Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal Junction

描述(由申请人提供)：摘要胃和胃食道交界处(GEJ)癌症是癌症死亡的主要原因。尽管开发了新的化疗方法，但这些肿瘤患者的应答率和中位存活率基本上仍然停滞不前。确定宿主和分子/生物肿瘤的特征以定制治疗可能会导致改善生存结果。回顾研究已经确定了预测治疗结果的遗传标记。然而，目前还没有关于胃癌和GEJ癌的前瞻性研究来评估这些遗传因素的临床应用。我们假设，基于基因的治疗将改善胃癌和GEJ癌症患者的预期应答率。我们提出了一项前瞻性的、多机构的II期临床试验，测试胸苷酸合成酶(TS)基因的种系多态，TS增强子区的串联重复数(TSER)作为治疗选择的标记。与Tser*2变体(两个串联重复序列)相比，由于肿瘤TS的高表达，赋予三个串联重复序列(Tser*3)的多态变体与5-FU耐药相关。Tser*3基因多态常见(等位基因频率为0.5~0.8)。在拟议的研究中，我们将前瞻性地对胃癌和GEJ癌患者进行基因分型。预期对5-FU敏感的患者(携带Tser*2等位基因)将接受包含5-FU的方案(5-FU、亚叶酸钙、奥沙利铂)。预期为5-FU耐药(TSER*3纯合子)的患者将不包括在研究中。在目标1中，我们将确定基于种系TSER多态状态的治疗选择是否提高了转移性胃和GEJ肿瘤患者的应答率。从这项研究中获得的应答率将与先前在非基因型患者中观察到的应答率进行比较。在目标2和目标3中，建议进行更多的相关研究，以确定可能改变这种治疗方法预期结果的混杂因素(例如，肿瘤TS等位基因的杂合性丢失和涉及所用治疗的反应/毒性的其他基因的变异)。在这项快速积累的小型研究中，TSER状态作为一个重要的预后因素的前瞻性确认可能为更大规模的前瞻性验证性试验提供充分的理由。这种方法的最终目标是在定制癌症治疗时可靠地使用遗传标记。胃和胃食道交界处癌症(GEJ)是一个重大的公共卫生问题，其发病率的增加速度比任何其他癌症都要快。在诊断时，大多数患有这些癌症的患者都是晚期疾病，存活率很低(5年时约为0%)。尽管化疗药物较新，但这些患者的治疗结果停滞不前，因此需要新的方法。在药物遗传学的指导下选择化疗治疗胃癌和GEJ癌是一种很有前途的方法，可以确定哪些患者最有可能从特定的化疗中受益。这项拟议的研究结果将为证明一项更大规模的研究的合理性提供坚实的科学证据，这项研究最终可能导致在定制癌症治疗中使用遗传标记。

DESCRIPTION (provided by applicant): Abstract Gastric and Gastroesophageal junction (GEJ) cancers are a leading cause of cancer mortality. Despite the development of newer chemotherapies, the response rates and median survival in patients with these tumors has remained essentially stagnant. Defining host and molecular/biologic tumor characteristics to customize treatment may lead to improved survival outcomes. Retrospective studies have identified genetic markers that predict treatment outcome. However, there have been no prospective studies in gastric and GEJ cancer evaluating the clinical utility of these genetic factors. We hypothesize that genomically based treatment will improve the expected response rate in patients with gastric and GEJ cancers. We propose a prospective, multi-institutional Phase II clinical trial testing a germline polymorphism in the thymidylate synthase (TS) gene, the number of tandem repeats in the TS enhancer region (TSER) as a treatment selection marker. The polymorphic variant conferring three tandem repeats (TSER*3) has been associated with 5-FU resistance due to high tumor TS expression in comparison to the TSER*2 variant (two tandem repeats). The TSER*3 polymorphism is common (allelic frequency of 0.5-0.8). In the proposed study, we will prospectively genotype patients with gastric and GEJ cancers. Patients who are expected to be 5-FU sensitive (carrying a TSER*2 allele) will receive a 5-FU containing regimen (5-FU, leucovorin, oxaliplatin). Patients who are expected to be 5-FU resistant (homozygous for TSER*3) will not be included in the study. In Aim 1, we will determine whether treatment selection based on germline TSER polymorphism status improves the response rate in patients with metastatic gastric and GEJ tumors. The response rate obtained from this study will be compared to previously observed response rates in non-genotype selected patients. In Aims 2 and 3, additional correlative studies are proposed to identify confounding factors that may alter the expected outcomes of this treatment approach (e.g. loss of heterozygosity of a tumor TS allele and variations in other genes involved in response/toxicity of the administered treatment). Prospective confirmation of the significance of TSER status as an important prognostic factor in this small, rapidly accruable study may provide sufficient rationale for larger prospective confirmatory trials. The eventual goal of this approach is the reliable use of genetic markers in customizing cancer treatment. Cancers of the stomach and gastroesophageal junction (GEJ) are a significant public health problem and are increasing in incidence at a greater rate than any other cancers. At the time of diagnosis, most patients with these cancers have advanced disease and a dismal rate of survival (~ 0 % at 5 years). Despite newer chemotherapy drugs, the treatment outcomes in these patients have stagnated, therefore new approaches are needed. Pharmacogenomically guided selection of chemotherapy for the treatment of gastric and GEJ cancer is a promising approach to identify patients who are most likely to benefit from a particular chemotherapy. The results of the proposed study will be important to provide solid scientific evidence to justify a larger study that may eventually lead to the use genetic markers in customizing cancer treatment.