Resistance to Combined Anthracycline-Taxane Chemotherapy Is Associated with Altered Metabolism and Inflammation in Breast Carcinomas.

Approximately 30% of early-stage breast cancer (BC) patients experience recurrence after systemic chemotherapy; thus, understanding therapy resistance is crucial in developing more successful treatments. Here, we investigated the mechanisms underlying resistance to combined anthracycline-taxane treatment by comparing gene expression patterns with subsequent therapeutic responses. We established a cohort of 634 anthracycline-taxane-treated patients with pathological complete response (PCR) and a separate cohort of 187 patients with relapse-free survival (RFS) data, each having transcriptome-level expression data of 10,017 unique genes. Patients were categorized as responders and non-responders based on their PCR and RFS status, and the expression for each gene was compared between the two groups using a Mann-Whitney U-test. Statistical significance was set at < 0.05, with fold change (FC) > 1.44. Altogether, 224 overexpressed genes were identified in the tumor samples derived from the patients without PCR; among these, the gene sets associated with xenobiotic metabolism (e.g., , ) exhibited significant enrichment. The genes and differentiated non-responders from responders with the highest AUC values (AUC > 0.75, < 0.0001). We identified 51 upregulated genes in the tumor samples derived from the patients with relapse within 60 months, participating primarily in inflammation and innate immune responses (e.g., , , ). Furthermore, the amino acid transporter , distinguishing non-responders from responders, had significantly higher expression in tumors and metastases than in normal tissues (Kruskal-Wallis = 8.2 × 10). The identified biomarkers underscore the significance of tumor metabolism and microenvironment in treatment resistance and can serve as a foundation for preclinical validation studies.