Validation of the MHC II Immune Activation Assay in Breast Cancer

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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.