PD50-07 GERMLINE GENETIC RISK FACTORS HELP PREDICT BIOPSY UPGRADE DURING ACTIVE SURVEILLANCE OF PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVES: Active surveillance (AS) is a guideline-based treatment option for low risk prostate cancer (PCa). High penetrance gene (HPG) mutations have recently been shown to associate with the risk of upgrading in a large AS cohort. The genetic risk score (GRS) incorporating germline multiple single nucleotide polymorphisms has also been well described to estimate overall risk for prostate cancer (PCa). However, the utility of germline mutations including HPG and GRS among men undergoing AS has not been evaluated. We sought to determine whether the GRS and HPG mutations predict biopsy upgrade independently of common biomarkers employed in AS. METHODS: 504 patients within a prospective IRB-approved AS cohort underwent next generation sequencing to define a 73-SNP GRS and 14 HPG panel (including BRCA1,BRCA2, ATM, HOXB13) after enrollment in AS. During surveillance they received PHI and PSA testing and underwent MRI-fusion confirmatory biopsy and scheduled rebiopsy. Biopsy upgrade was defined as any subsequent biopsy detecting a higher ISUP grade group cancer. Univariate and multivariable logistic regression determined predictors of biopsy upgrading. Predictive models were created using genetic variables to determine the additive effect to commonly available biomarkers. RESULTS: Of the 504 patients in the cohort, 151 (29.9%) were found to have biopsy upgrading on surveillance biopsies. On univariate analysis, age, PHI, PSA density, and mpMRI (presence of targetable lesion), and of an elevated GRS (defined as a score >1.5) were predictors of grade reclassification. (Table 1.) The presence of a HPG mutation (n=25) was marginally predictive of disease upgrading (OR 1.93, P=0.08). The addition of germline genetic mutations to a predictive model incorporating significant clinical variables in univariate analysis (age, PHI, MRI) increased the c-index from 0.71 to 0.76 (p<0.05). CONCLUSIONS: Elevated genetic risk defined as GRS >1.5 or the presence of HPG mutations is associated with grade reclassification during AS for PCa. These factors independently contribute to a predictive model of upgrading using currently employed biomarkers. This lends support to the utility of germline genetic testing among men with localized PCa.