Association of genetic polymorphisms in ERCC1 gene with PSA response to carboplatin chemotherapy in men with metastatic castration-resistant prostate cancer (CRPC).

Abstract

Background: Carboplatin (C) has activity as a second-line chemotherapy agent in metastatic CRPC. C covalently binds DNA, forms platinum-DNA adducts and causes DNA damage. Response and subsequent resistance to C is related, in part, to activity of the nuclear excision repair pathway. ERCC1 is known to be a key component of this pathway. We hypothesized that germline genetic variation at ERCC1 influences response to C. Methods: We identified 101 patients of European ancestry with CRPC treated at our institution with C after progression on docetaxel (D). We isolated DNA from peripheral blood from each subject and genotyped single nucleotide polymorphisms (SNPs) at ERCC1 that account for genetic variation across the gene (r2>0.8). A total of four SNPs were evaluated- rs11615, rs2298881, rs2336219 and rs3212986. Associations between genotype and 30% PSA response and overall survival were evaluated. Results: Among 101 CRPC patients, 94 (93%) received C plus D, 4 (4%) received single-agent C, 2 received C/D/estramustine, and 1 received C/D/bevacizumab. PSA declines (greater-than or equal to)30% were observed in 36 men (36%). At the time of analysis, 86 men (85%) had died. For SNP rs3212986, which resides in the 5' UTR of certain ERCC1 isoforms, the numbers of subjects carrying AA, AC, and CC genotypes were 9, 40, and 50, respectively. The A allele was significantly associated with a PSA decline (greater-than or equal to)30% (OR=3.99, 95% CI: 1.56-10.25, p=0.004). There were no significant imbalances in pre-study prognostic factors between the responder and non-responder groups. The association with response at rs3212986 did not correspond with an association with overall survival (p= 0.73). The majority of patients (59%) received further therapy after progressing on C. Conclusions: The findings support the hypothesis that germline genetic variation in ERCC1-in particular, variation at rs3212986-influences response to C in CRPC. Further analysis and validation of data are needed.