Advances and challenges in biomarker guided management of triple-negative breast cancer in the era of neoadjuvant chemo-immunotherapy

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancers and is characterized by the absence of hormone receptors and HER2 amplification. Early-stage TNBC is characterized by aggressive clinical behavior, high proliferative rates, early relapses, and a propensity for visceral metastases resulting in poor long-term outcomes despite initial chemosensitivity. The introduction of neoadjuvant chemo-immunotherapy, combining standard chemotherapy with immune checkpoint inhibitors (ICIs), has significantly improved pathological complete response (pCR) rates and has reshaped treatment paradigms in early TNBC. Despite these advances, a substantial proportion of patients still develop residual disease or relapse, underscoring the need for better biomarkers to guide treatment decisions. This review provides a comprehensive overview of current and emerging biomarkers in TNBC, focusing on their role in the era of neoadjuvant chemo-immunotherapy. Established clinical markers, such as pCR and residual cancer burden (RCB), remain essential for post-neoadjuvant risk stratification. Beyond these, emerging biomarkers, including tumor-infiltrating lymphocytes (TILs), programmed death ligand 1 (PD-L1), spatial immune profiling, circulating tumor DNA (ctDNA), microRNAs (miRNAs), and oncogenic signaling pathways (e.g., PI3K/AKT, MAPK, WNT/β-catenin), are under investigation for their potential to refine patient selection and predict response or resistance to therapy. The biological heterogeneity of TNBC, encompassing both tumor-intrinsic and immune microenvironment variations, contributes to differential treatment outcomes and complicates clinical decision-making. We discuss the challenges of integrating emerging biomarkers into routine clinical practice, including standardization, prospective validation, and development of combined predictive models. By summarizing both current and investigational biomarkers, this review aims to support clinicians in understanding how biomarker-driven strategies may optimize neoadjuvant therapy, reduce unnecessary toxicity, and ultimately improve long-term outcomes in TNBC.