Clinicopathologic characterization of hormone-receptor positive, human epidermal growth factor receptor 2 Null, Ultralow, and Low breast carcinoma in the metastatic setting

HER2-directed therapy landscape is rapidly evolving. Patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2) Low and HER2 Ultralow demonstrate clinically meaningful progression-free survival improvement with HER2-directed antibody drug conjugates. Herein, we assess rates of hormone receptor-positive (HR+), HER2 Null, HER2 Ultralow, and HER2 Low metastatic breast carcinoma (MBC) and review clinical and pathologic aspects of primary tumors. We retrospectively reviewed all patients diagnosed with HR+/HER2- MBC metastatic breast carcinoma between 01/2023-12/2023 and characterized patients with HER2 Low, Ultralow, and Null results. 99 samples from 95 patients showed HR+/HER2- MBC. Seventy (70.7%) patients had HR+/HER2 Low MBC, 21 (21.2%) had HR+/HER2 Ultralow MBC, and 8 (8.1%) had HR+/HER2 Null MBC. HR and HER2 status of primary breast carcinoma were available in 56 (56.6%) of 99 samples. Primary and metastatic breast carcinoma samples shared the same HER2 status in 39 (69.6%) of 56 cases. Two (4.1%) of HER2 Low and 1 (33.3%) of HER2 Ultralow primary breast carcinoma cases showed shift to HER2 Null in the metastatic setting, and 3 (75%) of HER2 Null primary breast carcinoma cases showed shift to HER2 Ultralow or HER2 Low. Our one-year single-institution retrospective study shows majority of MBC are HR+/HER2 Low, followed by HR+/HER2 Ultralow. While majority of primary and metastatic breast carcinoma samples share similar HER2 status, patients may show change in HER2 status on metastatic tumor samples and repeat biomarker testing on metastatic samples may meaningfully guide HER2-directed antibody drug conjugate therapy.