The 2025 National Breast Cancer Conference, held in Beijing from April 11 to 13, introduced significant updates to the 2025 edition of the CSCO Breast Cancer Guidelines (CSCO BC Guidelines). Among the most notable changes was a revision in the treatment approach for patients with HER2-low breast cancer. Oncology Frontier invited Professor Ying Yan from Beijing Cancer Hospital to provide insights into the new treatment strategies for HER2-low and HER2 ultra-low breast cancer.Oncology Frontier: The 2025 CSCO Breast Cancer Guidelines were officially released at this year’s conference. What are the main updates in HER2-targeted therapy?
Prof. Ying Yan: In HER2-targeted therapy, accurate diagnosis is the foundation. This year’s CSCO BC Guidelines feature updates for HER2-positive breast cancer as well as HER2-low and HER2 ultra-low breast cancer. Corresponding changes in pathological diagnostics were made in alignment with the 2024 edition of China’s HER2 Testing Guidelines for Breast Cancer, adapted to clinical practice.
The updates focus on diagnostic differentiation. In the DB-04 clinical trial, patients enrolled were primarily those with HER2-low expression. The DB-06 trial included mostly HER2-low patients but also a small number of HER2 ultra-low patients. This highlights the need for pathologists to distinguish between HER2-low and HER2 ultra-low in their reports.
Previously, HER2 ultra-low patients were often categorized under HER2-zero. However, both the updated CSCO BC Guidelines and the NCCN Guidelines now subcategorize HER2-zero patients further. Those with absolutely no membrane staining are classified as HER2-zero, while those with weak, incomplete staining in ≤10% of tumor cells fall under HER2 ultra-low. This is the key change in current diagnostic practice.
Oncology Frontier: Based on the new guidelines and expert consensus, what should clinicians prioritize in the management of HER2-low breast cancer?
Prof. Ying Yan: The most critical step is achieving an accurate diagnosis. Pathology must adhere strictly to updated criteria to identify true HER2-low expression. The DB-06 study has emphasized the need to distinguish between HER2 ultra-low and HER2-zero patients.
HER2-low breast cancer can be divided into two broad categories: HR-positive/HER2-low and HR-negative/HER2-low, the latter being triple-negative breast cancer (TNBC). The majority of patients fall into the HR-positive/HER2-low group. For this group, treatment typically follows protocols for HR-positive/HER2-negative breast cancer. In advanced cases, first-line treatment remains a CDK4/6 inhibitor combined with endocrine therapy.
Once the disease progresses, there are two general second-line approaches. One is to continue endocrine therapy, potentially combined with targeted agents such as PAM pathway inhibitors. The other is to initiate chemotherapy or use antibody-drug conjugates (ADCs). Previously, based on DB-04 data, patients often received one or two lines of chemotherapy before transitioning to T-DXd (trastuzumab deruxtecan).
However, with the publication of DB-06 data in 2024, this treatment paradigm has shifted. It is now recommended that patients move directly to T-DXd after CDK4/6 inhibitor progression. This recommendation is based on the finding that T-DXd offers longer progression-free survival, better clinical benefit compared to chemotherapy, and has acceptable safety and tolerability.
Accordingly, the updated CSCO BC Guidelines recommend T-DXd as the preferred second-line therapy in HR-positive/HER2-low patients who have progressed on CDK4/6 inhibitors. Chemotherapy remains an option but is supported by a lower level of evidence. T-DXd is supported by level 1A evidence, while chemotherapy is supported by level 2A evidence, based on results from the DB-04 and DB-06 trials.
Oncology Frontier: What changes do the 2025 CSCO Guidelines bring to the treatment landscape of HER2-low breast cancer?
Prof. Ying Yan: Earlier, we discussed treatment strategies for HR-positive/HER2-low breast cancer, especially after endocrine therapy failure. Now we turn to HR-negative/HER2-low breast cancer, which falls under the category of triple-negative breast cancer (TNBC).
For TNBC patients, first-line treatment continues to consist of chemotherapy combined with immunotherapy. For those with BRCA mutations, PARP inhibitors may be considered as a preferred option. In the second-line and beyond, patients with HER2-low TNBC should prioritize ADC-based therapies over standard chemotherapy.
However, it is not yet clear whether T-DXd, which targets HER2, or ADCs targeting Trop-2 are more appropriate in this setting. Further clinical trials are needed to provide clarity. This year’s guideline updates have helped define which patients with HER2-low or ultra-low expression are most likely to benefit from T-DXd therapy, and where this drug fits into the treatment landscape for both HR-positive/HER2-negative and triple-negative breast cancer.
In conclusion, for HR-positive/HER2-low patients, T-DXd is primarily used after failure of endocrine therapy, particularly after progression on CDK4/6 inhibitors. For triple-negative breast cancer patients with HER2-low expression, T-DXd is generally used in the second-line and beyond.
About Prof. Ying Yan
- Associate Chief Physician, Department of Breast Medical Oncology, Beijing Cancer Hospital
- PhD, Deputy Director (Acting), Breast Tumor Center, Beijing Cancer Hospital – Inner Mongolia Hospital (National Regional Medical Center)
- Specializes in medical treatment of breast cancer
- Committee Member, CSCO Breast Cancer Expert Committee
- Member, Beijing Breast Disease Society’s Internal Medicine Committee
- Vice Chair, Breast Cancer Division, Inner Mongolia Tumor Disease Quality Control Center
- Youth Member, Chinese Medical Education Association – Breast Disease Committee
