Editor’s Note: The 2026 National Breast Cancer Conference was successfully held in Beijing from April 10–12, during which the 2026 Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines were officially released. Oncology Frontier invited Professor Man Li from the Second Affiliated Hospital of Dalian Medical University to discuss three key clinical topics surrounding HER2-low and HER2-ultralow breast cancer: major updates in the 2026 guidelines, standardized interpretation of HER2-low/ultralow status, and sequencing strategies for antibody-drug conjugates (ADCs). Her insights provide more precise and practice-oriented guidance for the management of HER2-low and HER2-ultralow breast cancer in China.01
Oncology Frontier: What updates have been made in the 2026 CSCO Breast Cancer Guidelines regarding the management of HER2-low and HER2-ultralow breast cancer?
Professor Man Li: In the 2026 edition of the CSCO Breast Cancer Guidelines, recommendations for HER2-low breast cancer continue to stratify patients according to prior exposure to CDK4/6 inhibitors, while the overall treatment framework remains largely unchanged.
The Category I recommendations are unchanged. For patients who are naïve to CDK4/6 inhibitors, CDK4/6 inhibitor-based endocrine therapy remains the preferred first-line option (Level 1A evidence). For patients previously treated with CDK4/6 inhibitors, trastuzumab deruxtecan (T-DXd) continues to hold a Category I recommendation (Level 1A), primarily supported by evidence from the DESTINY-Breast04 (DB-04) and DESTINY-Breast06 (DB-06) trials.
The key updates in this edition are concentrated in the Category II recommendations. Sacituzumab tirumotecan has been given greater priority within the Category II recommendations (Level 2A) following its inclusion in the National Reimbursement Drug List, which has significantly improved clinical accessibility. Meanwhile, the recommendation positioning and evidence level for sacituzumab govitecan have been adjusted accordingly (Level 2A), influenced by both drug pricing considerations and data from the ASCENT-07 study.
In addition, datopotamab deruxtecan has been upgraded from a previous Category III recommendation to a Category II recommendation (Level 2A), further expanding later-line treatment options for advanced breast cancer.
Looking ahead, we hope that more HER2-targeted ADCs and Trop-2 ADCs supported by high-level clinical evidence will be incorporated into future guideline updates, thereby continuing to optimize the treatment landscape for this patient population.
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Oncology Frontier: From a clinician’s perspective, how should HER2-low and HER2-ultralow status be accurately identified, and how can clinicians collaborate with pathologists to support reliable treatment decisions?
Professor Man Li: Standardized interpretation of HER2-low and HER2-ultralow expression still requires further refinement in real-world clinical practice.
Traditionally, HER2 testing has relied on a binary classification system—HER2-positive versus HER2-negative. However, with the growing understanding of HER2 biology, it has become increasingly clear that HER2 expression exists along a spectrum rather than within a simple dichotomous framework.
Current ASCO guidelines and leading pathology journals have already proposed a four-tier HER2 immunohistochemistry (IHC) classification system, categorizing tumors as HER2-positive, HER2-low, HER2-ultralow, or HER2-zero. This more refined classification helps define HER2 expression thresholds more precisely, but it also places higher demands on collaboration between clinicians and pathologists.
In routine practice, clinicians should take a proactive role by providing comprehensive clinical information when submitting pathology requests. For patients with endocrine-resistant disease or other relevant clinical characteristics, physicians should specifically indicate the need for focused assessment of HER2-low or HER2-ultralow expression to support accurate pathological interpretation.
Pathology departments, in turn, must strictly adhere to standardized specimen handling protocols. Biopsy or surgical specimens should be placed in 10% neutral buffered formalin within 30 minutes of collection and fixed for 6–72 hours to ensure reliable testing results.
At present, interpretation of HER2-low and HER2-ultralow expression still faces several limitations. Existing testing systems continue to rely largely on conventional HER2-positive assessment standards, which may not fully meet the needs of evaluating HER2-low or ultralow disease. In addition, tumors exhibit temporal and spatial heterogeneity, meaning HER2 expression can change over the course of disease progression. Relying solely on the HER2 status of the primary lesion may therefore underestimate HER2-low or ultralow expression.
Clinical data suggest that approximately 30%–40% of patients initially classified as HER2-zero may be reclassified as HER2-low or HER2-ultralow after repeat biopsy of either the primary tumor or metastatic lesions following disease progression. Therefore, close collaboration between clinicians and pathologists is essential for improving the accuracy of HER2 assessment.
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Oncology Frontier: How should ADC sequencing strategies be developed for HER2-low and HER2-ultralow breast cancer in TNBC and HR-positive subtypes?
Professor Man Li: At present, ADC sequencing strategies for HER2-low and HER2-ultralow breast cancer still lack definitive guidance from high-level prospective studies. Based on currently available real-world evidence and clinical experience, two exploratory approaches have emerged with practical clinical relevance.
The first strategy involves introducing an interval of conventional chemotherapy after disease progression on ADC therapy. This approach may provide short-term clinical benefit in both hormone receptor-positive and triple-negative HER2-low breast cancer; however, progression-free survival tends to remain relatively limited.
The second strategy involves direct sequential use of different ADC agents. Real-world data from China suggest that after progression on one ADC, switching to another ADC with a different payload and/or target may provide more durable clinical benefit compared with using ADCs that share the same payload. Real-world studies from the United States have similarly demonstrated that sequential use of T-DXd and sacituzumab govitecan can prolong progression-free survival and improve objective response rates, regardless of which agent is used first-line.
Currently available preliminary clinical data and practical experience suggest that sequencing sacituzumab govitecan after T-DXd may represent a feasible treatment pathway for HER2-low breast cancer.
Of course, many important questions remain unanswered, including the optimal sequencing order of ADCs, patient selection, and long-term safety management. These issues will require larger, higher-quality clinical studies to provide clearer guidance. Moving forward, continued research and accumulation of evidence in Chinese patient populations will be essential to developing more precise and standardized ADC sequencing strategies, ultimately delivering longer survival and improved quality of life for patients with HER2-low and HER2-ultralow breast cancer.
Professor Man Li
MD, Professor, Doctoral Supervisor
Director of the Department of Oncology and Director of the Teaching and Research Division, Second Affiliated Hospital of Dalian Medical University
