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/m 2 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 bi-exponential 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 platinumlevels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13x10 -3 ). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58x10 -3 ). Patients with high residual platinum levels experienced greater Raynaud9s phenomenon than those with medium or low levels (age-adjusted OR high/low =1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR high/low = 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6x10 -8 , 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.