Rectal Cancer: Molecular Markers of Outcome and Toxicity

描述（由申请方提供）：本研究的目的是在接受氟尿嘧啶（5-FU）化疗和放疗的Dukes B2、B3或C期直肠癌患者中鉴定与临床结局和毒性相关的分子标志物（基因表达水平和生殖系多态性）。辅助治疗失败是直肠癌的主要问题，急性胃肠道和血液毒性反应相当严重，可能危及生命。建立耐药分子标志物、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小的化疗方案。作为初步研究的一部分，我们已经表明肿瘤内基因表达（例如，二嘧啶脱氢酶）和种系多态性（例如，胸苷酸合成酶（TS）可以预测5-FU治疗的转移性结肠癌患者的反应和总生存期。我们建议将重点放在几个关键途径的标记物上，包括5-FU和叶酸代谢，DNA修复和血管生成。在788例直肠癌患者中，（INT-0144，SWOG 9304）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的肿瘤内基因表达水平（RNA）是否与临床结局相关;以及2）编码参与5-FU和叶酸代谢、解毒和DNA修复或血管生成的蛋白质的基因的生殖系多态性（DNA）是否与毒性和临床结果相关。该研究使用了大量临床试验患者人群，对结局和毒性进行了出色的评估，并利用现有标本进行了成本效益分析。这项研究的结果可能有助于直肠癌患者未来治疗策略的制定。

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.