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

阐明 IDLE 超低风险病变的分子和背景基础以及高风险原位和浸润性乳腺癌的肿瘤免疫微环境

• 批准号: 10253262
• 负责人: ALEXANDER D BOROWSKY
• 金额: $ 65.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253262
• 关键词: Address; Attention; Behavior; Biological; Biological Assay; Biology; Breast Cancer Risk Factor; California; Categories; Collection; Data; Data Set; Detection; Diagnosis; Disease; ERBB2 gene; Early Intervention; Endocrine; Environment; Epithelial; Epithelium; Exhibits; Expression Profiling; Gene Expression Profiling; Genomics; Goals; Heterogeneity; Image; Immune; Immune response; Immunology procedure; In Situ; In Situ Lesion; Indolent; Intervention; Invasive Lesion; Label; Learning; Lesion; Longterm Follow-up; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Measures; Modeling; Molecular; Noninfiltrating Intraductal Carcinoma; Outcome; Pathologic; Pathology; Population; Predisposition; Prevention; Registries; Resources; Risk; Testing; Time; Woman; arm; base; breast cancer diagnosis; breast lesion; cancer diagnosis; cancer invasiveness; clinical care; genetic risk factor; high risk; hormone receptor-negative; malignant breast neoplasm; oncotype; overtreatment; prevent; prospective; prospective test; public health intervention; public health relevance; risk variant; routine screening; screening; screening policy; tumor; tumor-immune system interactions

 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.

 描述（由申请人提供）：仅在美国，乳腺癌每年仍导致45，000名妇女死亡，超过270，000名妇女被诊断为浸润性或原位疾病。筛查是我们主要的公共卫生干预措施。然而，我们可能过度诊断的妇女人数超过了我们通过筛查挽救的妇女人数，这并不影响最具侵略性的癌症的结果。我们已经收集了一组非凡的资源，其中包括长期随访的数据集以及独特的前瞻性试验，该试验将包括全面的宿主风险和肿瘤注释，以解决惰性（IDLE）和间隔癌症的潜在生物学（从肿瘤和宿主角度）。我们的目标是更好地识别 寻找方法来筛查和治疗最具侵袭性的癌症，避免过度诊断和过度治疗，以及无意中将惰性病变标记为癌症。可检验假设1.市售检测试剂盒可识别超低风险乳腺肿瘤（侵袭性癌症的MammaPrint Ultralow Risk，DCIS的Oncotype-DCIS-1类）。2.结合使用市售的检测方法加上其他基于基因组、病理学和免疫学的检测方法沿着检测模式，可以进一步区分IDLE和超低乳腺病变。3.在将筛查检测到的恶性特征与间隔期乳腺癌区分开的恶性特征中，有细胞和分子异质性的程度以及免疫微环境和宿主反应的类型/程度。4.由于间隔期癌症通常在生物学上与筛查检测到的癌症不同，我们假设遗传风险因素将有助于区分间隔期癌症与筛查检测到的癌症的风险。具体目标：1。将低风险侵袭性肿瘤分为低风险、超低风险和IDLE，将高风险分为间隔风险和筛查风险-使用基因表达谱、病理学特征、免疫谱在完全注释的侵袭性癌症数据集中进行检测，并在加利福尼亚州范围内的前瞻性筛查试验中验证最佳预测因子。 2.在已建立的数据集中，使用基因表达谱和肿瘤免疫微环境的测量，并使用300例DCIS病例的前瞻性登记研究，开发将DCIS病变分层为IDLE、超低、中等和高风险DCIS乳腺病变的连续性测定3。开发一个模型，使用已知的生殖系乳腺癌风险变异来预测倾向于超低和IDLE筛查检测到的肿瘤的女性，以及倾向于间隔检测到的乳腺癌的女性，使用来自加利福尼亚州范围内的完全注释的筛查试验的数据，包括生殖系和肿瘤分析。

项目成果

Characterizing the Tumor Immune Microenvironment with Tyramide-Based Multiplex Immunofluorescence.

• DOI: 10.1007/s10911-021-09479-2
• 发表时间: 2020-12
• 期刊: Journal of mammary gland biology and neoplasia
• 影响因子: 2.5
• 作者: Mori H;Bolen J;Schuetter L;Massion P;Hoyt CC;VandenBerg S;Esserman L;Borowsky AD;Campbell MJ
• 通讯作者: Campbell MJ

Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial.

• DOI: 10.1200/jco.21.02844
• 发表时间: 2022-12-10
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Detection of ductal carcinoma in situ and subsequent interval cancers.

检测导管原位癌和随后的间隔癌。

• DOI: 10.1136/bmj.i551
• 发表时间: 2016
• 期刊: BMJ (Clinical research ed.)
• 作者: Shieh,Yiwey;Eklund,Martin;Esserman,Laura
• 通讯作者: Esserman,Laura

Aging Mouse Models Reveal Complex Tumor-Microenvironment Interactions in Cancer Progression.

• DOI: 10.3389/fcell.2018.00035
• 发表时间: 2018
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Mori H;Cardiff RD;Borowsky AD
• 通讯作者: Borowsky AD

Clinical and molecular characteristics of estrogen receptor-positive ultralow risk breast cancer tumors identified by the 70-gene signature.

• DOI: 10.1002/ijc.33969
• 发表时间: 2022-06-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Johansson, Annelie;Yu, Nancy Y.;Iftimi, Adina;Tobin, Nicholas P.;'t Veer, Laura;Nordenskjold, Bo;Benz, Christopher C.;Fornander, Tommy;Perez-Tenorio, Gizeh;Stal, Olle;Esserman, Laura J.;Yau, Christina;Lindstrom, Linda S.
• 通讯作者: Lindstrom, Linda S.