Rectal Cancer: Molecular Markers of Outcome and Toxicity

描述(申请人提供)：这项研究的目标是确定与接受以氟尿嘧啶(5-FU)为基础的化疗和放射治疗的B2、B3或C期Dukes‘期直肠癌患者的临床结果和毒性相关的分子标记(基因表达水平和生殖系多态)。辅助治疗的失败是直肠癌的一个主要问题，急性胃肠道和血液毒性影响相当大，可能危及生命。建立耐药分子标记物、治疗反应和临床毒性之间的关联，可能最终导致直肠癌患者更成功和毒性更低的化疗方案。作为初步研究的一部分，我们已经证明，转移性结肠癌患者接受5-FU治疗后，肿瘤内基因表达(例如，二嘧啶脱氢酶)和生殖系基因多态(例如，胸苷合成酶，TS)可以预测疗效和总存活率。我们建议将重点放在几个关键途径的标记上，包括5-FU和叶酸代谢、DNA修复和血管生成。在788名登记参加直肠癌III期联合研究(INT-0144，SWOG 9304)的直肠癌患者中，我们将确定1)参与叶酸和5-FU代谢、DNA修复和生长因子的酶在肿瘤内的基因表达水平(RNA)是否与临床预后相关；2)5-FU和叶酸代谢、解毒和DNA修复或血管生成相关编码基因的种系多态性(DNA)是否与毒性和临床预后相关。这项研究使用了大量的临床试验患者群体，对结果和毒性进行了出色的评估，并利用现有的样本进行了成本效益分析。这项研究的结果可能有助于制定未来直肠癌患者的治疗策略。

DESCRIPTION (provided by applicant): The goal of this study is to identify molecular markers (gene expression levels and germline polymorphisms) associated with clinical outcome and toxicity among Dukes' stage B2, B3 or C rectal cancer patients treated with fluorouracil (5-FU) based chemotherapy and radiation. Failure of adjuvant therapy represents a major problem in rectal cancer, and acute gastrointestinal and hematologic toxic effects are considerable and can be life-threatening. Establishing associations between molecular markers of drug resistance, treatment response, and clinical toxicity, may ultimately result in more successful and less toxic chemotherapeutic regimens for rectal cancer patients. As part of initial studies, we have shown that intratumoral gene expression (e.g., dipyrimidine dehydrogenase) and germline polymorphisms (e.g., thymidylate synthase, TS) can predict response and overall survival in patients with metastatic colon cancer treated with 5-FU. We propose to focus on markers in several key pathways, including 5-FU and folate metabolism, DNA repair, and angiogenesis. Among 788 patients with rectal cancer registered to a collaborative Phase III study of rectal cancer (INT-0144, SWOG 9304) we will determine 1) whether intratumoral gene expression levels (RNA) of enzymes involved in folate and 5-FU metabolism, DNA repair, and growth factors, are associated with clinical outcome; and 2) whether germline polymorphisms (DNA) of genes encoding proteins involved in 5-FU and folate metabolism, detoxification and DNA repair, or angiogenesis, are associated with toxicity and clinical outcome. The study uses a large clinical trial patient population with excellent assessment of outcomes and toxicities, and utilizes existing specimens for a cost-effective approach. Results from this study may aid in the development of future treatment strategies for patients with rectal cancer.