Stromal MRI characteristics & gene expression profiles as predictors of outcome

描述（由申请人提供）：癌症相关间质已被发现是恶性肿瘤演变中的动态伙伴。 基因表达数据已经阐明了与特定生物学相关的功能特征，包括与基质相关的功能特征，并且最近发现其具有预后意义。 我们已经开发了技术工具来量化CE乳腺MRI中正常表现基质的增强百分比值。 在我们之前发表的研究中，我们发现乳腺基质的平均整体增强值与接受新辅助化疗的乳腺癌患者的无病生存率相关。 这项研究表明，宿主乳腺组织具有可通过MRI测量的预后性质。 我们进一步扩展这些研究，以评估间质与肿瘤邻近性的关系。 在我们目前的初步数据中，我们发现在所有患者中，肿瘤周边的增强百分比随着距离的增加而降低，并且该区域在组织学上与显着增加的血管生成相关。 我们假设，整体宿主组织特性和邻近肿瘤的癌症相关基质对肿瘤生物学至关重要，并将对局部晚期乳腺癌患者的结局具有预后意义。 在该提案中，我们的主要终点将是解决MRI表征的基质和基因表达阵列特征是否与在CALGB 15007/ ACRIN 6657对比增强乳腺MRI和相关科学研究中招募的浸润性乳腺癌患者的无复发生存期相关，以表征接受局部晚期乳腺癌新辅助治疗的患者的肿瘤反应（“ISPY”试验）。 公共卫生相关性：该项目解决了宿主组织和癌症相关基质具有生物学特性的假设，这些生物学特性是乳腺癌患者预后和预后的预测因素。 我们的策略将是将我们使用MRI开发的新工具应用于一项已完成的临床试验，该试验招募了浸润性乳腺癌患者接受新辅助化疗，并接受系列肿瘤活检和乳腺MRI，CALGB 15007/ ACRIN 6657对比增强乳腺MRI和相关科学研究，以表征接受局部晚期乳腺癌新辅助治疗的患者的肿瘤反应（“ISPY”试验）。 我们将使用治疗前MRI来测量每个患者的全局和局部增强值。定量测量将与无复发生存期相关，并将确定解释其他预后因素的多变量回归模型。 然后，将分析来自治疗前肿瘤活检的基因表达阵列数据的表达阵列特征及其与结果的关联。 还将研究具有生物学功能的基因表达特征，并且所有特征将与MRI表型和结果相关。 这些研究将使我们能够验证间质MRI测量是否是预后的，并确定癌症相关的间质基因表达特征是否改善了结果的预测。

DESCRIPTION (provided by applicant): The cancer associate stroma has come to light as a dynamic partner in the evolution of malignancy. Gene expression data have elucidated functional signatures that are associated with specific biology, including that associated with stroma and have recently been found to have prognostic significance. We have developed the technical tools to quantify percent enhancement values in normal appearing stroma from CE-breast MRIs. In our previously published work, we showed that mean global enhancement values of the breast stroma were associated with disease-free survival in patients with breast cancer receiving neoadjuvant chemotherapy. This study revealed that host breast tissue had properties measurable by MRI that were prognostic. We extended these investigations further to evaluate the stroma in relationship to tumor proximity. In our current preliminary data, we found that in all patients, percent enhancement decreased from the periphery of the tumor with increasing distance, and that this region was histologically associated with significantly increased angiogenesis. We hypothesize that both global host tissue properties, and cancer- associated stroma, adjacent to the tumor, are critical to tumor biology and will be prognostic for outcomes in patients with locally advanced breast cancer. In this proposal, our primary endpoints will be to address whether MRI-characterized stroma and gene expression array signatures are associated with relapse free survival in patients with invasive breast cancer enrolled in the CALGB 15007/ ACRIN 6657 Contrast-Enhanced Breast MRI and Correlative Science Studies to Characterize Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer ("ISPY" trial). PUBLIC HEALTH RELEVANCE: This project addresses the hypothesis that the host tissue and cancer-associated stroma have biologic properties that are prognostic and predictive of outcomes in breast cancer patients. Our strategy will be to apply the novel tools we have developed using MRI to a completed clinical trial that enrolled invasive breast cancer patients to receive neoadjuvant chemotherapy and undergo serial tumor biopsy and breast MRI, the CALGB 15007/ ACRIN 6657 Contrast-Enhanced Breast MRI and Correlative Science Studies to Characterize Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer ("ISPY" trial). We will use pre-treatment MRIs to measure enhancement values globally and topographically for each patient. Quantitative measures will be associated recurrence free survival, and a multivariable regression model that accounts for other prognostic factors will be determined. Then, gene expression array data from the pre-treatment tumor biopsy will be analyzed for expression array signatures and their association with outcomes. Gene expression signatures with biologic function will also be investigated, and all signatures will be correlated with MRI phenotypes and outcome. These studies will allow us to validate whether stromal MRI measurements are prognostic, and to determine whether cancer- associated stromal gene expression signatures improve prediction of outcomes.