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.

项目摘要/摘要 临床生物标志物测试的开发以评估ER+乳腺癌患者复发风险的发展已导致 为了显着改善患者护理和结局，包括化学疗法和 降低具有良好预后女性的不良副作用。目前没有临床生物标志物测试 可用于评估三重阴性乳腺癌（TNBC）患者或HER2+乳腺癌的复发风险 患者。这些患者均接受侵略性化疗治疗，并且经常患有长期不良 副作用，因为肿瘤学家无法知道哪些患者固有地具有良好的预后。 我们最近发现MHC II类抗原表现途径（MHCII）和 肿瘤浸润白细胞（TIL）的存在与长期无病生存（DFS）有关 TNBC和HER2+乳腺癌患者。我们开发了与福尔马林兼容的多基因表达测定 固定的石蜡嵌入乳腺肿瘤标本，可以准确地量化MHCII表达并将其定为TIL 为每个患者产生免疫激活评分。我们确认免疫激活评分可以 识别独立机构队列中复发风险非常低的患者。有趣的是， 高MHCII和TIL表达的患者具有长期无病生存率 接受了化学疗法。此外，小鼠研究表明，肿瘤中的MHCII表达增加了丁字el和 在没有化学疗法的情况下，可以保护免受复发，其他组最近报告说TNBC tils高的患者即使没有接受化学疗法也有改善的DFS。这些数据表明 MHCII免疫激活测定法可以鉴定出非常低的复发风险的TNBC和HER2+患者。 该UH3提案的主要目的是验证可以使用MHCII免疫激活测定法 鉴定通过分析临床的TNBC和HER2+乳腺癌患者的复发风险非常低 在经过CLIA认证的实验室中的试验标本。特定的目标1分析大型辅助试验的肿瘤 TNBC和HER2+患者的化学疗法，并且特定目标2分析了来自TNBC患者的活检 接受了新辅助化疗（NAC）。这样可以确保使用不同样本类型的测定方法 和治疗时机。次要目标是确定测定是否可以识别出良好的预后患者 无论他们的化学疗法方案是否包括紫杉醇，谁做得很好。探索性 目标包括确定高免疫激活评分是否可以预测病理完全反应 NAC，并确定NAC后MHCII免疫激活评分是否发生变化并与DFS相关。 这项研究的成功完成可能会产生第一个识别TNBC和的生物标志物测定法 复发风险较低的HER2+乳腺癌患者。这也将使以后的临床试验达到 利用该测定法以选择性入学良好的预后患者评估毒性治疗方案较少。