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 白金化合物是全球使用最广泛的细胞毒性药物。每年超过580万 患者被诊断出患有一线治疗可能包括粉末剂的癌症。尽管结束了 30年的使用，很少有能力识别有铂诱导的耳毒性或神经病风险的患者 可以提供替代疗法或减少剂量方案。对于必须接受白金的患者，没有 批准的预防性测量和几乎没有治疗这些毒性。为了帮助填补这些重要的空白，在我们的初始项目中 时期，我们建立了与2,000多种结构癌症生存（TC）的第一个特征良好的临床队列。 基于顺铂的化学疗法（没有其他耳毒/神经性药物），并进入 耳毒性和神经病的遗传学。我们的最初项目期间高产。我们出版了16本手稿（3个 在《临床肿瘤学杂志》中，加上另外3个正在审查。我们的基线，横截面结果表明80％ 我们的患者对听力测试有听力损失，其中1分之一分类为严重至可行性（听力的水平 建议使用艾滋病）； 56％的神经病； 40％的耳鸣。我们发现，耳聋基因WFS1中的SNP 与听力损失有关（p = 1.4x10-8）也显示出与顺铂剂量的显着相互作用，因此具有潜力 临床影响以预测敏感性。在年轻的中位年龄（37岁），38％的TC已经患有≥3个不良健康 结果（范围1-11）。鉴于这种早期的烧伤，仍然存在关键的未解决问题，并将在下一个 赠款周期：（1）表征铂毒性的纵向轨迹，包括合并症的作用， 可修改的危险因素和残留的血清铂水平； （2）毒性对与健康相关的生活质量和 患者功能； （3）进一步阐明遗传变异在铂毒性中的作用以鉴定高危 亚组。我们的目的是：目标1。表征与铂相关的耳毒性和神经病的纵向轨迹， 重复听力测定法，并首次扩展数据收集，以包括一组全面的物理和 为TCS随访的基于证据的指南提供事件开发的社会心理领域；目标2。 首次评估顺铂相关的听力损失，耳鸣和神经病及其严重程度对 身体，情感和社交患者的功能；目标3。确定易于患者的其他遗传变异 与铂相关的耳毒性和神经病变，并通过基因分型影响残留的血清铂水平 和整个外显子组测序。影响：从我们独特的临床队列中得出的发现将提供第一个 在任何大型，同质治疗的队列中，对多个铂相关的毒性进行全面的纵向评估 成人发作的癌症存活，并有助于告知事件开发基于证据的TCS的指南 - 向上。我们的发现还将为开发顺铂的预防和介入策略的发展提供基础。 相关的毒性不仅与显着的生活质量损害相关，而且还具有很大的发病率。