Correlative Studies of erbB-2/HER2 and p53 in CALGB Pro.

CALGB Pro 中 erbB-2/HER2 和 p53 的相关性研究。

• 批准号: 6613178
• 负责人: DANIEL F. HAYES
• 金额: $ 48.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613178
• 关键词: breast neoplasms; clinical research; doxorubicin; drug adverse effect; female; fluorescent in situ hybridization; gene expression; gene mutation; human tissue; immunocytochemistry; lymph nodes; neoplasm /cancer chemotherapy; p53 gene /protein; paclitaxel; protooncogene

DESCRIPTION (provided by applicant): The overall goal of this revised application is to determine whether HER-2 and/or p53 abnormalities in primary breast cancer tissues predict whether women with node positive breast cancer benefit from either doxorubicin dose escalation or addition of paclitaxel in the adjuvant setting. These studies will be performed using tissues that were prospectively collected from patients who participated in an NCI-supported, multi-institutional U.S. Inter-Cooperative Group clinical trial led by the Cancer and Leukemia Group B (CALGB 9344/INT0148). In this clinical trial, node positive patients with newly diagnosed breast cancer received adjuvant chemotherapy consisting of doxorubicin (AdriamycinTM) and cyclophosphamide for four cycles (ACX4) in which the doxorubicin was administered at 60, 75, or 90 mg/m2 in a randomly assigned fashion. After ACX4, patients were also randomly assigned to receive paclitaxel (TaxolTM) for four cycles or no further therapy. The preliminary results of this clinical trial suggest that for all patients, there has been little or no added benefit for doxorubicin dose escalation, while a small but statistically significant improvement has been observed for those patients who received paclitaxel. Both of these strategies are associated with increased toxicities compared to standard dose AC alone. It would be of substantial clinical importance to determine factors that identify subgroups of patients that might be more likely to benefit from either doxorubicin dose escalation or addition of paclitaxel. The randomized nature of the 9344 trial design permits direct evaluation for interactions between these therapeutic strategies and potential predictive markers for benefit from doxorubicin dose escalation or addition of paclitaxel. The major hypotheses to be tested in this proposal are that abnormalities (amplification, overexpression) in two oncogenes, HER-2 and p53, which are common in breast cancer, might serve as such predictive markers. Preliminary data generated by the investigators, and others, strongly support the hypothesis that abnormalities in these two oncogenes may lead to enhanced benefit from doxorubicin dose escalation and addition of paclitaxel. In Specific Aim 1, we will determine if HER-2 amplification (as determined by fluorescent in situ hybridization, FISH) and/or overexpression (as determined by immunohistochemistry, IHC) predicts for benefit from either doxorubicin dose escalation or addition of paclitaxel. In Specific Aim 2, we will similarly determine whether p53 abnormalities, as determined by immunohistochemistry, predicts for benefit from either of these two therapeutic strategies. In conclusion, these studies should enable us to determine whether or not HER-2 and/or p53 are important molecular predictors of added benefit from doxorubicin dose escalation and/or addition of paclitaxel in node positive patient with newly diagnosed breast cancer.

描述（由申请人提供）：本修订申请的总体目标是确定原发性乳腺癌组织中的 HER-2 和/或 p53 异常是否可以预测患有淋巴结阳性乳腺癌的女性是否受益于阿霉素剂量递增或添加紫杉醇。辅助设置。这些研究将使用前瞻性收集的患者组织进行，这些患者参加了由癌症和白血病 B 组 (CALGB 9344/INT0148) 领导的 NCI 支持的多机构美国合作组临床试验。在这项临床试验中，新诊断乳腺癌的淋巴结阳性患者接受了由阿霉素 (AdriamycinTM) 和环磷酰胺组成的辅助化疗四个周期 (ACX4)，其中阿霉素按 60、75 或 90 mg/m2 随机分配时尚。 ACX4 治疗后，患者还被随机分配接受紫杉醇 (TaxolTM) 四个周期或不接受进一步治疗。该临床试验的初步结果表明，对于所有患者来说，阿霉素剂量递增几乎没有或没有额外的益处，而接受紫杉醇治疗的患者观察到了微小但具有统计学意义的改善。与单独使用标准剂量 AC 相比，这两种策略都会增加毒性。确定确定更有可能从阿霉素剂量递增或添加紫杉醇中受益的患者亚组的因素具有重要的临床意义。 9344 试验设计的随机性质允许直接评估这些治疗策略与潜在预测标志物之间的相互作用，以从阿霉素剂量递增或添加紫杉醇中获益。该提案要测试的主要假设是乳腺癌中常见的两种癌基因 HER-2 和 p53 的异常（扩增、过度表达）可能作为此类预测标记。研究人员和其他人产生的初步数据有力地支持了这样的假设：这两种癌基因的异常可能导致阿霉素剂量递增和紫杉醇添加带来的益处增强。在具体目标 1 中，我们将确定 HER-2 扩增（通过荧光原位杂交 (FISH) 测定）和/或过度表达（通过免疫组织化学 (IHC) 测定）是否可以预测阿霉素剂量递增或添加紫杉醇的益处。在具体目标 2 中，我们将类似地确定通过免疫组织化学确定的 p53 异常是否可以预测这两种治疗策略中的任何一种的益处。总之，这些研究应该使我们能够确定 HER-2 和/或 p53 是否是新诊断乳腺癌淋巴结阳性患者中多柔比星剂量递增和/或添加紫杉醇带来的额外益处的重要分子预测因子。