Validation of the MHC II Immune Activation Assay in Breast Cancer

项目摘要/摘要 评估ER乳腺癌患者复发风险的临床生物标记物测试的发展已经导致 患者护理和结果的显著改善，包括降低化疗和 不良反应减少，预后良好的妇女。目前还没有临床生物标记物测试。 可用于评估三阴性乳腺癌(TNBC)或HER2乳腺癌患者的复发风险 病人。这些患者都接受了积极的化疗，并经常遭受长期的不良反应。 副作用，因为肿瘤学家无法知道哪些患者天生就有良好的预后。 我们最近发现，MHC-II类抗原提呈途径(MHCII)的表达和 肿瘤浸润性白细胞(TIL)的存在与患者的长期无病生存(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分析方法 固定石蜡包埋乳腺肿瘤标本可准确定量MHCII表达和TIL以 为每个患者生成一个免疫激活分数。我们确认免疫激活分数可以 在独立的机构队列中确定复发风险非常低的患者。有趣的是， MHCII和TIL高表达的患者无论是 接受了化疗。此外，小鼠研究表明，MHCII在肿瘤中的表达增加了TIL和 在没有化疗的情况下防止复发，其他组织最近报告说，TNBC 即使在没有接受化疗的情况下，高TIL的患者也改善了DFS。这些数据表明， MHCII免疫激活试验可以确定TNBC和HER2患者的复发风险非常低。 该UH3提案的主要目标是验证MHCII免疫激活试验是否可用于 通过临床分析确定具有极低复发风险的TNBC和HER2乳腺癌患者 在CLIA认证的实验室中测试样本。特异性目标1从一项大型佐剂试验中分析肿瘤 TNBC和HER2患者的化疗，以及特异性目标2分析了来自TNBC患者的活检组织 接受新辅助化疗(NAC)。这确保了使用不同类型的标本进行检测是可以预测预后的。 和治疗时机。第二个目标是确定化验是否能识别预后良好的患者。 无论他们的化疗方案是否包括紫杉醇，他们的效果都是一样好的。探索性的 目标包括确定高免疫激活评分是否预示病理完全应答 NAC，并确定MHCII免疫激活分数在NAC后是否发生变化并与DFS相关。 这项研究的成功完成可能会产生第一个用于鉴定TNBC和 HER2乳腺癌患者的复发风险较低。它还将使未来的临床试验能够 利用该试验对预后良好的患者进行选择性招募，以评估毒性较小的治疗方案。

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.