PD50-08 MEN WITH BRCA1 AND BRCA2 MUTATIONS AND LOW/INTERMEDIATE GRADE PROSTATE CANCER MAY HARBOR ADDITIONAL GENOMIC ALTERATIONS OF MORE AGGRESSIVE DISEASE: IMPLICATIONS FOR ACTIVE SURVEILLANCE

Abstract

INTRODUCTION AND OBJECTIVES: Active surveillance (AS) is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. BRCA1 or 2 germline mutations have been implicated in prostate cancer and affected men are at higher risk for developing prostate cancer and for failure after localized therapy. It is unknown if germline BRCA1/2 mutations in AS candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. METHODS: We analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of AS candidates among subjects with BRCA homodeletions and non-homodeletions. Tests for differences in the proportions were conducted using Fisher's Exact Test. Equivalence tests for proportions of AS candidates were conducted using the two-one sided tests (TOST) method. As a secondary outcome we studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions. RESULTS: Forty-one men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Rates of candidacy for AS based on histology and stage (defined as stage T2, Gleason 6) are not different between subjects with and without BRCA 1 or 2 homodeletions, within an equivalence margin of 10 percentage points. These findings are similar when the AS criteria are modified to add Gleason 3+4 subjects. Fifty percent of men with organ confined (pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p=0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR: 2.4, p<0.001), both of which are in close proximity on the long arm of chromosome 13. Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p=0.004). CONCLUSIONS:: In the TCGA data set, men with prostate cancer and BRCA1 or BRCA2 homodeletions present with similar stage and grade tumors than men without these deletions. Despite having low or low intermediate grade histology, however, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.