Dr Tolaney on the Future Roles of HER2 Expression in Breast Cancer Management

“We are seeing ADCs have a role irrespective of the degree of HER2 expression, which is novel.”

Sara M. Tolaney, MD, MPH, chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women's Cancers and a senior physician at Dana-Farber Cancer Institute; as well as an associate professor of medicine at Harvard Medical School, discussed the rapidly evolving clinical implications of HER2 expression in breast cancer management and the transformative influence of antibody-drug conjugates (ADCs), specifically fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).

Tolaney observed that the traditional binary classification of breast cancer as HER2-positive or -negative has transitioned into a more nuanced spectrum of expression. This shift has led to the establishment of T-DXd as a standard of care for patients presenting with HER2-low or HER2-ultralow disease who also have hormone receptor–positive breast cancer. Additionally, she noted that T-DXd has become a therapeutic standard for patients with triple-negative breast cancer that exhibits HER2-low expression levels. According to Tolaney, the ability of ADCs to provide clinical benefits irrespective of high HER2 expression levels represents a novel development in oncology.

To further refine these treatment protocols, Tolaney emphasized the necessity of investigating whether a minimum threshold of HER2 expression is required for therapeutic efficacy of HER2-targeted ADCs. Currently, there is a lack of definitive data regarding the use of T-DXd in patients with HER2-null disease, representing a gap in clinical knowledge. She highlighted the phase 3b DESTINY-Breast15 trial (NCT05950945) as a critical research effort designed to address this question. This trial is investigating T-DXd as monotherapy across several cohorts of patients with unresectable or metastatic breast cancer that has HER2-low expression or HER2 0 expression per immunohistochemistry. Patients must have received 1 or 2 prior lines of therapy in the metastatic setting, including targeted agents or endocrine therapy.