Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

Abstract

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 6,361 PC patients who initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 single nucleotide polymorphisms (SNPs) associated with conversion, 15 of which were not previously associated with PC risk. We found two genes associated with conversion (MAST3, p = 6.9x10-7 and GAB2, p = 2.0x10-6). Moreover, increasing values of a previously validated 269-SNP genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.