Nature Medicine | Long-term survival analysis of Trastuzumab Deruxtecan in HER2-low metastatic breast cancer

This study provides long-term survival data for Trastuzumab Deruxtecan (T-DXd) in patients with HER2-low metastatic breast cancer, demonstrating significantly better overall survival and progression-free survival compared to treatment selected by physicians (TPC). This updated analysis further solidifies T-DXd's position as a standard therapy for this patient population.

Literature Overview
The article, 'Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial', published in Nature Medicine, reviews and summarizes the long-term survival data from the DESTINY-Breast04 trial, emphasizing the significant efficacy and manageable safety profile of T-DXd in patients with HER2-low metastatic breast cancer.

Background Knowledge
HER2-low breast cancer is a newly defined molecular subtype with HER2 expression levels lower than the HER2-positive threshold (IHC 3+) but higher than the negative standard (IHC 0). HER2-low is defined as IHC 1+ or IHC 2+/ISH−. This subtype accounts for approximately 65% of all traditionally defined HER2-negative breast cancers and represents a patient population with therapeutic potential. Currently, T-DXd is the first HER2-targeted therapy to demonstrate significant efficacy in HER2-low patients. DESTINY-Breast04 is a multicenter, open-label, randomized, phase 3 clinical trial designed to evaluate the efficacy and safety of T-DXd versus TPC in patients with HER2-low metastatic breast cancer. The updated analysis of this study, with extended follow-up time of 32.0 months, further confirms the clinical benefit of T-DXd, providing robust long-term evidence for the treatment of HER2-low breast cancer.

Research Methods and Experiments
DESTINY-Breast04 trial (NCT03734029) is a multicenter, open-label, randomized, phase 3 study evaluating the efficacy and safety of T-DXd versus TPC in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) metastatic breast cancer. Patients were randomly assigned in a 2:1 ratio to receive T-DXd or TPC, which included capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel. The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR). Key secondary endpoints included overall survival (OS). Safety analysis was based on the incidence and severity of adverse events during treatment.

Key Conclusions and Perspectives

• In the overall cohort, median OS was 22.9 months in the T-DXd group versus 16.8 months in the TPC group (HR 0.69; 95% CI 0.55–0.86).
• In the hormone receptor-positive (HR+) cohort, median OS was 23.9 months in the T-DXd group versus 17.6 months in the TPC group (HR 0.69; 95% CI 0.55–0.87).
• In the hormone receptor-negative (HR−) cohort, median OS was 17.1 months in the T-DXd group versus 8.3 months in the TPC group (HR 0.58; 95% CI 0.31–1.08).
• Exploratory analysis showed that T-DXd maintained superior efficacy over TPC even in patients with low estrogen receptor (ER) expression (IHC 1%–10%) or high ER expression (IHC >10%).
• In terms of safety, the incidence of adverse events with T-DXd was comparable to TPC and manageable. The main reason for discontinuation was disease progression.
• This study further supports the classification of HER2-low as a treatable clinical entity with targeted therapy, prompting updates in HER2 testing and classification criteria.

Conclusion
The updated analysis of the DESTINY-Breast04 trial confirms the long-term survival benefit of T-DXd in patients with HER2-low metastatic breast cancer, regardless of hormone receptor status. Compared to TPC, T-DXd significantly prolongs both overall survival and progression-free survival, with a manageable safety profile. These results establish T-DXd as the standard of care following second-line therapy in HER2-low breast cancer patients. Furthermore, the redefinition of HER2-low expression is driving updates in HER2 testing and classification criteria, enabling more precise patient stratification and treatment decisions. In the future, as more targeted therapies emerge, the treatment landscape for HER2-low breast cancer will continue to expand, offering improved survival outcomes for patients.

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