Breast cancer is one of the leading causes of death for women worldwide. HER2, or human epidermal growth factor receptor 2, is a protein found on the surface of some cells in the body that regulate normal cell growth. In HER2-positive breast cancer, tumor cells have higher levels of HER2 proteins than normal cells. This can cause the cells to grow and divide more quickly, which can make the cancer more aggressive. With the development of medicines that specifically target and block the HER2 protein, most patients with HER2-positive breast cancer can benefit from HER2-targeted therapy. Breast cancer can be classified by HER2-positive and HER2-negative subtypes and by hormonal receptor status, which helps guide treatment decisions, including hormonal therapy.
However, researchers suggest that HER2 expression is a broad spectrum rather than a simple positive or negative result. HER2-negative breast cancers can be further classified as HER2-low, HER2-ultralow, or HER2-zero, based on the level of HER2 present.
Identifying very small amounts of HER2 by IHC, or immunohistochemistry testing, has become increasingly important with the development of new HER2-targeted therapies, particularly for patients with advanced breast cancer. One major challenge in distinguishing HER2-negative breast cancers is reproducibility and consistency among pathologists, known as interobserver variability.
Breast pathologists in the Department of Pathology Division of Women’s Health aimed to examine this variability among pathologists by conducting a study to investigate interobserver variability in HER2-negative breast cancers. Their study, “Revisiting HER2-negative breast cancer in the era of HER2-low and HER2-ultralow expression: Assessment of interobserver variability” was recently published in The Breast, an internationally recognized journal affiliated with the European Society for Medical Oncology.
Shi Wei, M.D., Ph.D.“A study of this scope is not easy to accomplish,” said Shi Wei, M.D., Ph.D., Hazel Gore, M.B.B.S., Endowed Professorship in Women’s Health, Division Director, Women’s Health. “It requires the participation of multiple pathologists, substantial time, and careful evaluation of many cases. From initial planning to completion, the study took approximately two years.”
The authors evaluated nearly 400 HER2-negative breast cancers, with a particular focus on the reproducibility of HER2-low and HER2-ultralow classifications. While significant interobserver variability has been reported in HER2 IHC scoring, specifically as the clinical importance of the HER2-low and HER2-ultralow categories has increased, the study found substantial agreement and good reliability among the UAB breast pathologists. These findings were significant compared to those reported in other similar studies.
“We found that despite the nuanced distinction between HER2-low and HER2-ultralow categories, IHC testing remains a reliable and reproducible method for evaluating HER2 expression in breast cancer,” said Wei. “Even in the era of expanded HER2-targeted therapies.”
Collaborators with Wei on the study include Sarah Anderson, D.O., Valeria Dal Zotto, M.D., Shuko Harada, M.D., Andrea Kahn, M.D., Xiao Huang, M.D., Ph.D., MD Anderson Cancer Center, Kanako Okamoto, M.D., Emory University, Meiling Zhou, Ph.D., Grand Valley State University, and Kui Zhang, Ph.D., Michigan Technological University.