Department of Medicine, University of Chicago, Chicago, Illinois.
Department of Medical Oncology, Indiana University, Indianapolis, Indiana.
Clin Cancer Res. 2019 Oct 1;25(19):5913-5924. doi: 10.1158/1078-0432.CCR-19-0113. Epub 2019 Jul 11.
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.
Eligible TCS given 300 or 400 (±15) mg/m 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.
Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted = 2.13 × 10). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted = 6.58 × 10). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR = 1.46; = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR = 1.68, = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 ( = 4.6 × 10, a SNP intronic to ).
This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.
顺铂为基础的化疗（CBC）完成后，血清中的铂可在数年内测量到。我们报告了迄今为止对 1010 名睾丸癌幸存者（TCS）进行的最大规模的血清铂水平调查，这些幸存者在 CBC 后 1-35 年接受了评估，并评估了这些水平的遗传贡献。
接受 300 或 400（±15）mg/m 顺铂治疗的合格 TCS 进行了广泛的听力测试、临床检查、完成了问卷调查，并测量了粗血清铂水平。在拟合调整随访时间和累积顺铂剂量的双指数模型后，评估了血清铂与各种风险因素和毒性之间的关系。使用剂量和时间调整模型的血清铂残差进行全基因组关联研究（GWAS）。
血清铂水平超过参考范围约 31 年，与随访时的肌酐清除率呈强烈负相关（年龄调整的 = 2.13 × 10）。我们观察到残留铂值与黄体生成素之间存在显著的正相关（年龄调整的 = 6.58 × 10）。残留铂水平较高的患者比中或低水平的患者更容易出现雷诺现象（年龄调整的 OR = 1.46； = 0.04），也更有可能出现耳鸣（年龄调整的 OR = 1.68， = 0.07）。GWAS 确定了一个单核苷酸多态性（SNP）达到全基因组显著水平，rs1377817（ = 4.6 × 10，位于 内含子中的 SNP）。
这项研究表明，残留铂值与几种顺铂相关的毒性相关。一个遗传变异与这些水平有关。
