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

• 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
• 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

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.

抽象的 乳腺癌死亡率在很大程度上归因于系统性，血源性造成的转移性疾病。 鉴于当前预后标准的局限性，鉴定可能转移和 需要对治疗的反应。基于多光子的静脉内成像表明浸润性癌细胞 在啮齿动物的乳腺肿瘤中，通过含有erna的emper表达肿瘤的血管周围结构静脉内 细胞，巨噬细胞和一个内皮细胞，都相互接触。这种细胞的三方排列 促进癌细胞进入血管。我们已经确定了人类的微环境 乳腺癌样品使用三重免疫接种蛋白用于福尔马林固定石蜡包裹的组织，类似 优质地标记3种细胞类型。我们称这三种细胞类型的直接应用为“ TMEM”，用于肿瘤微型 转移环境。最近，在Kaiser Permanente（KP）的一批患者中，我们表明 TMEM与ER+/HER2-乳腺癌中远处转移的风险呈正相关 IHC4，一种复合免疫组织化学评分（基于ER，PR，HER2，KI67），可提供预后 与OncotypeDX®复发评分（RS）相当的信息。扩展这项工作以包含 现在有必要与其他最近开发的预后标记（例如PAM50）进行比较。对于tmem， 使用侵入性癌细胞使用蛋白质标记物来鉴定出侵入性和迁移者细胞称为 具有多种剪接变体的“ MENA”：MENA11A是一种抗中性同工型，在上皮样中表达 但不是间充质样细胞 输入间充质样肿瘤细胞。最近，我们将多重定量免疫荧光用于 估计MENA缺乏抗转移性MENA11A同工型的抽象。我们证明了这个标记， enacalc，反映了肿瘤具有的上皮 - 间质转变（EMT）的相对量 经过经过的，以使肿瘤细胞可以参与TMEM组装并与TMEM相互作用，这是积极的 与乳腺癌死亡的风险有关。我们现在建议：检查这些标记的关联 （Menacalc/Menainv/tmem）在600个病例对照对的病例对照研究中，有远处转移的风险 嵌套在8769例乳腺癌病例的扩大的KP队列中，并在1000例乳腺癌病例中取样 B28试验（评估紫杉醇作为调整化疗的价值）；检查与 与和IN相比 IHC4和PAM50（KP研究）和OnCotypeDX®RS和PAM50（B28研究）[〜2/3的B28研究 样本将具有可用的Oncotypedx®RS结果]）；检查与TMEM相关的标记或标记 组合预测对治疗的反应（在B28中）；在B28研究人群中外部验证 TMEM/MENA得分（TMEM，Menacalc，Menainv的组合最与风险最密切相关） 在KP研究人群中发展。