Editor's Note: The Northern Breast Cancer Salon was recently held successfully in Qingdao. The meeting focused on the latest advances and clinical hot topics in breast cancer, bringing together numerous experts and scholars for in-depth academic exchange. During the meeting, Professor Wenyan Chen of Nanchang People's Hospital and Professor Ning Xie of Hunan Cancer Hospital respectively shared their perspectives on “Treatment options for HER2-positive metastatic breast cancer after failure of H-based therapy — T-DXd, SHR-A1811, and others.” Following the meeting, Oncology Frontier invited the two professors to further review and elaborate on their respective perspectives, with the aim of providing clinicians with clearer insights and practical guidance on treatment selection after failure of H-based therapy.Highlighting Key Perspectives and Exploring the Underlying Mechanisms
Professor Wenyan Chen: Indeed, in the absence of head-to-head clinical studies, it is difficult to definitively determine which agent should be prioritized for second-line treatment of HER2-positive advanced breast cancer.
First, we need to clarify the underlying mechanisms of treatment failure after H-based therapy. Existing studies suggest that resistance may involve multiple mechanisms, including abnormalities in intracellular signaling pathways, alterations in extracellular target expression, and structural mechanisms of resistance.
For example, mutations in the intracellular PI3K/AKT/mTOR pathway may contribute to resistance through bypass activation. Therefore, whether T-DXd can overcome this mechanism is an important consideration when determining whether it is an appropriate treatment option after failure of H-based therapy. The DESTINY-Breast03 (DB-03) study specifically analyzed patients with PI3K pathway mutations. The results showed that in the T-DXd group, treatment efficacy was comparable regardless of PI3K pathway mutation status. This analysis suggests that T-DXd can effectively overcome intracellular resistance pathways associated with failure of H-based therapy.
At the extracellular level, tumors may seek alternative survival pathways under the selective pressure of treatment after failure of H-based therapy. For example, HER2-positive tumors may shift to a HER2-negative phenotype, while HR-positive tumors may become HR-negative. However, available data have demonstrated that T-DXd is effective in patients with both HER2-positive disease and HER2-low/ultralow expression, indicating that this ADC can also overcome resistance mechanisms at the extracellular level.
In addition, T-DXd has demonstrated clinical activity in patients with structurally heterogeneous disease, including brain metastases and leptomeningeal metastases. Therefore, at least based on the resistance mechanisms currently understood, T-DXd appears capable of addressing almost all of these known mechanisms of resistance.
In the DB-03 study, second-line T-DXd achieved a progression-free survival (PFS) of 28.8 months, while the HORIZON-Breast01 study mentioned by Professor Xie reported a PFS of 30.6 months with SHR-A1811. Although there is a numerical difference between the two figures, they should not be interpreted as a direct comparison because these were not head-to-head studies. Differences in patient populations and baseline characteristics may have influenced the results.
It is worth noting that in DB-03, T-DXd achieved an objective response rate (ORR) of 78.5% and a complete response (CR) rate of 21.1%, with a higher proportion of patients achieving deep responses. This means that more patients may derive substantial benefit from this ADC in the second-line setting.
ADC drugs consist of three major components: the antibody, linker, and payload. Differences in these components may lead to distinct efficacy and safety profiles. These differences are also precisely why we have observed outstanding performance from different ADC agents in clinical research and practice.
Therefore, until head-to-head clinical data become available, I still believe that T-DXd remains the preferred option for second-line treatment at present.
Professor Ning Xie: In my view, these two drugs should not be considered competitors in a head-to-head sense. Rather, they are more likely to be complementary across different dimensions, with each possessing its own unique strengths.
Both agents are highly effective ADCs and share many similarities in various aspects. Their differences are mainly reflected in certain details, and these differences may result in varying degrees of differences in treatment efficacy and adverse-event profiles.
As clinicians specializing in breast cancer, when developing treatment strategies for individual patients, we need to comprehensively consider these differences. For patients with different baseline characteristics, medical histories, metastatic sites, and metastatic tumor burdens, as well as different considerations regarding safety and financial burden, individualized treatment selection strategies should be developed.
Ultimately, the choice between these ADCs should be based on a comprehensive assessment of each patient’s specific clinical characteristics and treatment needs, rather than relying solely on cross-trial comparisons of efficacy data.
Professor Wenyan Chen
Professor Ning Xie
