Abstract:Neoadjuvant therapy has become an increasingly important component of comprehensive breast cancer treatment. Its value extends beyond tumor downstaging and increasing breast-conservation rates, as it also provides an opportunity to evaluate treatment response and guide subsequent individualized therapy. Pathological complete response (pCR) is currently the most widely used surrogate endpoint for assessing neoadjuvant therapy efficacy; however, its ability to predict long-term survival benefit remains limited. Increasing evidence indicates substantial heterogeneity in the prognostic significance of pCR among different molecular subtypes. Patients achieving pCR may still experience recurrence, whereas a considerable proportion of patients without pCR can achieve long-term survival. Because pCR primarily reflects local tumor response, it cannot adequately evaluate occult micrometastatic disease or systemic tumor burden. Therefore, improvements in pCR rates do not necessarily translate into survival benefits. Recently, liquid biopsy technologies, particularly circulating tumor DNA (ctDNA) analysis, have provided a novel approach for evaluating neoadjuvant therapy efficacy. ctDNA enables dynamic monitoring of tumor burden, molecular residual disease, and clonal evolution, demonstrating potential advantages over conventional imaging and pathological assessment in treatment response monitoring, minimal residual disease detection, and recurrence-risk prediction. The systemic tumor burden (STB) model based on longitudinal ctDNA monitoring integrates baseline and postoperative ctDNA status to accurately stratify systemic recurrence risk and may provide a new framework for guiding escalation or de-escalation of adjuvant therapy after neoadjuvant therapy. In the future, the evaluation paradigm of neoadjuvant therapy in breast cancer may shift from focusing solely on “local pathological eradication” toward achieving “STB eradication.” Integrating pathological, radiological, and molecular biomarkers may facilitate more precise risk stratification and individualized treatment strategies.