Dr Bardia on the Limitations of HER2 Testing Assays in HER2-Low and -Ultralow Breast Cancer

Aditya Bardia, MD, MPH, FASCO, professor, Department of Medicine, Division of Hematology/Oncology, Director of Translational Research Integration, the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, UCLA Health, discusses the need for expanded HER2 testing assays for patients with HER2-low and -ultralow metastatic breast cancer.

Current HER2 immunochemistry (IHC) assays were initially designed to identify high levels of HER2 expression and were not intended to detect low HER2 expression in patients with breast cancer, Bardia begins. Despite this limitation, studies involving fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) have shown efficacy even in tumors with low HER2 expression per IHC testing, Bardia reports. For instance, the phase 3 DESTINY-Breast06 trial (NCT04494425) included patients with hormone receptor–positive breast cancer that was either HER2-low or -ultralow, he explains.

At the 2024 ASCO Annual Meeting, results from the primary analysis of the randomized, multicenter, open-label showed that treatment with T-DXd led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy alone in pretreated patients with hormone receptor–positive, HER2-low and -ultralow metastatic breast cancer. Notably, patients with HER2-low disease (n = 359) experienced a median PFS of 13.2 months when treated with the investigational agent compared with 8.1 months for those given investigator’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P < .0001). In the intention-to-treat (ITT) population comprised of patients with HER2-low and -ultralow disease, the median PFS was 13.2 months for T-DXd (n = 436) vs 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; P <.0001). An exploratory analysis showed that in patients with HER2-ultralow disease, T-DXd (n = 76) generated a median PFS of 13.2 months vs 8.3 months for chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

Although the HER2 IHC assay has been effective in identifying high HER2 expression, the limitations in detecting low HER2 expression highlight the need for improved diagnostic tools, Bardia emphasizes. This raises the question of whether oncologists need better assays, as the current HER2 IHC assay is inadequate for identifying low-expressing tumors, he concludes.