HER2-Low Breast Cancer: A Review of Epidemiology, Diagnostic Challenges, Targeted Therapies, and Clinical Outcomes

Background: Breast cancer is the most common malignancy among women. The HER2-low subgroup represents one of its prevalent subtypes; however, due to its unique characteristics, it presents challenges in diagnosis and treatment, complicating clinical management. This narrative review aims to synthesize evidence regarding the epidemiology, diagnosis, treatment, and prognosis of this subgroup. Methods: In this narrative review, following a search of PubMed, Web of Science, Scopus, and Google Scholar databases and the evaluation of 91 studies, findings were synthesized qualitatively and descriptively. Additionally, cohort studies, systematic reviews, and meta-analyses were utilized to explore associations and summarize prognostic trends. Results: The prevalence of HER2-low varied between 30% and 65% across different populations, with most studies reporting an association with hormone receptor (HR)-positive status and age over 50 years. Diagnostic challenges primarily stemmed from poor inter-pathologist agreement and laboratory variability. However, emerging technologies such as artificial intelligence (AI) and radiomics have shown promising results in diagnosis. Therapeutically, trastuzumab deruxtecan (T-DXd) demonstrated efficacy with response rates ranging from 21% to 62%; nevertheless, cross-resistance to antibody–drug conjugates (ADCs) and high drug costs remain significant barriers. Patient prognosis and survival, beyond HER2 status, depended on factors such as HR status, Ki-67 index, lymph node involvement, and treatment response. Conclusions: HER2-low tumors constitute a distinct, highly prevalent subgroup with specific clinical features, necessitating differentiated diagnostic and therapeutic approaches. Despite the efficacy of T-DXd, obstacles such as intragroup heterogeneity, treatment resistance, high costs, and the lack of standardized diagnostic criteria persist. Therefore, attention to molecular profiling, standardization of diagnostic methods, and the development of cost-effective strategies are essential for equitable access to treatment.