PD11-08 A 30-GENE HEREDITARY CANCER MUTATION ANALYSIS PREDICTS TIME TO BIOCHEMICAL RECURRENCE IN CLINICALLY LOCALIZED PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVES: Pathogenic germline DNA repair mutations are enriched in men with advanced prostate cancer (PC) and are harbingers of an aggressive, lethal course. Though guidelines recommend testing, beyond BRCA2 little is known about the prognostic implications of other heritable mutations and their potential associations with family history and clinical outcomes in early PC patients. METHODS: We examined a single-institution cohort of PC patients with histologically confirmed PC and germline DNA testing. DNA was isolated from blood lymphocytes or buccal swabs, and targeted next-generation sequencing was conducted with use of a previously validated panel of 30 genes associated with an elevated risk for common cancers (Color Genomics). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between mutation status and other PC prognostic factors with time to biochemical recurrence (BCR) and metastasis-free survival (MFS). RESULTS: Of 244 patients (median age 62, range 42-89) in the entire cohort, 174 (71%) presented with localized disease and are the focus of this analysis. Ofthose, 128 (73%) underwent radical prostatectomy (RP) and 98 (56%) received primary or adjuvant radiation (RT). 106 (61%) experienced BCR after definitive treatment, while 58 (33%) developed distant metastases during follow up. 146 (84%) had a positive family history of cancer in any relative, and 128 (73%) had family history in a first-degree relative. 21 pathogenic mutations were identified in germline DNA samples from 20 corresponding patients (11%), affecting the following genes: BRCA2 (n = 7, 4%), APC (n = 6, 3.4%), CHEK2 (n = 4, 2.3%), ATM (n = 2, 1.1%), NBN (n = 1, 0.6%), MSH2 (n = 1, 0.6%). The presence of heritable gene alterations from the 30-gene panel was significantly more frequent in patients with a positive family history of ovarian cancer in a first degree relative (p = 0.05). Median time to BCR was significantly shorter in mutation carriers (8 vs 42 mos, p = 0.001). There was also a trend towards worse median MFS (21 vs 78 mos, p=0.2) in these patients. On multivariate analysis, after adjusting for stage ( T3), nodal status (N0 vs N1), Gleason sum (< vs > 8), PSA at diagnosis, and treatment effect (RP, RT, ADT), the presence of germline mutations within this 30-gene panel emerged as an independent predictor of time to BCR [HR: 3.4 (1.3-8.7), p = 0.009], together with Gleason (p = 0.025), RT (p = 0.043) and ADT (p = 0.005). CONCLUSIONS: Heritable genetic alterations are common in selected patients with clinically localized prostate cancer. In addition to familial "cascade" implications, the use of a targeted panel of high-susceptibility cancer-associated genes may have prognostic value in early PC. If confirmed in larger prospective studies, detection of germline mutations could be used as a tool for early implementation of closer surveillance and perhaps more aggressive therapy.