Association of COMT and TPMT with treatment failure (TF), neuropathy (NTOX), and ototoxicity (OTOX) in patients with testicular cancer (TC) after cisplatin-based chemotherapy (CBCT).

Abstract

e15076 Background: Adult TC patients have variable treatment response and risk of NTOX and OTOX after CBCT. COMT and TPMT are important genes for cisplatin metabolism and are associated with OTOX in children after CBCT [Nat Genet, 2009]. We hypothesized that single nucleotide polymorphisms (SNPs) of these genes causing increased cisplatin metabolism may be associated with higher TF and lower risk of NTOX and OTOX in adult TC patients after CBCT. Methods: TC patients who had CBCT, ≥ 1 year of follow-up since diagnosis, and genotyping completed as part of a genome-wide association study were included for analysis. We analyzed 42 SNPs each in COMT and TPMT.TF was defined as incomplete response to or relapse after first-line CBCT. NTOX and OTOX were assessed using surveys adapted from existing questionnaire instruments. For each SNP and outcome, we used a test for trend across ordered groups to determine statistical significance (p ≤ 0.05). Odds ratio (OR) and 95% confidence interval (CI) estimates were determined by logistic regression. Results: Of 118 patients who met eligibility criteria to date, TF status was ascertained on 78 and toxicity surveys were completed by 41. We noted significant associations of TF with 3 SNPs (COMT: rs7287604, rs5993882; TPMT: rs10949476), the strongest of which was a 4-fold (OR=3.9, 95% CI 1.3, 12) increased risk for carriers of the rs5993882 minor allele (dominant model). As expected, we noted inverse associations of NTOX with 3 SNPs (COMT: rs4646316; TPMT: rs12194394, rs1886330) and OTOX with 5 SNPs (COMT: rs12158214, rs7289747, rs887201; TPMT: rs9396834, rs6938294), the strongest of which was a 10-fold (OR=0.13 95% CI 0.03, 0.71) reduced risk of OTOX for carriers of the rs6938294 minor allele. Associations were not confounded by host, tumor or treatment characteristics. Conclusions: Our preliminary results are the first to show associations of genetic variants of COMT and TPMT with TF, NTOX, or OTOX in adult TC patients after CBCT. Requests for completion of the toxicity surveys and review of medical charts is ongoing. These findings may allow us to identify TC patients at risk for these outcomes based on genetic markers.