Genetic Susceptibility and Biomarkers of Platinum-related Toxicities

铂相关毒性的遗传易感性和生物标志物

• 批准号: 10466861
• 负责人: Lois B. Travis
• 金额: $ 109.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10466861
• 关键词: Accounting; Address; Adult; Age; Alternative Therapies; Blood Banks; Cancer Survivor; Cisplatin; Clinical; Clinical Oncology; Collection; Cytotoxic agent; Data; Data Collection; Development; Diagnosis; Dose; Emotional; Future; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genotype; Grant; Health; Hearing Aids; Hearing Tests; Heavy Drinking; Hypertension; Impact evaluation; Impairment; Intervention; Journals; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of testis; Manuscripts; Morbidity - disease rate; Neuropathy; Outcome; Patients; Pharmaceutical Preparations; Physical Examination; Platinum; Platinum Compounds; Predisposition; Prevention strategy; Preventive measure; Public Health; Publishing; Quality of life; Regimen; Residual state; Risk; Risk Factors; Role; Serum; Severities; Smoking; Subgroup; Survival Rate; Testing; Time; Tinnitus; Tobacco use; Toxic effect; Treatment-related toxicity; WFS1 gene; base; chemotherapy; cohort; comorbidity; cost; deafness; design; dosage; evidence based guidelines; exome; exome sequencing; follow-up; genetic architecture; health related quality of life; hearing impairment; high risk; modifiable risk; ototoxicity; psychosocial; risk prediction model; social; symptom management; symptomatic improvement; young cancer survivor

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.

抽象的 铂化合物是全球使用最广泛的细胞毒性药物，每年使用量超过 580 万。 患者被诊断患有癌症，一线治疗可能包括电镀剂，尽管已经超过了。 经过 30 年的使用，几乎没有什么方法可以识别有铂类引起的耳毒性或神经病变风险的患者： 对于必须接受铂类治疗的患者，可能会提供替代疗法或减少剂量的治疗方案。 为了帮助填补这些重要的空白，我们在最初的项目中阻止了针对这些毒性的批准措施和少数疗法。 在此期间，我们建立了第一个特征明确的临床队列，其中包括 2,000 多名睾丸癌幸存者 (TCS) 基于顺铂的均质化疗（不含其他耳毒性/神经病药物）并取得了进展 我们最初的项目期间发表了 16 篇手稿（3 篇）。 发表在《临床肿瘤学杂志》上），加上其他 3 个正在审查的基线、横断面结果显示 80% 的患者。 我们的患者在听力测试中出现听力损失，其中五分之一的患者被归类为重度至极重度听力损失（听力损失的水平） 推荐使用辅助器具）；56% 患有神经病；40% 患有耳鸣。 与听力损失相关（P=1.4x10-8）也显示出与顺铂剂量的显着相互作用，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 已经出现 ≥3 种不良健康状况。 考虑到这一早期负担，关键的未解答问题仍然存在，并将在下一步中解决。 资助周期：（1）铂毒性纵向轨迹的特征，包括合并症的作用， 可改变的危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) 进一步阐明遗传变异在铂毒性中的作用，以识别高风险 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， 重复听力测试，并首次扩大数据收集范围，包括一套全面的身体和 社会心理领域为 TCS 后续行动的循证指南的最终制定提供信息； 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影响 目标 3. 识别导致患者易感的其他遗传变异 与铂相关的耳毒性和神经病变，并通过基因分型影响残留血清铂水平 和全外显子组测序：来自我们独特的临床队列的研究结果将提供第一个结果。 在任何大型、同质治疗队列中对多种铂相关毒性进行全面、纵向评估 成人发病的癌症幸存者，并帮助最终制定 TCS 循证指南 我们的研究结果还将为制定顺铂的预防和干预策略提供基础。 相关毒性不仅与生活质量的显着损害有关，而且与严重的发病率有关。