Elucidating the molecular and contextual basis for IDLE ultralow risk lesions and the tumor immune microenvironment of high risk in situ and invasive breast cancers

 描述(申请人提供)：仅在美国，每年仍有45000名女性死于乳腺癌，超过27万名女性被诊断为浸润性疾病或原位疾病。筛查是我们主要的公共卫生干预措施。然而，我们过度诊断的女性可能与我们通过筛查挽救的女性一样多或更多，而且这不会影响最具侵袭性的癌症的结果。我们汇集了一套非凡的资源，其中包括具有长期随访的数据集，以及一项独特的前瞻性试验，该试验将包括全面的宿主风险和肿瘤注释，以解决惰性(闲置)和间歇性癌症的潜在生物学(从肿瘤和宿主的角度)。我们的目标是更好地识别 筛查和治疗最具侵袭性的癌症的方法，避免过度诊断和过度治疗，以及无意中将惰性病变贴上癌症标签。可测试的假设1.商业上可用的分析可以识别超低风险的乳腺肿瘤(MammaPrint超低风险的浸润性癌症，Oncotype-DCIS-DCIS的1类)。2.结合使用商业上可用的检测方法以及其他基于基因组、病理学和免疫的检测方法，以及检测模式，可以进一步区分乳房病变的低度和低度。3.筛查发现的与间歇性乳腺癌不同的恶性特征包括细胞和分子的异质性程度以及免疫微环境和宿主反应的类型/程度。4.由于间歇性癌症通常与筛查发现的癌症在生物学上是不同的，我们假设遗传危险因素将有助于区分间歇性癌症和筛查发现的癌症的风险。具体目标：1.将低风险侵袭性肿瘤分为低风险、超低风险、空闲和高风险，分成间隔和筛查检测，使用全注释浸润性癌症数据集中的基因表达谱、病理学特征和免疫谱检测，并在一项预期的加州范围的筛查试验中验证最佳预测因素。 2.开发辅助分析方法，利用基因表达谱将DCIS病变分为空闲、超低、中等和高危DCIS乳腺病变，并在已建立的数据集中测量肿瘤免疫微环境，并使用300例DCIS病例的预期登记进行验证。3.使用已知的种系乳腺癌风险变量来预测女性倾向于超低和空闲筛查发现的肿瘤，以及那些倾向于间隔检测乳腺癌的女性，使用来自加州范围内的一项全面注释的筛查试验的数据，该试验包括种系和肿瘤概况。

 DESCRIPTION (provided by applicant): Breast cancer still kills 45,000 women a year in the US alone and over 270,000 women are given a diagnosis of either invasive or in situ disease. Screening is our major public health intervention. And yet we likely overdiagnose as many or more women than we save with screening and it does not impact the outcomes of the most aggressive cancers. We have assembled an extraordinary set of resources that include datasets with long term follow-up as well as a unique prospective trial that will include comprehensive host risk and tumor annotation to address the underlying biology (from both the tumor and host perspective) of indolent (IDLE) and interval cancers. Our goal is to identify better ways to screen for and treat the most aggressive cancers and avoid overdiagnosis and overtreatment as well as the inadvertent labeling of indolent lesions as cancers. Testable Hypotheses 1. Commercially available assays can identify ultralow risk breast tumors (MammaPrint Ultralow Risk for invasive cancer, Oncotype-DCIS-category 1 for DCIS). 2. The combined use of commercially available assays plus additional genomic, pathology, and immune based assays along with mode of detection can further differentiate IDLE from ultralow breast lesions. 3. Among the malignant features differentiating screen-detected from interval breast cancers are the degrees of cellular and molecular heterogeneity and type/extent of immune microenvironment and host response. 4. Since interval cancers are often biologically distinct from screen detected cancers, we hypothesize that genetic risk factors will be useful to distinguish the risk of interval from screen detected cancers. Specific Aims: 1. Stratify low risk invasive tumors into low vs. ultralow vs. IDLE and high risk into interval vs. screen- detected using gene expression profiling, pathology features, immune profiling in fully annotated invasive cancer data sets and validate the best predictors in a prospective California-wide screening trial. 2. Develop adjunctive assays to stratify DCIS lesions into IDLE, ultralow, moderate and high-risk DCIS breast lesions using gene expression profiling, and measures of tumor immune micro-environment in established data sets and validate using a prospective registry of 300 DCIS cases 3. Develop a model using known germline breast cancer risk variants to predict women predisposed toward ultralow and IDLE screen detected tumors, and those predisposed to interval detected breast cancers, using data from a fully annotated California-wide screening trial that includes germline and tumor profiling.