Determinants of response to neoadjuvant chemotherapy in breast cancer: Integrated roles of immune pathways, DNA damage response, and cell cycle regulators.

Breast cancer (BC) is the most commonly diagnosed malignant disease in women worldwide. Resistance to neoadjuvant chemotherapy (NAC) still limits treatment efficacy despite the enormous progress in systemic therapy. Because pathological complete response (pCR) is strongly associated with favorable clinical outcomes, especially in triple-negative and HER2-positive breast cancer, the discovery of reliable predictive biomarkers before treatment has become a key clinical goal. This narrative review summarizes the available evidence of genetic and transcriptomic biomarkers associated to responses to conventional anthracycline, taxane and platinum-based NAC. Current evidence suggests biomarkers can be broken down into three interconnected biological pathways. Dysregulation of immune and interferon signaling, including interferon-stimulated genes (ISG15, IFIH1, MX1, OAS family, IFI27, and IFITM1), affects chemotherapy response by modulating immune activation, apoptosis, and DNA damage tolerance. Second, alterations in DNA damage response (DDR) pathways for BRCA1, TP53, PARP1, ATM, and CHK1 affect the cells' vulnerability to genotoxic stress and contribute to the subtype-specific differences in treatment efficacies. Third, dysregulated cell cycle components (CCND1, CDK4/6, RB1, and E2F1) affect proliferation, checkpoint control, and susceptibility to chemotherapy-induced apoptosis. These pathways act in concert, rather than as independent mechanisms, to influence NAC sensitivity. Available data suggest that no single biomarker has sufficient predictive accuracy for all breast cancer subtypes. Subtype-specific multi-gene models integrating immune, DDR and cell-cycle biomarkers represent a more powerful tool to predict pCR and improve patient stratification before NAC. Further prospective clinical validation is needed before these biomarkers can be implemented in routine clinical practice.