ANALYSIS AND THERAPEUTIC TARGETING OF BREAST CANCER DISSEMINATED TUMOR CELLS

描述(申请人提供)：转移是导致乳腺癌患者死亡的最重要因素。在乳腺癌患者中，骨髓(BM)被认为是播散性肿瘤细胞(DTC)的储存库，播散性肿瘤细胞是转移过程中的假想中间体。我们的目标是对DCs进行分子分类，以用于预测性生物标记物识别和治疗靶向。我们已经开发了一种策略来识别与DTCs相关的基因，并开发了一种用于分析它们的多重分析方法--纳米串计数器。我们假设，在临床实践中引入一套经过验证的分子标记来检测和分类DTCs，以实施靶向治疗，将通过阻断转移来阻止转移疾病的发展。 卡斯卡德。我们的目标是利用120名临床II/III期乳腺癌患者的骨髓样本，提炼和验证46基因表达谱，用于检测和分类DCs，并进行II期随机试验，评估曲妥珠单抗在早期Her2阴性、表达BM DCs的乳腺癌患者中消除ERRB2阳性播散性肿瘤细胞和DFS的效果。我们的提案将提供原则性证据，证明我们可以根据患者DTC的预测性生物标记物表达谱确定对特定靶向治疗有反应的患者亚群，并且消除DTC会带来DFS益处。该项目将导致基于DTC预测生物标记物表达谱的早期乳腺癌患者治疗模式的转变。

DESCRIPTION (provided by applicant): Metastasis is the most significant contributor to mortality in breast cancer patients. In breast cancer patients, bone marrow (BM) is thought to serve as a reservoir for disseminated tumor cells (DTCs), which are the hypothesized intermediaries in the metastatic process. Our goal is to molecularly classify DTCs for predictive biomarker identification and therapeutic targeting. We have developed a strategy for identifying genes associated with DTCs and a multiple assay, Nanostring nCounter for their analysis. We hypothesize that introducing a validated set of molecular markers for the detection and molecular classification of DTCs into clinical practice for the implementation of targeted therapies will result in a halting of metastatic disease development by interrupting the metastatic cascade. Our goals are to refine and validate a 46-gene expression profile for the detection and classification of DTCs using BM specimens from a 120 patient cohort of clinical stage II/III breast cancer patients and to conduct a phase II randomized trial evaluating the effect of trastuzumab on the elimination of ERRB2-positive disseminated tumor cells and DFS in early stage Her2-negative primary breast cancer patients with ERBB2 expressing BM DTCs. Our proposal will provide proof of principle that we can identify subsets of patients who will respond to specific targeted therapies based on the predictive biomarker expression profile of their DTCs and that eliminating DTCs results in a DFS benefit. This project will result in paradigm shift for treating early stage breast cancer patients based on the DTC predictive biomarker expression profile.