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TMEM, MENAcalc, and MENAINV as Prognostic and Predictive Markers for Breast Cancer Metastasis

TMEM、MENAcalc 和 MENAINV 作为乳腺癌转移的预后和预测标志物

基本信息

批准号：
10657591
负责人：
JOHN S CONDEELIS
金额：
$ 86.65万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657591
关键词：
Adjuvant Chemotherapy Antibodies Axillary lymph node group Biological Assay Blood Vessels Breast Cancer Patient Breast Cancer Risk Factor Breast cancer metastasis Case/Control Studies Cells Cessation of life Characteristics Cities Clinical Development Diagnosis Disease Disease-Free Survival Distant Metastasis ERBB2 gene Endothelial Cells Epidermal Growth Factor Epithelium Estrogen receptor negative Estrogen receptor positive Formalin Gene Expression Profiling Genomics Health Hematogenous Human Immunofluorescence Immunologic Individual Label Macrophage Malignant Epithelial Cell Mammary Neoplasms Mediating Mesenchymal Methods Modeling Morbidity - disease rate Mus Neoplasm Metastasis Neoplasms Nested Case-Control Study Paclitaxel Paraffin Embedding Patients Phenotype Positive Lymph Node Prediction of Response to Therapy Predictive Value Progesterone Receptors Prognostic Marker Protein Isoforms RNA Splicing Rattus Recommendation Recurrence Score Redwood Relapse Risk Rodent Sampling Sampling Studies Skin Carcinoma Structure Time Tissue Embedding Variant Woman Work cancer cell case control cell type chemotherapy clinical prognostic cohort intravital imaging malignant breast neoplasm mortality mortality risk multi-photon neoplastic cell oncotype overexpression patient population predictive marker predictive test prognostic prognostic assays prognostic value protein biomarkers receptor side effect study population translational potential treatment arm tumor tumor microenvironment

项目摘要

ABSTRACT Breast cancer mortality is largely attributable to systemic, hematogenously-disseminated metastatic disease. Given the limitations of current prognostic criteria, new methods to identify tumors likely to metastasize and respond to therapy are needed. Multiphoton-based intravital imaging has shown that invasive carcinoma cells in rodent mammary tumors intravasate via peri-vascular structures containing a Mena over-expressing tumor cell, a macrophage, and an endothelial cell, all contacting each other. This tri-partite arrangement of cells facilitates entry of carcinoma cells into the blood vessel. We have identified this microenvironment in human breast cancer samples using a triple immunostain for formalin-fixed paraffin-embedded tissue that simultan- eously labels the 3 cell types. We call the direct apposition of these 3 cell types “TMEM”, for Tumor Micro- Environment of Metastasis. Recently, in a cohort of patients at Kaiser Permanente (KP), we showed that TMEM was positively associated with risk of distant metastasis in ER+/HER2- breast cancer independently of IHC4, a composite immunohistochemical score (based on ER, PR, HER2, Ki67) that provides prognostic information comparable to the Oncotype Dx® Recurrence Score (RS). Extension of this work to encompass comparison to other recently developed prognostic markers (e.g., PAM50) is now warranted. For TMEM, the invasive carcinoma cells are identified using a protein marker for invasive and migratory cancer cells called “Mena”, which has multiple splice variants: Mena11a is an anti-metastatic isoform expressed in epithelial-like but not mesenchymal-like tumor cells, while Mena invasive (MenaINV) confers a potent pro-metastatic pheno- type in mesenchymal-like tumor cells. Recently, we used multiplex quantitative immunofluorescence to estimate the abundance of Mena lacking its anti-metastatic Mena11a isoform. We showed that this marker, Menacalc, which reflects the relative amount of epithelial-mesenchymal transition (EMT) that a tumor has undergone so that tumor cells can participate in TMEM assembly and interact with TMEMs, was positively associated with risk of breast cancer death. We now propose to: examine the association of these markers (Menacalc/MenaINV/TMEM) with risk of distant metastasis both in a case-control study of 600 case-control pairs nested in an expanded KP cohort of 8769 breast cancer cases, and in 1000 breast cancer cases sampled from the B28 trial (which assessed the value of paclitaxel as adjuvant chemotherapy); examine the association with risk of distant metastasis of the strongest TMEM-related marker or marker combination in comparison to and in addition to IHC4 and PAM50 (KP study) and Oncotype Dx® RS and PAM50 (B28 study) [~2/3 of the B28 study sample will have Oncotype Dx® RS results available]); examine whether TMEM-related marker or marker combination predicts response to therapy (in B28); and externally validate in the B28 study population the TMEM/Mena score (the combination of TMEM, Menacalc, MenaINV most strongly associated with risk) developed in the KP study population.

摘要