Emerging Landscape of Targeted Therapy of Breast Cancers With Low Human Epidermal Growth Factor Receptor 2 Protein Expression

Context.—Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1＋ or 2＋ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective. Objective.—To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-low–expressing breast cancers by immunohistochemistry. Data Sources.—We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors’ practice experience. Conclusions.—The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy.