Dr Bardia on the Importance of HER2 Testing in HER2-Expressing Breast Cancer

"It’s now critical to look for any expression of HER2 by IHC, because even if it’s on 1% to 2% of the [tumor] cells, that qualifies [the patient for] the use of T-DXd."

Aditya Bardia, MD, MPH, FASCO, a professor in the Department of Medicine in the Division of Hematology/Oncology, as well as the director of Translational Research Integration at the UCLA Health Jonsson Comprehensive Cancer Center, discusses how the FDA approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with pretreated HER2-low and -ultralow metastatic breast cancer could affect and refine future HER2 testing strategies for this population.

The FDA approved T-DXd on January 27, 2025, for adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low or -ultralow breast cancer, as determined by an FDA-approved test, who have progressed on at least 1 endocrine therapy in the metastatic setting. Notably, HER2-low disease was defined as that with an immunohistochemistry (IHC) score of 1+ or an IHC score of 2+ with negative in situ hybridization (ISH), whereas HER2 ultralow was classified as IHC 0 with membrane staining.

Given this approval, evaluating HER2 expression by IHC in patients with breast cancer is now critical, as even minimal expression (1%-2% of tumor cells) qualifies a patient for treatment with T-DXd, Bardia emphasizes. However, the efficacy of T-DXd in patients with a HER2 IHC score of 0 remains unclear, he says. Although HER2 IHC 0 does not necessarily indicate a complete absence of HER2 expression, patients with IHC 0 disease were not included in the pivotal phase 3 DESTINY-Breast06 trial (NCT04494425), Bardia notes. Accordingly, the ongoing phase 3 DESTINY-Breast15 trial (NCT05950945) is investigating whether T-DXd has activity in patients with HER2 IHC 0 breast cancer.

For now, treatment decisions should adhere to the T-DXd FDA label, Bardia states. If a pathology report indicates IHC 0, Bardia advises determining whether any cells exhibit HER2 expression, which could reclassify the tumor as HER2 ultralow (HER2 0+), he clarifies. This distinction between HER2 expression levels may have future therapeutic implications as research continues to refine HER2-targeted treatment strategies, Bardia concludes.