A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways

HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset). We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the "Immunity" metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28-11.91], p = 0.019) than weak expression, and with a better prognosis in HER2-positive/ER-negative breast cancers (HR = 0.58 [0.36-0.94], p = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs). The identification of a predictive and prognostic immune module in HER2-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation.