Recent clinical trial results are reshaping the treatment landscape for patients with HER2-low and ultra-low breast cancer, as trastuzumab deruxtecan (T-DXd) demonstrates compelling efficacy across broader patient populations than previously established.
Expanding Efficacy in HER2-Low Disease
The DESTINY-Breast04 trial set the initial groundwork, enrolling patients with HER2-low, unresectable and/or metastatic hormone receptor (HR)-positive breast cancer. The study showed impressive results with T-DXd compared to physician's choice treatment, achieving a median progression-free survival (PFS) of 10.1 versus 5.4 months (HR 0.51; 95% CI, 0.40-0.64; P < .001). More notably, overall survival improved to 23.9 months compared to 17.5 months (HR 0.64; P = .003).
Breaking New Ground with DESTINY-Breast06
Building on these findings, DESTINY-Breast06 has pushed boundaries by investigating T-DXd's efficacy in patients with HER2 ultra-low expression (IHC 0 to 1+). This trial specifically targeted patients who had progressed on endocrine therapy but were entering first-line chemotherapy, representing an earlier treatment setting.
The results were striking, with T-DXd demonstrating superior efficacy in the intention-to-treat population, achieving a median PFS of 13.2 months compared to 8.1 months with standard chemotherapy (HR 0.62; 95% CI, 0.52-0.75; P < .001). Importantly, this benefit was maintained across subgroups, including the ultra-low cohort.
Clinical Implications and Future Directions
Dr. Laura Huppert, a clinical expert, notes the evolving treatment paradigm: "With the more recent data with trastuzumab deruxtecan in HER2-low and now ultra-low disease, I am often emailing the pathologist to see if the patient has any level of [HER2] expression and sliding that in before sacituzumab."
While current pathological classifications may need refinement to accommodate these findings, ongoing trials are investigating T-DXd in true IHC 0 patients. The consistency of benefit across subgroups suggests that traditional HER2 IHC scoring may not be the optimal biomarker for predicting T-DXd response.
Treatment Sequencing Considerations
The emerging data is influencing treatment sequencing decisions in HR-positive, HER2-negative breast cancer. While endocrine therapy remains the foundation, the positioning of T-DXd earlier in the treatment algorithm is gaining support, particularly before other chemotherapy options like capecitabine or sacituzumab govitecan.
Though formal approval for ultra-low expression is pending, these findings suggest a potential paradigm shift in how we classify and treat breast cancer patients traditionally considered HER2-negative. The consistent efficacy signals across varying levels of HER2 expression challenge current diagnostic frameworks and may lead to expanded treatment options for a broader patient population.
