Pharmacogenomic predictors of cisplatin oto- and nephrotoxicity in head and neck cancer patients treated with chemoradiation

Abstract

Background: Cisplatin-based chemoradiotherapy (CRT) remains a standard treatment for patients ( pts) with locally advanced head and neck squamous cell carcinomas (HNSCCs). However, use of cisplatin may cause oto- and nephrotoxicity which may compromise both treatment delivery and longterm quality of life. We hypothesized that polymorphisms (SNPs) in cisplatin methyltransferases (TPMT, COMT), acylphosphatases (ACYP2) and transporters (CTR1, OCT2, MATE1, ABCC2, ABCC3) could predict oto- and nephrotoxicity and investigated this in a prospective cohort study. Methods: Consenting HNSCC pts with adequate baseline hearing and renal function treated with CRT were prospectively enrolled. Audiometric testing was done at baseline, and 3, 6, 12 & 18 months. Serum creatinine was assessed baseline & weekly during CRT. Ototoxicity was defined as ≥grade 2 audiometric change from baseline (CTCAE v4.02) present 12 months post-treatment. Nephrotoxicity was defined as ≥grade 2 acute kidney injury after initiation of cisplatin. Relationships between clinical variables, genotype and outcomes were assessed using Cox regression with interval censoring and reported as a hazard ratio (HR). Results: 207 consecutive HNSCC pts have been enrolled. To date ≥grade 2 ototoxicity has developed in 64% and ≥grade 2 nephrotoxicity observed in 22% of 170 evaluable pts. In multivariate analyses TPMT and COMT SNP carriers were at increased risk of developing ototoxicity (HR 4.47 [95%CI 1.66-12.03, p < 0.05] and HR 3.09 [95%CI 1.65-5.82, p < 0.001, respectively). MATE1 SNP carriers were at reduced risk (HR 0.36 [95%CI 0.14-0.96 p < 0.05]). SNP allele prevalence was: TPMT rs12201199 7.8%, COMT rs9332377 32.3%, MATE1 rs2289669 14.4%. Analyses including all remaining pts, ACYP2 as a predictor and nephrotoxicity as outcome are underway and will be presented. Conclusions: Oto- and nephrotoxicity occur frequently in HNSCC pts treated with CRT. SNPs in both cisplatin metabolizing enzymes and transporters appear to predict vulnerability to these. We plan to assess the clinical utility of these SNPs for toxicity avoidance in a prospective clinical trial.