate cancer (PCa) [1], [2]. While cancer-specific outcomes are comparable for AS and curative intervention, some men left untreated develop disease progression [3], [4].
Older age [5]and African American race [6] are associated with reclassification to a higher-grade cancer among men on AS. Family history does not appear to predispose to disease progression on AS [7]. Germline mutations contribute to familial disease; however, the association between changes in cancer grade and germline mutations in AS is not known.
Mutations in DNA repair genes are associated with aggressive PCa phenotypes [8], [9]. A comparison between men with lethal and men with low-risk PCa found that mutation carrier rates of BRCA1/2 and ATM were significantly higher in lethal cases [10]. Furthermore, carrier rates were directly and significantly associated with earlier age at death and shorter survival after diagnosis.
To our knowledge, germline mutations in PCa-associated genes have not been evaluated among men undergoing AS. We hypothesized that mutation status and grade reclassification (GR) to a higher grade during AS might be associated.
Section snippets
Study cohorts
AS was offered to patients as part of an institutional review board-approved protocol at Johns Hopkins (JH) [5] and North Shore (NS) University Health Systems [11]. The JH program was initiated in 1995 and NS in 2011. After enrollment, a confirmatory biopsy was performed at 6–12 mo followed by prostate-specific antigen (PSA) and digital rectal examination at 6-mo intervals. Surveillance biopsies are recommended every 2–4 yr after confirmation biopsy.
Cohort demographics
Cancer extent on prostate biopsy and the proportion of men with GG ≥2 at diagnosis was greater in the NS cohort than in the JH cohort (Table 1). Follow-up time and interval between diagnosis and upgrading was greater at JH than at NS. The JH cohort was more ethnically diverse than NS.
Carrier rates of pathogenic mutations
Considering all 1211 men, the carrier rates of mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than those not reclassified (1.6% and
Discussion
AS is an option for men diagnosed with favorable-risk and intermediate-risk PCa [1], [2]. However, there is a wide variation in selection of candidates for AS. In part, practice variation is due to uncertainty of the “true” disease phenotype because biopsy sampling can misclassify cancer grade and extent. Thus, some men will lose the opportunity for curative treatment either because of misclassification at diagnosis or disease progression during follow-up [3], [4]. Consequently, there is
Conclusions
Our study supports the findings of others that mutations in BRCA1/2 and ATM are associated with a more aggressive PCa phenotype. Mutation status of BRCA1/2 and ATM can help inform decisions between AS and curative intervention.
Author contributions: H. Ballentine Carter had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Isaacs, Xu, Helfand, Carter.
