HER2-Low Breast Cancer

HER2-low breast cancer describes tumors with a HER2 immunohistochemistry (IHC) score of 1+ or 2+ when in situ hybridization (ISH) is negative. It has emerged as a new treatment category in recent years. Historically these tumors were classified as 'HER2-negative' and were considered unresponsive to anti-HER2 therapies. After the failure of trastuzumab emtansine (T-DM1) and earlier anti-HER2 drugs in HER2-low disease, the revolutionary design of trastuzumab deruxtecan (T-DXd) — high drug-antibody ratio (DAR around 8), bystander effect, and the highly potent topoisomerase I inhibitor deruxtecan payload — suggested it could be effective in HER2-low tumors as well.

The DESTINY-Breast04 trial (2022) compared T-DXd with standard chemotherapy in metastatic HER2-low breast cancer and showed that T-DXd improved both progression-free survival (9.9 vs 5.1 months) and overall survival (23.4 vs 16.8 months). The FDA subsequently approved T-DXd for metastatic HER2-low breast cancer (2022), creating a new therapeutic category. An estimated 45-55% of breast cancers can be classified as HER2-low, meaning a substantial portion of patients previously labeled triple negative or HR+/HER2- can now be reclassified. Benefit was observed in both HR+ and HR- (triple negative) subgroups in the trial.

Diagnosis of HER2-low: IHC scoring depends on pathologist interpretation, and the distinction between 0 and 1+ is acknowledged as challenging; therefore HER2 'ultra-low' tumors (IHC 0 with some staining) are also being evaluated for T-DXd benefit (DESTINY-Breast06). Standardization and inter-laboratory consistency are important issues. HER2 expression can change during tumor progression; primary-metastasis discordance is around 15-20%, so re-evaluating HER2 status in the metastatic setting is recommended. Treatment approach: HER2-low patients are still treated based on HR status — endocrine therapy with or without a CDK4/6 inhibitor (HR+) or chemotherapy/immunotherapy (TN PD-L1+) first. Following progression on these therapies, T-DXd is an effective option in the metastatic HER2-low subgroup.