Nature Reviews. Clinical Oncology | Evolution of HER2 Testing and Companion Diagnostic Updates

This article systematically reviews the development of HER2 testing technologies, deeply discusses the limitations of traditional methods, and the challenges in precisely identifying patient populations who benefit from treatment in HER2-low tumors. It emphasizes the clinical value and future direction of quantitative testing technologies.

 

Literature Overview

The article 'HER2 testing: evolution and update for a companion diagnostic assay,' published in Nature Reviews. Clinical Oncology, reviews and summarizes the evolution of HER2 testing methods from early immunohistochemistry to current companion diagnostics. The article details HER2 as a critical therapeutic target in breast cancer and various other solid tumors, and how the clinical application of targeted therapies such as trastuzumab and antibody–drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) has driven continuous updates to HER2 testing standards. The study further analyzes the challenges of current testing methods in interpreting HER2-low expression status, including insufficient sensitivity and subjectivity, and proposes that quantitative testing technologies may become key to future precision medicine. The entire section is coherent and logically structured, ending with a Chinese period.

Background Knowledge

HER2 (human epidermal growth factor receptor 2) is a transmembrane tyrosine kinase receptor encoded by the ERBB2 gene, whose overexpression or amplification drives tumor progression in multiple solid tumors. In breast cancer, HER2 overexpression occurs in approximately 15–30% of cases and has long served as a biomarker for targeted therapies such as trastuzumab. Traditional testing relies on immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), using semi-quantitative scoring (0 to 3+) and gene amplification to determine HER2 status. However, with the highly effective ADC drug T-DXd demonstrating significant efficacy in HER2-low patients (IHC 1+ or 2+ without ERBB2 amplification), traditional methods face significant challenges in accurately detecting low-level expression. HER2 expression is highly heterogeneous, and the limited dynamic range of IHC leads to high inconsistency rates between IHC 0 and 1+ interpretations. Furthermore, HER2 expression patterns differ significantly across tumor types (e.g., gastric, colorectal, lung cancers), with no unified scoring standard. Thus, accurately identifying the HER2-low patient population and avoiding false negatives or positives has become a critical bottleneck in clinical decision-making. The limitations of current methods highlight the urgent need to develop more sensitive, quantitative, and standardized testing technologies to support personalized treatment strategies.

 

 

Research Methods and Experiments

This article is a review study in which the authors systematically examine literature from the 1980s onward, when HER2 was first identified as an oncogenic target. The review encompasses key clinical trials (e.g., ToGA, DESTINY-Breast04), FDA approval documents, and updated guidelines from authoritative bodies such as ASCO/CAP and ESMO. The study traces the evolution of HER2 testing technologies, including early immunohistochemistry (IHC) methods such as clinical trial assays (CTA) and commercial HercepTest, as well as the application and limitations of molecular testing techniques like FISH, CISH, and RT-PCR. The authors analyze HER2 expression characteristics, testing criteria differences, and clinical responses across various solid tumors (breast, gastric, colorectal, non-small cell lung, and endometrial cancers). Particular attention is given to the evolving definition of HER2-low, assessing current IHC interpretation inconsistencies and challenges based on results from the DESTINY trials. The article also explores the potential of emerging quantitative technologies such as digital immunofluorescence, RNA detection, and automated image analysis systems, proposing future directions for companion diagnostics.

Key Conclusions and Perspectives

• HER2 testing has evolved from initial qualitative methods to a multimodal assessment system, but traditional IHC exhibits significant subjectivity and insufficient sensitivity in HER2-low interpretation
• With T-DXd demonstrating efficacy in HER2-low tumors, accurately distinguishing IHC 0 from 1+ has become clinically critical, yet current methods lack standardization and dynamic range in the low-expression range
• HER2 expression patterns (e.g., membrane staining distribution, heterogeneity) vary significantly across solid tumors, necessitating tumor type–specific scoring criteria
• Guidelines from ASCO/CAP, ESMO, and other organizations define HER2-low inconsistently, leading to variable interpretations in clinical practice and potential missed treatment opportunities
• Quantitative testing technologies (e.g., immunofluorescence, RNA detection) have the potential to overcome the limitations of traditional IHC by providing continuous numerical values instead of categorical scores, thereby improving result reproducibility
• Current HER2 testing workflows lack a clear definition of HER2-ultralow (near IHC 0) status, which may affect patient enrollment and efficacy prediction
• Future companion diagnostics should evolve toward standardization, automation, and quantification to support precise identification of patients who benefit from ADC therapy

Research Significance and Prospects

The article emphasizes the urgency of redefining HER2 testing standards in the ADC era. While traditional companion diagnostic methods are effective in HER2-high tumors, they face sensitivity limitations in identifying HER2-low patients. As T-DXd indications expand to gastric, lung, and other solid tumors, a unified and precise testing standard is essential for broadening treatment accessibility. Future efforts should focus on validating the clinical utility of quantitative methods through multicenter studies and establishing cross-platform standardization.

The study calls for collaboration between the pathology community and pharmaceutical companies to develop next-generation companion diagnostics that incorporate testing technologies with broader dynamic ranges, reducing human interpretation bias. Additionally, exploring the potential of monitoring HER2 expression in blood samples or integrating multi-omics data to improve predictive accuracy represents a promising research direction. The ultimate goal is to enable individualized assessment of HER2 expression profiles, allowing more patients to benefit from targeted therapies.

 

 

Conclusion

This article comprehensively reviews the evolution of HER2 testing technologies and their pivotal role in companion diagnostics. As the antibody–drug conjugate T-DXd demonstrates significant efficacy in HER2-low tumors, the limitations of traditional immunohistochemistry in interpreting low-level expression are increasingly evident, including high subjectivity, narrow dynamic range, and inconsistent standards across tumor types. The article highlights that current HER2 testing systems struggle to accurately differentiate IHC 0 from 1+, potentially causing patients to miss effective treatment opportunities. The authors emphasize the need to advance the clinical translation of quantitative testing technologies (e.g., immunofluorescence, RNA detection) and establish standardized, automated interpretation workflows to improve result reproducibility and accuracy. Furthermore, tumor-specific scoring criteria should be developed to accommodate unique expression patterns. Ultimately, the evolution of companion diagnostics will enable more precise patient stratification, optimize targeted therapy strategies, and improve outcomes for patients with solid tumors。

 

Charles J Robbins, Katherine M Bates, and David L Rimm. HER2 testing: evolution and update for a companion diagnostic assay. Nature reviews. Clinical oncology.