Validation of the MHC II Immune Activation Assay in Breast Cancer

MHC II 免疫激活测定在乳腺癌中的验证

• 批准号: 10650846
• 负责人: PHILIP S BERNARD
• 金额: $ 34.45万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650846
• 关键词: Address; Adjuvant Chemotherapy; Adjuvant Study; Antigen Presentation Pathway; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Breast Cancer Patient; CLIA certified; Chemotherapy-Oncologic Procedure; Clinical Trials; Data; Diagnosis; Diagnostic; Disease-Free Survival; ERBB2 gene; Enrollment; Ensure; Estrogen receptor positive; Excision; Exclusion; Formalin; Future; Gene Expression; Gene Expression Profiling; Goals; Health Care Costs; High Prevalence; Histocompatibility Antigens Class II; In complete remission; Institution; International; Laboratories; Leucocytic infiltrate; Mammary Neoplasms; Measures; Modernization; Mus; National Cancer Institute of Canada; Neoadjuvant Therapy; Oncologist; Operative Surgical Procedures; Paclitaxel; Paraffin Embedding; Pathologic; Patient Care; Patient-Focused Outcomes; Patients; Phase; Prognosis; Prognostic Factor; Quality of life; Randomized, Controlled Trials; Recurrence; Recurrent disease; Reporting; Residual Neoplasm; Risk; Risk Assessment; Sampling; Specificity; Specimen; Testing; Treatment Protocols; Treatment-related toxicity; Validation; Woman; chemotherapy; clinical biomarkers; clinical development; cohort; experience; immune activation; improved; malignant breast neoplasm; participant enrollment; patient prognosis; prognostic; research clinical testing; side effect; triple-negative invasive breast carcinoma; tumor

Project Summary/Abstract The development of clinical biomarker tests to assess risk of recurrence in ER+ breast cancer patients has led to dramatic improvements in patient care and outcomes, including the de-escalation of chemotherapy and reduction of adverse side-effects for women with good prognosis. There are currently no clinical biomarker tests available to assess risk of recurrence in triple negative breast cancer (TNBC) patients or HER2+ breast cancer patients. These patients are all treated with aggressive chemotherapy, and often suffer from long-term adverse side-effects, because oncologists have no way of knowing which patients inherently have a good prognosis. We recently discovered that expression of the MHC Class II antigen presentation pathway (MHCII) and the presence of tumor infiltrating leukocytes (TILs) was associated with long-term disease-free survival (DFS) in TNBC and HER2+ breast cancer patients. We developed a multigene expression assay compatible with formalin fixed paraffin embedded breast tumor specimens that can accurately quantify MHCII expression and TILs to generate an Immune Activation Score for each patient. We confirmed that the Immune Activation Score could identify patients who have a very low risk of recurrence in an independent institutional cohort. Interestingly, patients with high MHCII and TIL expression have long-term disease-free survival regardless of whether they received chemotherapy. Additionally, mouse studies show that MHCII expression in tumors increases TILs and protects from recurrence in the absence of chemotherapy, and other groups have recently reported that TNBC patients with high TILs have improved DFS even without receiving chemotherapy. These data suggest that the MHCII Immune Activation Assay can identify TNBC and HER2+ patients who have a very low risk of recurrence. The primary objective of this UH3 proposal is to validate that the MHCII Immune Activation assay can be used to identify TNBC and HER2+ breast cancer patients who have a very low risk of recurrence by analyzing clinical trials specimens in a CLIA-certified laboratory. Specific Aim 1 analyzes tumors from a large trial of adjuvant chemotherapy in TNBC and HER2+ patients, and Specific Aim 2 analyzes biopsies from TNBC patients who received neoadjuvant chemotherapy (NAC). This ensures the assay is prognostic using different specimen types and treatment timing. A secondary objective is to determine if the assay can identify good prognosis patients who do equally well regardless of whether their chemotherapy regimens include paclitaxel. Exploratory objectives include determining if high Immune Activation Scores are predictive of pathological complete response to NAC, and determining if MHCII Immune Activation Scores change after NAC and are associated with DFS. The successful completion of this study could produce the first biomarker assay for identifying TNBC and HER2+ breast cancer patients who have a low risk of recurrence. It would also enable future clinical trials to utilize the assay for selective enrollment of good prognosis patients to evaluate less toxic treatment regimens.

项目概要/摘要 用于评估 ER+ 乳腺癌患者复发风险的临床生物标志物测试的开发已引领 显着改善患者护理和结果，包括化疗和治疗的逐步减少 减少女性不良副作用，预后良好。目前尚无临床生物标志物测试 可用于评估三阴性乳腺癌 (TNBC) 患者或 HER2+ 乳腺癌患者的复发风险 患者。这些患者均接受积极的化疗，并且常常遭受长期不良反应。 副作用，因为肿瘤学家无法知道哪些患者本身就有良好的预后。 我们最近发现 MHC II 类抗原呈递途径 (MHCII) 和 肿瘤浸润白细胞（TIL）的存在与长期无病生存（DFS）相关 TNBC 和 HER2+ 乳腺癌患者。我们开发了一种与福尔马林兼容的多基因表达测定法 固定石蜡包埋的乳腺肿瘤标本，可以准确量化 MHCII 表达和 TIL，以 为每位患者生成免疫激活评分。我们确认免疫激活分数可以 确定在独立机构队列中复发风险极低的患者。有趣的是， MHCII 和 TIL 高表达的患者无论是否具有长期无病生存率 接受化疗。此外，小鼠研究表明，肿瘤中的 MHCII 表达会增加 TIL 和 在没有化疗的情况下可以防止复发，其他研究小组最近报道了 TNBC 即使未接受化疗，TIL 高的患者的 DFS 也有所改善。这些数据表明 MHCII 免疫激活检测可以识别复发风险极低的 TNBC 和 HER2+ 患者。 该 UH3 提案的主要目的是验证 MHCII 免疫激活测定是否可以使用 通过分析临床来识别复发风险极低的 TNBC 和 HER2+ 乳腺癌患者 在 CLIA 认证的实验室中试验样本。具体目标 1 通过大型佐剂试验分析肿瘤 TNBC 和 HER2+ 患者的化疗，Specific Aim 2 分析了 TNBC 患者的活检结果 接受新辅助化疗（NAC）。这确保了使用不同样本类型进行的检测具有预测性 和治疗时机。第二个目标是确定该检测是否可以识别预后良好的患者 无论化疗方案是否包含紫杉醇，他们的表现都一样好。探索性 目标包括确定高免疫激活分数是否可以预测病理完全缓解 NAC 后，确定 MHCII 免疫激活分数是否在 NAC 后发生变化并与 DFS 相关。 这项研究的成功完成可能会产生第一个用于识别 TNBC 和 复发风险较低的 HER2+ 乳腺癌患者。它还将使未来的临床试验能够 利用该测定选择性招募预后良好的患者来评估毒性较小的治疗方案。