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 乳腺癌死亡率主要归因于全身性血行播散性转移性疾病。 鉴于当前预后标准的局限性，识别可能转移和转移的肿瘤的新方法 需要对治疗有反应。基于多光子的活体成像表明，侵袭性癌细胞 在啮齿动物乳腺肿瘤中，通过含有 Mena 过度表达肿瘤的血管周围结构进行渗入 细胞、巨噬细胞和内皮细胞，全部相互接触。这种细胞的三部分排列 促进癌细胞进入血管。我们已经在人体中发现了这种微环境 使用三重免疫染色对乳腺癌样本进行福尔马林固定石蜡包埋组织，同时 有效地标记了 3 种细胞类型。我们将这 3 种细胞类型的直接并置称为“TMEM”，即肿瘤微- 转移环境。最近，在 Kaiser Permanente (KP) 的一组患者中，我们发现： TMEM 与 ER+/HER2- 乳腺癌远处转移风险呈正相关，独立于 IHC4，一种综合免疫组织化学评分（基于 ER、PR、HER2、Ki67），可提供预后 与 Oncotype Dx® 复发评分 (RS) 相当的信息。扩展这项工作以涵盖 现在有必要与其他最近开发的预后标志物（例如 PAM50）进行比较。对于 TMEM 来说， 使用侵袭性和迁移性癌细胞的蛋白质标记来识别侵袭性癌细胞，称为 “Mena”，具有多种剪接变体：Mena11a 是一种以上皮样细胞表达的抗转移亚型 但不是间充质样肿瘤细胞，而 Mena 侵袭性 (MenaINV) 赋予有效的促转移表型 间质样肿瘤细胞的类型。最近，我们利用多重定量免疫荧光技术 估计缺少抗转移性 Mena11a 亚型的 Mena 丰度。我们证明了这个标记， Menacalc，反映肿瘤上皮间质转化 (EMT) 的相对量 使肿瘤细胞能够参与 TMEM 组装并与 TMEM 相互作用，这是积极的 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) 在 600 个病例对照对的病例对照研究中均存在远处转移风险 嵌套在包含 8769 例乳腺癌病例的扩展 KP 队列中，以及从以下样本中抽取的 1000 例乳腺癌病例中 B28 试验（评估紫杉醇作为辅助化疗的价值）；检查与的关联 与 和 相比，最强 TMEM 相关标记物或标记物组合的远处转移风险 除了 IHC4 和 PAM50（KP 研究）以及 Oncotype Dx® RS 和 PAM50（B28 研究）[~ B28 研究的 2/3] 样品将提供 Oncotype Dx® RS 结果])；检查是否有 TMEM 相关标记或标记 组合预测对治疗的反应（在 B28 中）；并在 B28 研究人群中进行外部验证 TMEM/Mena 评分（TMEM、Menacalc、MenaINV 的组合与风险关联性最强） 在 KP 研究人群中开发。