Genetic Susceptibility and Biomarkers of Platinum-related Toxicities

摘要 铂化合物是全世界使用最广泛的细胞毒性药物。每年超过580万 患者被诊断患有癌症，其一线治疗可能包括铂化剂。尽管有超过 30年的使用，有几种方法来确定患者的铂诱导的耳毒性或神经病变的风险， 可能会提供替代疗法或减少剂量的方案。对于必须接受铂的患者， 批准的预防措施和很少的治疗这些毒性。为了填补这些重要的空白，在我们最初的项目中， 在此期间，我们建立了第一个具有良好特征的临床队列，其中有2,000多名睾丸癌幸存者（TCS）， 均质顺铂为基础的化疗（没有其他耳毒性/神经病药物），并取得了进展， 耳毒性和神经病的遗传学。我们最初的项目阶段是非常富有成效的。发表论文16篇（3 在临床肿瘤学杂志），加上其他3个正在审查。我们的基线，横截面结果显示，80%的 我们的患者在听力测试中有听力损失，五分之一的患者被归类为重度至极重度（听力损失的程度）。 艾滋病的建议）; 56%有神经病变;和40%耳鸣。我们发现耳聋基因WFS 1中的一个SNP， 与听力损失相关（P=1.4x10-8），也显示与顺铂剂量有显著的相互作用，因此具有潜在的 预测易感性的临床影响。在年轻的中位年龄（37岁），38%的TCS已经有≥3次不良健康状况 结果（范围1-11）。鉴于这一早期负担，关键的未回答问题仍然存在，将在下一个 赠款周期：（1）铂毒性的纵向轨迹表征，包括合并症的作用， 可改变的风险因素和残留血清铂水平;（2）毒性对健康相关生活质量的影响， 患者功能;（3）进一步阐明铂毒性中遗传变异的作用，以识别高风险 分组。我们的目标是：目标1。描述铂相关耳毒性和神经病变的纵向轨迹， 重复测听，并首次扩大数据收集，以包括一套全面的身体和 心理社会领域，为TCS随访的循证指南的最终制定提供信息;目标2. 首次评估顺铂相关听力损失、耳鸣和神经病变及其严重程度对 患者的身体、情感和社会功能;目标3。识别使患者易患的其他遗传变异 铂相关的耳毒性和神经病，并通过基因分型影响残留的血清铂水平 和全外显子组测序。影响：来自我们独特的临床队列的发现将提供第一个 在任何大型均质治疗队列中对多种铂类药物相关毒性进行全面纵向评估 的成年发病癌症幸存者，并帮助告知最终发展的循证指南TCS遵循- 起来我们的研究结果也将为顺铂的预防和干预策略的发展提供基础- 相关毒性不仅与生活质量的显著损害相关，而且与大量发病率相关。

ABSTRACT Platinum compounds are the most widely used group of cytotoxic drugs worldwide. Each year more than 5.8 million patients are diagnosed with a cancer for which first-line therapy can potentially include platinating agents. Despite over 30 years of use, there are few means of identifying patients at risk for platinum-induced ototoxicity or neuropathy who might be offered alternative therapy or reduced-dose regimens. For patients who must receive platinum, there are no approved preventive measures and few therapies for these toxicities. To help fill these important gaps, in our initial project period, we established the first well-characterized clinical cohort of over 2,000 testicular cancer survivors (TCS) cured with homogeneous cisplatin-based chemotherapy (without other ototoxic/neuropathic drugs) and made inroads into the genetics of ototoxicity and neuropathy. Our initial project period was highly productive. We published 16 manuscripts (3 in the Journal of Clinical Oncology), plus 3 others under review. Our baseline, cross-sectional results showed that 80% of our patients had hearing loss on audiometric testing, with 1 in 5 classified as severe-to-profound (a level at which hearing aids are recommended); 56% had neuropathy; and 40% had tinnitus. We found that a SNP in deafness gene WFS1 that was related to hearing loss (P=1.4x10-8) also showed a significant interaction with cisplatin dose, thus having potential clinical impact to predict susceptibility. At a young median age (37 years), 38% of TCS already had ≥3 adverse health outcomes (range 1-11). Given this early burden, critical unanswered questions remain and will be addressed in the next grant cycle: (1) characterization of the longitudinal trajectory of platinum toxicities, including the role of comorbidities, modifiable risk factors, and residual serum platinum levels; (2) the impact of toxicities on health-related quality of life and patient functioning; and (3) further elucidation of the role of genetic variation in platinum toxicities to identify high-risk subgroups. Our aims are: Aim 1. Characterize the longitudinal trajectory of platinum-related ototoxicity and neuropathy, repeating audiometry, and expanding data collection for the first time to include a comprehensive set of physical and psychosocial domains to inform the eventual development of evidence-based guidelines for TCS follow-up; Aim 2. Evaluate for the first time the impact of cisplatin-related hearing loss, tinnitus and neuropathy and their severity on physical, emotional and social patient functioning; Aim 3. Identify additional genetic variation that predisposes patients to platinum-related ototoxicity and neuropathy and that influences residual serum platinum levels through genotyping and whole exome sequencing. IMPACT: Findings derived from our unique clinical cohort will provide the first comprehensive, longitudinal assessment of multiple platinum-related toxicities in any large, homogenously treated cohort of adult-onset cancer survivors and help inform the eventual development of evidence-based guidelines for TCS follow- up. Our findings will also provide the basis for the development of preventive and interventional strategies for cisplatin- related toxicities associated not only with significant impairment of quality of life, but substantial morbidity.