从“局部病理清零”到“系统肿瘤负荷清零”：乳腺癌新辅助治疗评估新范式

From local pathological eradication to systemic tumor burden clearance: a new paradigm for evaluating neoadjuvant therapy in breast cancer

摘要:

乳腺癌新辅助治疗在乳腺癌综合治疗中的地位日益重要，其价值不仅在于实现肿瘤降期和提高保乳率，更在于通过治疗反应评估患者预后并指导后续个体化治疗。目前，病理完全缓解（pCR）是评估新辅助治疗疗效最常用的替代终点，但其预测长期生存获益的能力存在明显局限。研究显示，pCR的预后价值在不同分子亚型间存在显著异质性，达到pCR的患者仍可能发生复发，而未达到pCR者中相当一部分患者仍可获得长期生存。由于pCR主要反映局部肿瘤对治疗的应答，难以充分评估亚临床微转移灶及系统肿瘤负荷，因此提高pCR率并不一定能够转化为生存获益。近年来，液体活检技术，尤其是循环肿瘤DNA（ctDNA）检测，为新辅助治疗疗效评估提供了新的策略。ctDNA可动态反映肿瘤负荷变化、分子残留病灶及克隆演变过程，在治疗反应监测、微小残留病灶识别及复发风险预测方面展现出较传统影像学和病理学更高的敏感性。基于ctDNA动态监测构建的系统肿瘤负荷模型，通过整合基线及术后ctDNA状态，实现对患者系统性复发风险的精准分层，为新辅助治疗后辅助治疗的升阶或降阶提供新的决策依据。未来乳腺癌新辅助治疗疗效评价体系可能由单纯关注“局部病理清零”逐渐转向关注“系统肿瘤负荷清零”，通过融合病理、影像及分子标志物建立综合评价体系，实现更加精准的风险分层和个体化治疗。

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.