Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (15) mg/m² cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P ¼ 2.13 10³). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P ¼ 6.58 10³). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR_high/low ¼ 1.46; P ¼ 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR_high/low ¼ 1.68, P ¼ 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P ¼ 4.6 10⁸, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.