Dr Gallagher on the Emergence of HER2-Low Metastatic Breast Cancer

Christopher M. Gallagher, MD, medical director, Cancer Services, Washington Cancer Institute, teaching attending physician, MedStar Washington Hospital Center, discusses treatment sequencing considerations with antibody-drug conjugates (ADCs) in patients with HER2-low metastatic breast cancer.

Oncologists should be aware of the potential presence of HER2-low disease when treating patients with metastatic breast cancer, Gallagher says. Prior to the readout of research such as the phase 3 DESTINY-Breast04 trial (NCT03734029), HER2-low was not considered a category of breast cancer, Gallagher notes. Instead, breast cancer with HER2 expression of 1+ or 2+ by immunohistochemistry was defined as hormone receptor (HR)–positive/HER2-negative or triple-negative disease, Gallagher explains. However, HER2-low disease can be either HR-positive or HR-negative, according to Gallagher.

DESTINY-Breast04 evaluated fam-trastuzumab deruxtecan-nxki (Enhertu) vs physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer who had received 1 or 2 prior lines of chemotherapy. In all patients, trastuzumab deruxtecan elicited a median progression-free survival (PFS) of 9.9 months (95% CI, 9.0-11.3) vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63).

In the population of patients with HR-positive disease, the median PFS was 10.1 months (95% CI, 9.5-11.5) with trastuzumab deruxtecan vs 5.4 months (95% CI, 4.4-7.1) with chemotherapy (HR, 0.51; 95% CI, 0.40-0.64). In the population of patients with HR-negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with the ADC vs 2.9 months (95% CI, 1.4-5.1) with chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). These data backed the FDA approval of trastuzumab deruxtecan for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

One future challenge of treating patients with HER2-low metastatic breast cancer will be determining the optimal sequence of ADCs in this setting, Gallagher emphasizes. Some ADCs may be more effective in earlier lines of treatment in this patient population, and investigators need to determine the role of treatment sequencing on patient outcomes, Gallagher says. Ongoing studies are evaluating the optimal treatment sequencing with trastuzumab deruxtecan and TROP2-directed ADCs, such as sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan (Dato-DXd), Gallagher concludes.