UGT2B17 as a predictive biomarker of complete pathological response in HER2 + breast cancer.

BACKGROUND: Pathological complete response (pCR) after neoadjuvant therapy is a robust surrogate marker for long-term outcomes in breast cancer. Despite major advances with targeted therapies, a significant proportion of patients fail to achieve pCR, underscoring the urgent need for reliable biomarkers that can predict treatment response and guide patient stratification. METHODS: We conducted a two-phase study including 53 patients with HER2-positive, hormone receptor–negative breast cancer treated with neoadjuvant chemotherapy plus anti-HER2 agents. Transcriptomic profiling (discovery cohort, n = 13) identified differentially expressed genes associated with therapeutic response, which were validated by qPCR in an independent cohort (n = 40). Functional enrichment analysis was performed to explore the biological pathways underlying the differential response. RESULTS: Differential expression analysis revealed 6251 genes associated with response, with significant enrichment in xenobiotic metabolism and steroid hormone biosynthesis pathways. Within these, members of the UGT2B family (UGT2B10, UGT2B17, UGT2B28) were overexpressed in non-responders. Validation confirmed UGT2B17 (p = 0.023, AUC = 0.699, sensitivity 77.2%, specificity 64.5%) and UGT2B28 (p = 0.046, AUC = 0.677) as predictive biomarkers of resistance to neoadjuvant therapy. UGT2B17 showing the highest discriminative value. CONCLUSIONS: UGT2B17 overexpression is associated with resistance to neoadjuvant therapy in HER2-positive breast cancer, supporting its potential role as a predictive biomarker. Integration of UGT2B17 into molecular panels could improve patient stratification and guide personalized therapeutic strategies in this subtype.