Editor's Note: From trastuzumab opening the door to HER2-targeted therapy, to dual-targeted regimens becoming the cornerstone of first-line treatment, and now to ADCs reshaping survival outcomes, the treatment history of HER2-positive advanced breast cancer reflects the continuous evolution of precision oncology. The 2026 Northern Breast Cancer Forum was successfully held in Qingdao from July 25 to 26. During the meeting, Oncology Frontier interviewed Prof. Xueli Mo from Peking University Shougang Hospital, who discussed the major milestones in HER2-targeted therapy for advanced breast cancer, the current three-way first-line treatment landscape, and the clinical value and impact of domestically developed ADCs, providing practical insights for clinical decision-making.Oncology Frontier: The treatment of HER2-positive advanced breast cancer has undergone a remarkable transformation from having limited therapeutic options to entering the era of precision-targeted therapy. From trastuzumab initiating the era of HER2-targeted treatment, to the establishment of dual-targeted therapy, and now the emergence of ADCs, which milestones do you believe have truly reshaped the treatment landscape of HER2-positive advanced breast cancer?
Prof. Xueli Mo: For patients with HER2-positive breast cancer, the emergence of targeted therapy fundamentally changed the classification and treatment landscape of breast cancer. Looking back at the development of anti-HER2 therapy, there have been several particularly important milestones.
First, the introduction of trastuzumab marked the beginning of the targeted therapy era.
Before trastuzumab became available, HER2-positive breast cancer was considered one of the breast cancer subtypes associated with the poorest prognosis, with relatively short survival. The introduction of trastuzumab represented a landmark milestone in the treatment of HER2-positive breast cancer. Since its FDA approval in 1998 for first-line treatment of HER2-positive advanced breast cancer, trastuzumab has significantly improved outcomes for these patients. Multiple studies, including H0648g and M77001, established the role of trastuzumab combined with chemotherapy as first-line treatment for HER2-positive metastatic breast cancer.
Second, the CLEOPATRA study established dual HER2-targeted therapy as a new treatment cornerstone.
The publication of the CLEOPATRA results in 2012 fundamentally changed the treatment landscape of HER2-positive advanced breast cancer. In this landmark study, docetaxel combined with trastuzumab and pertuzumab, namely the THP regimen, prolonged median progression-free survival to 18.5 months, while median overall survival exceeded four years for the first time. Long-term follow-up subsequently showed that the THP regimen could extend median overall survival to nearly five years, reaching 57.1 months. Since then, dual HER2-targeted therapy combined with chemotherapy has become a globally recognized first-line standard, substantially reshaping the first-line treatment landscape for HER2-positive advanced breast cancer.
Third, the PHILA study introduced a “Chinese strategy” combining large- and small-molecule targeted therapies.
In 2023, the Chinese-led PHILA study reported its results, demonstrating that trastuzumab combined with the small-molecule TKI pyrotinib and docetaxel achieved a median PFS of 24.3 months. This innovative combination of large- and small-molecule HER2-targeted therapies provided another highly effective option for Chinese patients with HER2-positive advanced breast cancer and represented an important contribution from Chinese researchers to the global development of anti-HER2 treatment.
Fourth, the approval of T-DM1, the first HER2-directed ADC in solid tumors, opened the ADC era in second-line treatment.
EMILIA was a phase III study comparing T-DM1 with capecitabine plus lapatinib as second-line treatment for patients with HER2-positive advanced breast cancer. The results showed median PFS of 9.6 versus 6.4 months, with T-DM1 reducing the risk of disease progression or death by 35%. Median OS was 30.9 versus 25.1 months, with a 32% reduction in the risk of death. This study provided the first definitive evidence of a survival benefit from an ADC in later-line HER2-positive breast cancer and marked the beginning of the ADC era.
Fifth, the DESTINY-Breast series marked the rise of next-generation ADCs.
The emergence of next-generation ADCs represented by trastuzumab deruxtecan (T-DXd) has continued to redefine survival outcomes for patients with HER2-positive advanced breast cancer. In the second-line setting, DESTINY-Breast03 demonstrated a median PFS of 29.0 months with T-DXd compared with 7.8 months with T-DM1, while median overall survival exceeded four years, ultimately reaching 56.4 months. In the first-line setting, the results of DESTINY-Breast09 reported in 2025 showed that T-DXd plus pertuzumab achieved a median PFS of 40.7 months, significantly longer than the 26.9 months observed with THP, representing an improvement of 13.8 months and a 44% reduction in the risk of disease progression or death (HR=0.56). This was the first phase III study in more than a decade to successfully challenge the THP first-line standard.
From the single-target era of trastuzumab, to the dual-targeted era of trastuzumab plus pertuzumab, and now to the precision treatment era led by ADCs, these successive breakthroughs have collectively shaped the current treatment landscape of HER2-positive advanced breast cancer.
Oncology Frontier: In the first-line treatment of HER2-positive advanced breast cancer, China has now developed a parallel landscape involving dual-targeted therapy with trastuzumab and pertuzumab and large- plus small-molecule targeted therapy. At the same time, next-generation ADCs are challenging the established first-line standard. With multiple first-line options now available, how should clinicians make the optimal treatment choice for individual patients?
Prof. Xueli Mo: Following the publication of the DESTINY-Breast09 results, first-line treatment for HER2-positive advanced breast cancer has evolved into a new “three-way” landscape.
The first option is the traditional dual-targeted regimen of trastuzumab plus pertuzumab combined with chemotherapy, or THP, which has established a solid cornerstone position in first-line advanced disease. The second is the large- and small-molecule combination of trastuzumab, pyrotinib, and docetaxel. The third is the new ADC-based regimen of T-DXd plus pertuzumab, which provides another highly effective option for clinical practice.
In clinical decision-making, several factors need to be considered comprehensively, including treatment efficacy and survival benefit, safety, the patient’s previous treatment history and comorbidities, drug accessibility, and economic considerations. Based on available evidence, clinicians should integrate tumor biology, previous treatment exposure, clinical characteristics such as brain metastases, safety and tolerability, as well as drug accessibility, in order to develop an individualized first-line treatment strategy for each patient.
Oncology Frontier: In recent years, several breakthroughs have emerged in HER2-positive advanced breast cancer, and domestically developed ADCs such as SHR-A1811 and A166 have been incorporated into the CSCO Breast Cancer Guidelines. How do you view the clinical value and differentiated advantages of domestic ADCs in HER2-positive advanced breast cancer? How might their inclusion in the guidelines affect the existing treatment landscape?
Prof. Xueli Mo: In recent years, China has made significant breakthroughs in the independent development of HER2-directed ADCs. Based on the results of the HORIZON-Breast01 and KL166-III-06 studies, SHR-A1811 and A166 have both received NMPA approval and have been incorporated into the 2026 CSCO Breast Cancer Guidelines for the treatment of patients with HER2-positive advanced breast cancer. The rapid review and approval of these domestically developed ADCs, followed by their inclusion in clinical guidelines, has substantially improved treatment accessibility and enabled more Chinese patients to benefit from innovative therapies that are aligned with international advances.
These domestically developed ADCs are also having an important impact on the treatment landscape. First, they provide new and highly effective treatment options for patients with previously treated HER2-positive advanced breast cancer. Second, they are enriching the range of “Chinese strategies.” These ADCs have been developed with Chinese clinical characteristics and unmet needs in mind and are increasingly contributing to the evolution of treatment strategies, while also providing Chinese experience and solutions to the global breast cancer community. Third, they demonstrate the strength of China’s original drug development capabilities. The transition of domestically developed ADCs from “following” to “parallel development” and, in some areas, potentially “leading,” reflects the rapid momentum of China’s innovative pharmaceutical research.
Overall, supported by robust clinical evidence, differentiated characteristics, and improved accessibility, domestically developed ADCs have established an increasingly important position in the treatment landscape of HER2-positive advanced breast cancer. As more head-to-head studies and real-world evidence become available, these agents are expected to play an increasingly important role in clinical decision-making.
Prof. Xueli Mo
