From Negative to Low: Understanding HER2-Low Breast Cancer

Abstract Breast cancer (BC) is the most common solid organ malignancy among women globally, with HER2 playing a notable role in its molecular classification and treatment. Traditionally, only HER2-positive tumors (IHC 3+ or IHC 2+/ISH+) were eligible for targeted therapy. However, emerging research has identified a subset of BC that have been defined as HER2-low (IHC 1+ or 2+/ISH−). These BC cases historically have been categorized as HER2-negative and not considered eligible for targeted therapy. However, this subset has shown potential responsiveness to newer antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd). This study aims to review the evolving concept of HER2-low BC in terms of its definition, diagnostic challenges, molecular features, prognostic significance, and recent therapeutic advancements, particularly the ADC-based targeted therapy. A comprehensive literature review was conducted for publications from 2015 to 2025 using peer-reviewed journals and authoritative guidelines such as ASCO, CAP, and NCCN. Studies addressing HER2-low diagnostic criteria, molecular characterization, clinical trials, treatment outcomes, and diagnostic challenges were included. Data extraction focused on HER2-low definitions, prevalence, PAM50/MammaPrint-based molecular profiling, ADC efficacy, interobserver variability, and implications of HER2 IHC heterogeneity. HER2-low BC accounts for approximately 40 to 50% of all BCs and is more prevalent in hormone receptor-positive tumors. Molecular profiling reveals that HER2-low cancers are mainly luminal A/B subtypes, with some basal-like and HER2-enriched tumors. The clinical benefit of T-DXd in HER2-low metastatic BC was confirmed by the DESTINY-Breast04 trial, significantly improving progression-free and overall survival. However, accurate HER2-low identification remains challenging due to intratumoral heterogeneity, borderline IHC scoring (particularly between 0 and 1+), and poor interobserver concordance (as low as 26%). Diagnostic pitfalls arise from staining variability, technical artifacts, and differences between primary and metastatic sites. Emerging digital image analysis and machine learning tools show promise in refining HER2 IHC interpretation but require further validation. HER2-low BC has emerged as a distinct and clinically actionable entity due to the efficacy of HER2-targeted ADCs. This shift necessitates precise HER2 assessment by pathologists, with emphasis on distinguishing IHC 0 from 1+ and standardizing preanalytical and analytical protocols. Enhanced diagnostic accuracy is essential to guide appropriate therapy and support the expanding landscape of personalized BC treatment. Future updates in testing guidelines and integration of digital tools may further optimize HER2-low classification and patient outcomes.