Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.

Abstract

283 Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.