HER2-Low Breast Cancer—Diagnostic Challenges and Opportunities for Insights from Ongoing Studies: A Podcast

Breast cancer has been traditionally classified as either human epidermal growth factor receptor 2 (HER2)-positive or HER2-negative based on immunohistochemistry (IHC) scoring and/or gene amplification. HER2-positive breast cancer (defined as IHC 3+ or IHC 2+ and in situ hybridization [ISH]+) is routinely treated with HER2-targeted therapies, while HER2-negative breast cancer (defined as IHC 0, IHC 1+, or IHC 2+/ISH−) was not previously eligible for HER2-targeted therapy. Some tumors traditionally defined as HER2-negative express low levels of HER2 (i.e., HER2-low breast cancer, defined as IHC 1+ or IHC 2+/ISH−). Recently reported results from the DESTINY-Breast04 trial demonstrated that the HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) improved survival in patients with previously treated advanced or metastatic HER2-low breast cancer, leading to the approval of T-DXd in the US and EU for patients with unresectable or metastatic HER2-low breast cancer after prior chemotherapy in the metastatic setting or disease recurrence within 6 months of adjuvant chemotherapy. As the first HER2-targeted therapy approved for the treatment of HER2-low breast cancer, this represents a change in the clinical landscape and presents new challenges, including identifying patients with HER2-low breast cancer. In this podcast, we discuss the strengths and limitations of current methodologies for classifying HER2 expression and future research that will help refine the identification of patients expected to benefit from HER2-targeted therapy, such as T‑DXd or other antibody–drug conjugates. Although current methodologies are not optimized to identify all patients with HER2-low breast cancer who may potentially benefit from HER2-targeted antibody–drug conjugates, they are likely to identify many. Ongoing studies—including the DESTINY-Breast06 trial evaluating T-DXd in patients with HER2-low breast cancer and those with tumors expressing very low levels of HER2 (IHC > 0 to < 1+)—will provide insights that may improve the identification of patient populations expected to benefit from HER2-targeted antibody–drug conjugates.