Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal Junction

摘要胃和胃食管交界处（GEJ）癌症是癌症死亡的主要原因。尽管开发了新的化疗方法，但这些肿瘤患者的反应率和中位生存期基本上仍然停滞不前。确定宿主和分子/生物肿瘤特征来定制治疗可能会改善生存结果。回顾性研究已经确定了预测治疗结果的遗传标记。然而，尚无前瞻性研究评估这些遗传因素在胃癌和胃癌中的临床应用。我们假设基于基因组的治疗将提高胃癌和胃癌患者的预期缓解率。我们提出了一项前瞻性的、多机构的II期临床试验，测试胸腺苷酸合成酶（TS）基因的种系多态性，TS增强子区（TSER）串联重复序列的数量作为治疗选择的标记。具有三个串联重复序列的多态变异（TSER*3）与5-FU耐药有关，因为与TSER*2变异（两个串联重复序列）相比，肿瘤TS的表达较高。TSER*3多态性较为常见（等位基因频率为0.5 ~ 0.8）。在本研究中，我们将对胃癌和胃癌患者进行前瞻性基因分型。预计对5-FU敏感（携带TSER*2等位基因）的患者将接受含有5-FU的方案（5-FU、亚叶酸钙、奥沙利铂）。预计5-FU耐药（TSER*3纯合子）的患者将不包括在研究中。在Aim 1中，我们将确定基于种系TSER多态性状态的治疗选择是否能提高转移性胃肿瘤和GEJ肿瘤患者的反应率。从这项研究中获得的应答率将与先前在非基因型选择患者中观察到的应答率进行比较。在目标2和目标3中，提出了额外的相关研究，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等位基因的杂合性缺失以及与所给治疗的反应/毒性有关的其他基因的变异）。在这项小型、快速积累的研究中，对TSER状态作为一个重要预后因素的重要性的前瞻性确认，可能为更大规模的前瞻性验证性试验提供充分的依据。这种方法的最终目标是在定制癌症治疗中可靠地使用遗传标记。胃癌和胃食管交界处癌（GEJ）是一个重大的公共卫生问题，其发病率的增长速度超过任何其他癌症。在诊断时，大多数患有这些癌症的患者已经病情进展，生存率很低（5年生存率约为0%）。尽管有较新的化疗药物，但这些患者的治疗效果却停滞不前，因此需要新的治疗方法。在药物基因组学指导下选择治疗胃癌和胃癌的化疗是一种很有前途的方法，可以确定最有可能从特定化疗中受益的患者。这项研究的结果将为一项更大规模的研究提供可靠的科学证据，这可能最终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.