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: 6892171
• 负责人: DANIEL F. HAYES
• 金额: $ 45.33万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892171
• 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）：修订后的应用的总体目标是确定原发性乳腺癌组织中的HER-2和/或p53异常是预测乳腺癌阳性阳性的妇女是在辅助环境中是否会受益于阿霉素剂量升级或添加紫杉醇。这些研究将使用来自参与NCI支持的，多机构的美国合作组间临床试验的患者进行前瞻性收集的组织进行，由癌症和白血病B组（CALGB 9344/INT0148）进行。在这项临床试验中，新诊断的乳腺癌阳性患者接受了四个周期（ACX4）的辅助化疗，包括阿霉素（Adrimycintm）和环磷酰胺，其中阿霉素以60、75或90 mg/m2的方式随机分配。 ACX4之后，还将患者随机分配接受四个周期或没有进一步治疗的紫杉醇（taxoltm）。这项临床试验的初步结果表明，对于所有患者，阿霉素剂量升级几乎没有额外的好处，而对于那些接受紫杉醇的患者来说，已经观察到了较小但统计学上的显着改善。与仅标准剂量AC相比，这两种策略都与毒性增加有关。确定鉴定可能更可能从阿霉素剂量升级或添加紫杉醇的患者亚组的因素，这将是重要的临床重要性。 9344试验设计的随机性质允许对这些治疗策略与潜在预测标记之间的相互作用进行直接评估，从而获得阿霉素剂量升级或添加紫杉醇的益处。在该提案中要测试的主要假设是，在乳腺癌中常见的两个癌基因HER-2和P53中的异常（放大，过表达）可能是这种预测标记。研究人员和其他人产生的初步数据强烈支持以下假设：这两种癌基因的异常可能会导致阿霉素剂量升级和添加紫杉醇的益处。在特定的目标1中，我们将确定Her-2扩增（由荧光原位杂交，鱼）和/或过表达（由免疫组织化学确定，IHC确定）是否可以预测毒素剂量升级或添加紫杉醇会受益。在特定目标2中，我们将类似地确定由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。总之，这些研究应使我们能够确定HER-2和/或p53是否是阿霉素剂量升级和/或在新诊断为乳腺癌的阳性患者中添加紫杉醇剂量升级和/或添加紫杉醇的重要分子预测指标。

项目成果

Tamoxifen: Dr. Jekyll and Mr. Hyde?

他莫昔芬：化身博士和海德先生？

• DOI: 10.1093/jnci/djh191
• 发表时间: 2004
• 期刊: Journal of the National Cancer Institute
• 作者: Hayes,DanielF

Playing the old piano: another tune for endocrine therapy?

弹奏旧钢琴：内分泌治疗的另一首曲子？

• DOI: 10.1093/jnci/djg111
• 发表时间: 2003
• 期刊: Journal of the National Cancer Institute
• 作者: Hayes,DanielF

Adjuvant chemotherapy for elderly women with hormone receptor-positive breast cancer: an old(er) problem.

患有激素受体阳性乳腺癌的老年女性的辅助化疗：一个老问题。

• DOI: 10.1200/jco.2004.07.961
• 发表时间: 2004
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Schott,Anne;Hayes,DanielF
• 通讯作者: Hayes,DanielF