Breast cancer chemotherapy in transition: predictive markers, resistance mechanisms, and new treatment approaches

Breast cancer remains the most frequently diagnosed malignancy among women worldwide and continues to be a major cause of cancer-related mortality despite substantial therapeutic progress. Chemotherapy remains a central component of treatment, especially in high-risk early breast cancer, triple-negative breast cancer (TNBC), HER2-positive disease, and selected hormone receptor-positive tumors. Over the last two decades, the role of chemotherapy in breast cancer has evolved from a largely uniform cytotoxic approach to a more nuanced strategy guided by tumor biology, response dynamics, and residual disease burden. Neoadjuvant chemotherapy has become particularly important, not only for tumor downstaging but also for providing an in vivo test of chemosensitivity, with pathologic complete response (pCR) serving as a useful marker of long-term outcome in aggressive biological subtypes. At the same time, increasing knowledge of predictive biomarkers such as BRCA1/2 status, homologous recombination deficiency (HRD), tumor-infiltrating lymphocytes (TILs), Ki-67, intrinsic molecular subtypes, and circulating tumor DNA (ctDNA) has improved patient stratification and opened opportunities for more personalized treatment. However, chemotherapy resistance remains a major obstacle. Resistance arises through multiple mechanisms, including drug efflux, enhanced DNA repair, apoptotic dysregulation, epithelial-mesenchymal transition, cancer stem cell plasticity, metabolic adaptation, and tumor microenvironment-mediated immune suppression. These mechanisms limit durable response and contribute to relapse, particularly in TNBC and residual disease after neoadjuvant therapy. Recent therapeutic advances have focused on overcoming resistance through platinum agents, PARP inhibitors, immune checkpoint blockade, post-neoadjuvant escalation with capecitabine or trastuzumab emtansine, and emerging antibody-drug conjugates. This review summarizes the advancement of chemotherapy in breast cancer.