Dr Alkassis on Cathepsin Protease Expression and Its OS Association With T-DXd in Metastatic Breast Cancer

“Overall with trastuzumab deruxtecan, we did not observe any significant effect of these [cathepsin protease] enzymes on overall survival [OS]. However, when we examined the subgroup analyses, mainly patients with HER2-positive and HER2-[low or -ultralow] disease—we found that in patients with HER2-positive disease, higher cathepsin expression was associated with worse OS.”

Samer Alkassis, MD, PhD, a clinical instructor in the Division of Hematology/Oncology at UCLA, discussed emerging translational insights into biomarkers of response and resistance to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in metastatic breast cancer, with a particular focus on the role of cathepsin protease expression as a potential determinant of therapeutic outcomes.

His team collaborated with Tempus by integrating real-world genomic and clinical data to evaluate whether tumor cathepsin activity enzymes implicated in extracellular matrix remodeling and intracellular processing may influence T-DXd efficacy across HER2-defined subgroups.

Alkassis explained that the retrospective cohort included 453 patients with metastatic breast cancer who underwent tumor biopsy within 1 year prior to initiating T-DXd or ado-trastuzumab emtansine (T-DM1; Kadcyla), or within 15 days after treatment start. The analysis examined cathepsin expression patterns and correlated them with survival outcomes to explore whether protease levels modulate therapeutic activity of T-DXd, a topoisomerase I–directed antibody–drug conjugate.

When considering the full, unstratified population treated with T-DXd, Alkassis noted that cathepsin expression did not demonstrate a statistically significant association with overall survival [OS]. However, once tumors were stratified by HER2 status, a more nuanced and clinically relevant pattern emerged.

Among patients with HER2-positive metastatic breast cancer, higher cathepsin expression correlated with worse OS. Alkassis emphasized that this may indicate an interaction between elevated protease activity and disease biology—potentially reflecting more aggressive tumor behavior or altered ADC processing—although the mechanism remains to be elucidated. In contrast, for patients with HER2-low or HER2-ultralow disease, the direction of association reversed: higher cathepsin expression was linked to improved OS with T-DXd. This divergent biomarker signal suggests distinct biological contexts in which ADC payload release, trafficking, or bystander effects may differ based on the interplay between HER2 expression and protease activity.

Alkassis underscored that these findings are hypothesis-generating but highlight the need for refined biomarker strategies that move beyond HER2 expression alone. As the therapeutic footprint of T-DXd expands across HER2-positive and HER2-low disease settings, understanding how tumor microenvironmental factors—such as cathepsin protease levels—shape response could inform future patient selection frameworks and guide prospective validation studies.