Identifying responders to chemotherapy in invasive lobular carcinoma of the breast: development of a multivariable clinical prediction tool

项目摘要/摘要 浸润性小叶癌(ILC)是乳腺癌中发病率第二高的肿瘤，是乳腺癌中最常见的肿瘤。 美国常见的影响女性的恶性肿瘤。尽管ILC具有独特的分子和临床特征 它的特点是，它没有得到很好的研究，也没有针对它的具体治疗策略。面临的主要挑战之一 女性ILC的治疗是决定是否应该使用细胞毒性化疗。 目前可用的基因表达分析(例如，肿瘤型和Mammaprint测试)可以对大多数ILC进行分类 肿瘤在分子上是“低风险”的，这表明细胞毒性化疗将无效。然而，ILC 比其他类型的乳腺癌更有可能出现在有淋巴转移的晚期， 这使得这些患者在临床上具有“高风险”。这种“临床高风险”状态促使患者使用化疗。 与ILC，尽管分子检测的结果不一致。事实上，大多数结节阳性的ILC患者 接受化疗，尽管没有数据表明对任何单个患者都有好处。有一个 迫切需要改进患者选择，以便化疗只能用于受益的患者 从它，而其他可以免于其毒副作用。同时，对于预测反应差的患者 标准化疗，我们需要针对所涉及的独特分子途径的个性化方法 在ILC。我们对国际法委员会的理解最近有了进展，几个团体现在已经确定 在这组肿瘤中表现出显著异质性的ILC特异性基因特征。考虑到这一新的 我们现在可以开始将ILC特定的工具整合到临床实践中，并开发出量身定做的 ILC女性患者的治疗策略。在这项提案中，我将通过以下三个方面来解决这个问题 接近了。首先，我将评估ILC化疗反应的一个新的早期指标，改善我们的 确定肿瘤是否有反应的能力。鉴于ILC患者的数量相对较少 在临床试验中，我将使用乳腺癌患者的12个组合数据集进行汇集分析 术前(新辅助)化疗。第二，我将利用最近发现的ILC- I-SPY2试验中的特定基因表达特征和数据，以开发一种预测工具 确定化疗应答者(化疗在小叶乳腺癌中的有效性和应答性 [清除]得分)。最后，我将进行一项初步研究，测试一种新型的靶向制剂与 I-SPY2试验中的内分泌治疗，通过一种名为内分泌优化途径的新ARM。这 该项目解决了一个重要的、相关的临床问题，使用了新的数据集和分子签名说明 以前提供的，而且重要的是，将使我能够在指导环境中发展技能和知识， 将促进我为患有ILC的女性设计和进行前瞻性临床试验的能力。

Project Summary/Abstract Invasive lobular carcinoma (ILC) is the second most prevalent breast cancer, which is the most common malignancy affecting women in the United States. Although ILC has unique molecular and clinical features, it is not well-studied, and no specific therapeutic strategies exist for it. One of the major challenges in the treatment of women with ILC is determining whether cytotoxic chemotherapy should be utilized or not. Currently available gene expression assays (e.g. Oncotype and Mammaprint tests) classify the majority of ILC tumors as molecularly “low risk,” which suggests that cytotoxic chemotherapy will be ineffective. However, ILC is more likely than other types of breast cancer to present at advanced stages with lymph node involvement, making these patients clinically “high risk.” This “clinical high risk” status drives chemotherapy use in patients with ILC, despite discordant results from molecular assays. Indeed, the majority of node-positive ILC patients receive chemotherapy, despite the absence of data suggesting benefit for any individual patient. There is a huge need to improve patient selection, so that chemotherapy can be utilized only in patients who will benefit from it, while others can be spared its toxic side effects. In parallel, for patients with predicted poor response to standard chemotherapy, we need personalized approaches that target the unique molecular pathways involved in ILC. There have been recent advances in our understanding of ILC, and several groups have now identified ILC specific gene signatures that show significant heterogeneity within this group of tumors. Given this newly available data, we can now start incorporating ILC specific tools into clinical practice and develop tailored treatment strategies for women with ILC. In this proposal, I will address this via the following three approaches. First, I will evaluate a novel early indicator of chemotherapy responsiveness in ILC, improving our ability to determine whether a tumor has responded or not. Given the relatively small numbers of ILC patients in clinical trials, I will conduct a pooled analysis using 12 combined datasets from breast cancer patients treated with pre-operative (neoadjuvant) chemotherapy. Second, I will leverage the recent discovery of ILC- specific gene expression signatures and the data available in the I-SPY2 Trial to develop a predictive tool to identify chemotherapy responders (Chemotherapy in Lobular breast cancer Effectiveness and Response [CLEAR] score). Finally, I will conduct a pilot study testing a novel, targeted agent in combination with endocrine therapy in the I-SPY2 Trial, through a new arm termed the Endocrine Optimization Pathway. This project addresses an important, relevant clinical issue, utilizes new datasets and molecular signatures not previously available, and importantly, will allow me to develop skills and knowledge in a mentored setting that will facilitate my ability to design and conduct prospective clinical trials for women with ILC.