Genome-Wide Predictors of Treatment-Related Toxicities

描述(申请人提供)：在接受乳腺癌治疗时，许多女性会经历持续数年的严重副作用，毒副作用通常会导致剂量和疗效的降低。人们对可能预测药物毒性的因素知之甚少。药物遗传学已被用于确定与治疗相关的毒性的敏感性，采用候选基因方法，并已在硫嘌呤和伊立替康的代谢方面取得了一些重要发现。对于常用于治疗乳腺癌的环磷酰胺(C)、蒽环类药物(A)和紫杉烷(T)等多种药物方案所致毒性的易感基因变异的评估进展较少。我们建议在一项正在进行的乳腺癌临床试验中进行全基因组扫描，并检查与3级和4级毒性有关的遗传变异。使用一项大型治疗试验(S0221)的数据和样本(n=2000)，我们将进行GWA以确定与AC节段的3级和4级血液和胃肠道毒性以及T节段的神经毒性显著相关的SNPs。来自S0221 GWAS的结果将在CALGB 40101中得到验证，这是一项对2,200名接受相同化疗药物的具有类似入选标准的女性进行的试验。这两项试验的数据也将汇集起来进行荟萃分析，以增强统计能力。通过使用GWAS方法，以前没有考虑过的重要途径很可能被揭示为对治疗相关毒性的易感性的重要途径，识别那些使用替代药物或减少剂量的风险最大的人，并为预防乳腺癌化疗患者中经常危及生命的毒性开辟新的研究领域。 公共卫生相关性：我们建议进行全基因组扫描，在不同剂量的阿霉素(A)、环磷酰胺(C)和紫杉醇(T)的临床试验的背景下，比较经历过严重毒性的乳腺癌患者和没有发生严重毒性反应的乳腺癌患者。我们预计这项研究将揭示与正常细胞对化疗药物损伤的敏感性有关的遗传变异。对这些遗传变异的识别可以1)针对那些对剂量调整或替代药物使用最敏感的患者；2)更好地理解药物毒性发生的机制；3)开发保护正常组织的方法。这项研究有能力确定乳腺癌常规治疗后与毒性相关的遗传变异来源。因此，这是将这些数据转化为临床数据并定义这些破坏性的和鲜为人知的终点的生物学的第一步。

DESCRIPTION (provided by applicant): When undergoing treatment for breast cancer, many women experience severe side effects that can persist for years, and toxicities often result in reduced dose and efficacy. Little is understood regarding factors that may predict drug toxicities. Pharmacogenetics has been used to determine susceptibility to treatment-related toxicities, using a candidate gene approach, and some important findings have been made in relation to metabolism of thiopurines and irinotecan. There has been less progress in assessment of genetic variants that predispose to toxicities resulting from a multi-drug regimen of cyclophosphamide (C), anthracyclines (A), and taxanes (T), commonly used to treat breast cancer. We propose to conduct a Genome-Wide Scan (GWAS) in an ongoing clinical trial for breast cancer, and examine genetic variants in relation to Grade 3 and 4 toxicities. Using data and samples (n=2000) from a large therapeutic trial (S0221), we will perform a GWAS to identify SNPs significantly associated with grades 3 and 4 hematological and gastrointestinal toxicities during the AC segment, and neurological toxicities during the T segment. Results from S0221 GWAS will be validated in CALGB 40101, a trial of 2200 women with similar entry criteria receiving the same chemotherapy agents. Data from the two trials will also be pooled for meta-analysis, enhancing statistical power. By using a GWAS approach, it is likely that important pathways not previously considered will be revealed as important in susceptibility to treatment-related toxicities, identifying those at greatest risk for alternate drugs or dose reduction, and opening new areas of research for prevention of often life-threatening toxicities among patients receiving chemotherapy for breast cancer. PUBLIC HEALTH RELEVANCE: We propose to conduct a genome-wide scan, comparing breast cancer patients who experience severe toxicities to those who do not, in the context of a clinical trial of differing doses of doxirubicin (A), cyclophosphamide (C) and paclitaxel (T). We expect that this study will reveal genetic variants that are associated with sensitivity of normal cells to damage from chemotherapeutic agents. Identification of these genetic variants may 1) allow targeting of patients who are most susceptible for either dose adjustment or alternate agent use; 2) lead to better understanding of mechanisms whereby drug toxicities occur and 3) lead to development of approaches to protect normal tissue. This research study has the ability to identify sources of genetic variation associated with toxicities after common treatments for breast cancer. Thus, it is the first step towards both translating these data clinically and defining the biology of these devastating and poorly understood endpoints.