The treatment of breast cancer has fully entered the era of precision therapy. Sentinel lymph node biopsy (SLNB) first replaced axillary lymph node dissection (ALND) in breast cancer patients with clinical negative lymph nodes (cN0). Subsequent clinical studies have confirmed the feasibility of using SLNB alone in selected patients with limited lymph node metastasis, which has changed clinical practice. For even lower-risk patients, there is growing evidence supporting the complete omission of axillary surgery. Furthermore, with the emerging evidence from studies on axillary preservation after neoadjuvant therapy in patients from cN+ (clinical positive lymph nodes) to cN0 status, it has become possible for these patients to avoid ALND. Even for those with persistent node-positive disease after neoadjuvant therapy, the possibility of avoiding ALND is under clinical investigation. However, it is important to acknowledge the remaining uncertainties in clinical practice. These include the challenges to the conventional concept of radical resection, the balance between axillary surgery and radiotherapy, the implications of de-escalated axillary staging on systemic therapy decisions. Careful evaluation and a balanced integration of surgery, radiotherapy, and systemic therapy are crucial to achieving truly precise de-escalation in axillary management.
ObjectiveTo analyze the clinical repositioning and individualized treatment strategies of trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the era of trastuzumab deruxtecan (T-DXd). MethodsThe latest evidence-based data for T-DM1 were systematically reviewed to identify two optimized clinical approaches: intensified combination therapy and de-escalation. For advanced and brain metastastic HER2-positive breast cancer, the synergistic antitumor efficacy of T-DM1 combined with tyrosine kinase inhibitors, along with data from pivotal trials such as HER2CLIMB-02, was analyzed. For early-stage HER2-positive breast cancer, the feasibility of chemotherapy-free de-escalation regimens was evaluated based on the WSG-ADAPT trial and other relevant studies. ResultsThe differentiated value of T-DM1 is defined by its lower risk of interstitial lung disease and established long-term survival benefit, as evidenced by the 7-year invasive disease-free survival (iDFS) rate of 80.8% reported in the KATHERINE trial. Regarding intensified combinations, exploratory analyses of the KATE2 trial revealed synergistic potential of T-DM1 plus immune checkpoint inhibitors in the programmed death-ligand 1-positive subgroup. In patients with brain metastastatic HER2-positive, the HER2CLIMB-02 study confirmed a median progression-free survival benefit by adding tucatinib to T-DM1 [HR (95%CI)=0.64 (0.46, 0.89)]. In terms of de-escalation, the WSG-ADAPT trial reported a 5-year iDFS rate of 92.1% with chemotherapy-free regimens in molecularly selected populations. Additionally, the “decoupling” of pathological complete response from long-term outcomes observed in the KRISTINE trial provides biological rationale for de-escalation strategies, interpreted through the lenses of immune memory and senescence-associated tumor cell fate. Moreover, the sequential switching strategy—grounded in the non-cross-resistant payload mechanism—and the clinical accessibility brought by T-DM1’s inclusion in China’s National Reimbursement Drug List serve as additional dimensions supporting its clinical repositioning. ConclusionsIn the era of T-DXd, clinical decision-making regarding T-DM1 for HER2-positive breast cancer is shifting toward risk-stratified, precision-based management. The core strategic framework comprises an intensified combination pathway for patients with brain metastases and a de-escalation pathway for those with toxicity-driven de-escalation. However, specific implementation still requires comprehensive evaluation tailored to individual patient characteristics, biomarker profiles, and drug accessibility.