Genome-Wide Predictors of Treatment-Related Toxicities

描述（由申请人提供）：在接受乳腺癌治疗时，许多女性会经历严重的副作用，这种副作用可能持续多年，毒性通常会导致剂量和疗效降低。对可能预测药物毒性的因素了解甚少。药物遗传学已被用于使用候选基因方法确定对治疗相关毒性的易感性，并且已经在硫嘌呤和伊立替康的代谢方面取得了一些重要发现。在评估遗传变异方面进展较少，这些遗传变异易导致环磷酰胺（C）、蒽环类药物（A）和紫杉烷类药物（T）的多药方案（常用于治疗乳腺癌）引起的毒性。我们建议在正在进行的乳腺癌临床试验中进行全基因组扫描（GWAS），并检查与3级和4级毒性相关的遗传变异。使用来自大型治疗性试验（S0221）的数据和样本（n=2000），我们将进行GWAS以鉴定与AC段期间的3级和4级血液学和胃肠道毒性以及T段期间的神经毒性显著相关的SNP。来自S0221 GWAS的结果将在CALGB 40101中进行验证，这是一项对2200名接受相同化疗药物的具有相似入选标准的女性进行的试验。还将汇总两项试验的数据进行荟萃分析，以增强统计功效。通过使用GWAS方法，可能会发现以前未考虑的重要途径在治疗相关毒性的易感性中具有重要意义，确定替代药物或剂量减少的最大风险，并开辟新的研究领域，以预防接受化疗的乳腺癌患者中经常危及生命的毒性。

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.