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: 10177971
• 负责人: JOHN S CONDEELIS
• 金额: $ 85.21万
• 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/10177971
• 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; Epithelial; Estrogen receptor negative; Estrogen receptor positive; Formalin; Gene Expression Profiling; Genomics; Health; Hematogenous; Human; Immunofluorescence Immunologic; Individual; Label; Lead; 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; Predictive Value; Progesterone Receptors; Prognostic Marker; Protein Isoforms; RNA Splicing; Rattus; Recurrence Score; Redwood; Relapse; Risk; Rodent; Sampling; Sampling Studies; Skin Carcinoma; Structure; Time; Tissue Embedding; Variant; Woman; Work; base; cancer cell; case control; cell type; chemotherapy; cohort; intravital imaging; macrophage; malignant breast neoplasm; mortality; mortality risk; neoplastic cell; oncotype; patient population; predicting response; predictive marker; predictive test; prognostic; prognostic assays; prognostic value; protein biomarkers; receptor; side effect; study population; 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.

摘要 乳腺癌死亡率主要归因于全身性、造血播散性转移性疾病。 鉴于目前预后标准的局限性，识别可能转移的肿瘤的新方法， 需要对治疗作出反应。基于多光子的活体成像显示，侵袭性癌细胞 在啮齿动物乳腺肿瘤中，通过含有Mena过表达肿瘤的血管周围结构内渗 细胞、巨噬细胞和内皮细胞，它们都彼此接触。这种细胞的三分排列 促进癌细胞进入血管。我们已经确定了人类的这种微环境， 使用福尔马林固定石蜡包埋组织的三重免疫染色的乳腺癌样本， 同时标记3种细胞类型。我们将这3种细胞类型的直接并置称为“TMEM”，用于肿瘤微- 转移的环境。最近，在Kaiser Permanente（KP）的一组患者中，我们发现， TMEM与ER+/HER 2-乳腺癌的远处转移风险呈正相关， IHC 4，一种综合免疫组化评分（基于ER、PR、HER 2、Ki 67），可提供预后 与Oncotype Dx®复发评分（RS）相当的信息。这项工作的扩展包括 与其它最近开发的预后标志物（例如，PAM 50）现在是有保证的。对于TMEM， 侵袭性癌细胞是用侵袭性和迁移性癌细胞的蛋白质标记物来鉴定的， “Mena”，其具有多个剪接变体：Mena 11 a是在上皮样细胞中表达的抗转移同种型。 而不是间充质样肿瘤细胞，而Mena侵袭性（MenaINV）赋予了一种有效的促转移表型， 型间质样肿瘤细胞。最近，我们使用多重定量免疫荧光， 估计缺乏其抗转移性Mena 11 a同种型的Mena的丰度。我们发现这个标记， Menacalc，反映了肿瘤具有的上皮-间质转化（EMT）的相对量。 肿瘤细胞可以参与TMEM组装并与TMEM相互作用， 与乳腺癌死亡风险相关。我们现在建议：检查这些标记的关联 （Menacalc/MenaINV/TMEM）与远处转移风险，在600例病例对照对的病例对照研究中 嵌套在8769例乳腺癌病例的扩展KP队列中，并在1000例乳腺癌病例中取样， B28试验（评估紫杉醇作为辅助化疗的价值）;检查与 最强TMEM相关标志物或标志物组合的远处转移风险与 除了IHC 4和PAM 50（KP研究）和Oncotype Dx® RS和PAM 50（B28研究）之外[约2/3的B28研究] 样本将有Oncotype Dx® RS结果可用]）;检查TMEM相关标志物或标志物 联合预测对治疗的反应（B28）;并在B28研究人群中外部验证 TMEM/Mena评分（TMEM、Menacalc、MenaINV的组合与风险最强相关） 在KP研究人群中发展。