Human Epidermal Growth Factor Receptor 2 Loss Following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer

Abstract Purpose: Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) which is HER2-positive (immunohistochemistry [IHC] score of 3+ or ISH positivity) or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2 overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 receptor status might change following T-DXd therapy. Design: We retrospectively reviewed patients with MBC who received T-DXd at The University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. Results: We included 41 patients with MBC who received treatment with T-DXd, and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients (32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)) following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. Conclusions: HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Re-evaluation of HER2 status post-T-DXd should be considered prior to certain alternate HER2-targeted therapies which require HER2 overexpression for efficacy.