Breast density and collagen alignment as predictors of DClS disease-free survival

项目名称：乳腺密度和胶原排列作为DCIS无病生存期的预测因子 项目概要：DCIS诊断率的提高是当前乳腺癌筛查过程所固有的-几乎30%的筛查检测到的乳腺癌是DCIS。由于DCIS自然史的不确定性，人们普遍担心过度治疗。不幸的是，目前无法确定哪些DCIS病变可能进展到潜在致命的侵入性阶段。因此，目前的指南建议对所有患有DCIS的女性进行相对积极的治疗，包括手术，放射治疗和考虑激素治疗。为了优化乳腺癌筛查过程，迫切需要鉴定DCIS预后标志物，以允许个性化治疗策略。 乳腺钼靶摄影乳腺密度是一个很有前途的候选人作为一个预后指标，预测从DCIS进展为浸润性疾病的可能性。然而，目前，只有很少的数据，关于乳腺密度和疾病进展之间的关联的性质，以及我们对乳腺密度的生物学机制的理解有很多不确定性。胶原蛋白是乳腺密度的主要组成部分，实验室研究表明，它在促进肿瘤侵袭中起着关键作用。我们建议的目标是将这些实验室发现转化为乳腺密度作为DCIS预后标志物的进展。我们的目标是：1）确定乳腺钼靶摄影乳腺密度与DCIS女性无病生存期之间的关联; 2）确定胶原重组与DCIS女性无病生存期之间的关联; 3）评估乳腺钼靶摄影乳腺密度与无病生存期之间的关联是否由胶原重组介导。为了实现这些目标，我们将使用来自佛蒙特州乳腺癌监测系统的数据和组织，其中包括约1，400例DCIS病例的相关患者风险因素，乳房X光检查，病理学，治疗和癌症结局数据，随访时间长达16年。我们将使用三种不同的乳腺密度测量方法：分类BIF^DS评估、二维定量计算机辅助方法（Cumulus）和三维定量体积密度评估，后者允许测量DCIS病变附近特定感兴趣区域的乳腺密度。多光子显微镜将用于评价存档DCIS肿瘤标本中的胶原重组。本研究将评估乳腺X线摄影乳腺密度和胶原重组作为识别不太可能进展或仅需最小干预即可治疗的DCIS病例的潜在标志物的潜力。这可能会导致我们的能力大大提高，以尽量减少乳腺癌筛查（过度治疗）的危害，同时保持好处（降低乳腺癌发病率和死亡率）。

PROJECT TITLE: Breast density and collagen alignment as predictors of DCIS disease-free survival PROJECT SUMMARY: Elevated rates of DCIS diagnoses are inherent to current breast cancer screening processes - almost 30% of screen-detected breast cancers are DCIS. Due to uncertainty in the natural history of DCIS, there is widespread concern regarding overtreatment. Unfortunately, it is currently impossible to determine which DCIS lesions are likely to progress to a potentially lethal invasive stage. Thus, current guidelines recommend relatively aggressive treatment for all women with DCIS, including surgery, radiation, and consideration of hormone therapy. To optimize the breast cancer screening process, there is an urgent need for identification of DCIS prognostic markers that would permit personalized treatment strategies. Mammographic breast density is a promising candidate as a prognostic marker to predict the likelihood of progression from DCIS to invasive disease. Currently, however, there is only scarce data regarding the nature of the association between breast density and disease progression, and much uncertainty in our understanding of the biological mechanisms of breast density. Collagen is a major component of breast density and laboratory studies have shown that it plays a key role in facilitating tumor Invasion. The objective of our proposal is to translate these laboratory findings into advances in the development of breast density as a prognostic marker for DCIS. We aim to 1) determine the association between mammographic breast density and disease-free survival among women with DCIS; 2) determine the association between collagen reorganization and disease-free survival among women with DCIS; and 3) assess whether the association between mammographic breast density and disease-free survival is mediated by collagen reorganization. To accomplish these aims, we will use data and tissue from the Vermont Breast Cancer Surveillance System, which includes linked patient risk factor, mammography, pathology, treatment, and cancer outcomes data for approximately 1,400 DCIS cases with up to 16 years of follow-up. We will use three different measures of breast density: the categorical BIF^DS assessment, a 2-D quantitative computer-assisted method (Cumulus), and a 3-D quantitative volumetric density assessment that permits measurement of breast density in specific regions of interest adjacent to the DCIS lesion. Multiphoton microscopy will be used to evaluate collagen reorganization in archived DCIS tumor specimens. This study will evaluate the potential for mammographic breast density and collagen reorganization to serve as potential markers for identifying DCIS cases that are not likely to progress or could be treated with only minimal intervention. This could lead to a substantial improvement in our ability to minimize the harms of breast cancer screening (overtreatment) while preserving the benefits (reductions in breast cancer morbidity and mortality).