May 2025—Since the hunt began to identify low levels of HER2 in metastatic breast cancers, the action has revealed itself like the plot of a Henry James novel: Nothing much happens. Also, a lot happens. And each narrative thread is conveyed in hard-to-parse language. The goal has been to qualify patients for the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which was shown in the Destiny-Breast04 trial to significantly improve survival in so-called HER2-low cases. Immunohistochemistry assays were designed to identify strongly positive cases, however, and thus not useful for those at the 0 and 1+ end of the spectrum. Now, several years after the presentation of the D-B04 results at the ASCO 2022 annual meeting, which launched the low-end ship, pathologists and oncologists are adjusting to the implications of the most recent Destiny trial, D-B06. In late January, the FDA approved the drug Enhertu for HER2-low or HER2-ultralow cases, as well as the Ventana Pathway HER2 (4B5) companion diagnostic for assessing these lower levels of HER2 in patients with metastatic breast cancer.
