T-DXd in HER2-Low Breast Cancer: Real-World Outcomes, Resistance Mechanisms, and Evolving Standards
Real-world data show trastuzumab deruxtecan achieved a 56.3% response rate and 7.4-month median progression-free survival in HER2-low metastatic breast cancer. Preclinical findings show HER2-low subclones can drive ADC resistance, and experts say T-DXd is now standard for HER2-low disease, with DESTINY-Breast15 studying HER2-null patients.
Trastuzumab deruxtecan (T-DXd) demonstrated a real-world overall response rate of 56.3%, median real-world progression-free survival (rwPFS) of 7.4 months, and 12-month overall survival (OS) of 62% in patients with HER2-low metastatic breast cancer treated across US community oncology settings, according to a retrospective study of 300 randomly sampled patients. The findings, presented at the Miami Breast Cancer Conference®, showed that most patients received T-DXd monotherapy (87.3%), and the study authors concluded that T-DXd demonstrated favorable effectiveness in real-world community oncology patients with hormone receptor-positive (HR+) and hormone receptor-negative (HR-) HER2-low metastatic breast cancer, despite this population appearing older, frailer, and more heavily pretreated than typical clinical trial patients. In the real-world study, HR-positive patients received T-DXd in later lines (3 lines or more: 88.7% HR+ vs 53.6% HR-), and median rwPFS was 7.7 months in HR+ patients versus 4.9 months in HR- patients. Among HR+ patients, T-DXd showed greater effectiveness in chemotherapy-naive patients (n = 41) compared with non-chemotherapy-naive patients (n = 190): rwPFS was 10.2 vs 7.4 months and 12-month OS was 74% vs 62% (P < .05 for both).
The traditional binary classification of breast cancer as HER2-positive or negative has transitioned into a more nuanced spectrum of expression, according to the chief of the Division of Breast Oncology at Dana-Farber Cancer Institute. T-DXd has become a standard of care for patients presenting with HER2-low or HER2-ultralow disease who also have hormone receptor-positive breast cancer. Additionally, T-DXd has become a therapeutic standard for patients with triple-negative breast cancer that exhibits HER2-low expression. The ability of antibody-drug conjugates to provide clinical benefit irrespective of high HER2 expression levels represents a novel development in oncology. There is a lack of definitive data regarding the use of T-DXd in patients with HER2-null disease; the phase 3b DESTINY-Breast15 trial (NCT05950945) is investigating T-DXd as monotherapy across several cohorts of patients with unresectable or metastatic breast cancer that has HER2-low expression or HER2 0 expression per immunohistochemistry, who must have received 1 or 2 prior lines of therapy in the metastatic setting.
New preclinical research published in Cancer Discovery provides further insight into intratumoral HER2 heterogeneity, which has emerged as an important challenge for HER2-targeted treatment. Using HER2-heterogeneous breast cancer models composed of matched HER2-high and HER2-low cell populations from the same tumor, researchers found that HER2-low cells can drive resistance to HER2-targeted antibody-drug conjugates, including T-DXd. HER2-low cells showed reduced sensitivity to the antibody-drug conjugates T-DXd and trastuzumab emtansine compared with matched HER2-high cells, but remained sensitive to HER2 kinase inhibitors, including neratinib and tucatinib. When HER2-high and HER2-low cells were grown together and treated with HER2-targeted agents, T-DXd and T-DM1 promoted the outgrowth of HER2-low populations, and after repeated ADC exposure, HER2-low cells became dominant in several models. The authors also identified two potential therapeutic vulnerabilities, ABCC1 and USP9X, that may increase the activity of T-DXd in HER2-heterogeneous tumors. According to the authors, HER2 heterogeneity may occur in up to 40% of HER2-positive breast cancers.