Transcriptomic Features Associated to Neoadjuvant Chemotherapy Response in Four Molecular Breast Cancer Subtypes

PURPOSE Breast cancer (BC) represents a major public health issue. The effectiveness of neoadjuvant chemotherapy (NAC) varies among breast cancer patients, with some experiencing incomplete pathological responses. This variability in treatment response may be attributed to differences in tumor heterogeneity and its microenvironment (TME). This study investigates gene expression patterns associated to non-response to NAC in invasive BC patients, emphasizing the role of genes, pathways and the variability among BC subtypes. METHODS A transcriptomic study analyzed 58 baseline samples from women with advanced breast cancer at the Colombian National Cancer Institute, categorizing them into 29 NAC responders and 29 non-responders. The study comprised gene expression comparison, enrichment analysis, tumor microenvironment estimation via xCell, and therapeutic efficacy of targeted drugs using PrRophetic package. RESULTS Different gene expression profiles distinguished responders from non-responders among various breast cancer subtypes, highlighting immune-related pathways like IL-17 and TNF signaling, B and T cell receptor signaling, complement and coagulation cascades, natural killer cell-mediated cytotoxicity, and NF-kB signaling. Non-responders in Luminal B HER2- subtype exhibited increased endothelial cells and immune and microenvironment scores, while Luminal B HER2+ non-responders showed higher levels of CD4 Tcm, CD4 Tem, and megakaryocytes. Sensitivity to multiple potential therapeutic drugs (Lestaurtinib, Avagacestat, GSK3 inhibitor, Veliparib, Tretinoin, Afatinib, Vinorelbine, RSK1 inhibitor, Motesanib) varied distinctly among non-responders. CONCLUSION Immune-related genes and diverse immune cell subtypes within the TME correlate with response to NAC, with significant changes observed between response groups and subtypes. Comprehensive detection and evaluation of TME components are crucial for predicting NAC efficacy and preventing disease relapse. These findings underscore the importance of studying mixed populations to uncover novel insights and address disparities.