The landscape of cancer diagnostics has witnessed transformative advancements, particularly in the realm of human epidermal growth factor receptor 2 (HER2) testing. Initially pivotal in breast cancer management, HER2 has emerged as a critical biomarker across an expanding spectrum of solid tumors. The journey of HER2 testing from rudimentary detection techniques to sophisticated, quantitative methods showcases a relentless pursuit of precision medicine, where accurately identifying HER2 status can decisively influence therapeutic outcomes. This evolving paradigm, underscored by the advent of novel HER2-targeted therapies, demands a thorough reexamination of testing modalities to ensure clinical relevance and efficacy.
Historically, HER2 testing was grounded in techniques such as western blotting and immunohistochemistry (IHC), which served as the backbone for patient stratification in trastuzumab therapy. The introduction of HercepTest marked a milestone, establishing a standardized companion diagnostic that enabled reliable detection of HER2 protein overexpression. However, as clinical applications broadened and the spectrum of HER2 expression became more nuanced, the limitations of these methods started to surface. For instance, traditional IHC, while practical and widely accessible, often grapples with issues of subjectivity and semi-quantitative interpretation, which can affect the accuracy of HER2 status determination.
Fluorescence in situ hybridization (FISH) complemented IHC by providing gene amplification analysis, adding a genomic dimension to HER2 assessment. The integration of FISH helped resolve equivocal cases in IHC and enriched diagnostic confidence. Despite this symbiosis, both IHC and FISH remained largely qualitative or semi-quantitative techniques, which may be insufficient for capturing the complexity of HER2 expression, particularly in tumors exhibiting low or borderline levels. This gray zone of “HER2-low” expression has gained spotlight due to its therapeutic implications with next-generation HER2-targeted agents.
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The therapeutic landscape itself has experienced a paradigm shift with the emergence of antibody–drug conjugates (ADCs) such as trastuzumab deruxtecan. Unlike conventional HER2-targeted therapies requiring high-level HER2 expression, ADCs demonstrate efficacy even in tumors classified as HER2-low, a group previously not considered candidates for HER2-directed treatment. This breakthrough has ignited a series of challenges and opportunities in HER2 testing, emphasizing the necessity for refined diagnostic criteria and more sensitive, quantitative assay technologies that can discern subtle but clinically significant HER2 expression.
In light of these advances, the oncology community is increasingly advocating for revisiting HER2 testing algorithms to embrace quantitative methods that transcend traditional IHC scoring systems. Quantitative immunofluorescence (QIF) emerges as a promising avenue, leveraging fluorescence-based detection to provide continuous, objective measurements of HER2 protein levels. This approach reduces interobserver variability and enhances reproducibility, facilitating a finer stratification of patients. Similarly, RNA-based assays investigating ERBB2 mRNA expression offer complementary molecular insights, enabling a multi-layered diagnostic strategy that bridges protein expression and gene transcription dynamics.
Moreover, the integration of digital pathology and artificial intelligence offers additional layers of precision in HER2 testing. Advanced image analysis algorithms can assess staining intensity and distribution with unprecedented granularity, potentially automating the interpretation process and minimizing human error. These technologies promise to harmonize diagnostic workflows across laboratories worldwide, fostering consistency that is vital for therapeutic decision-making in heterogeneous clinical settings.
The clinical guidelines governing HER2 testing across various solid tumors are in flux, adapting to incorporate insights from evolving methodologies and therapeutic paradigms. Breast cancer remains the prototypical disease model, but HER2 testing has become increasingly relevant in gastric, gastroesophageal, and even colorectal cancers. This expansion underscores the importance of assay adaptability and validation across tissue types, considering the variable biology and HER2 expression patterns encountered outside breast malignancies.
Challenges persist, particularly in harmonizing assay performance, establishing robust cutoff thresholds, and defining the clinical significance of HER2-low categories. The variability in pre-analytical factors such as tissue handling, fixation duration, and staining protocols further complicates accurate HER2 quantification. Consequently, consensus-building efforts among pathologists, oncologists, and assay developers are paramount to calibrate testing standards that can reliably guide therapy choices.
The stakes of precise HER2 testing are high, given that it directly influences patient eligibility for life-extending HER2-targeted therapies. Misclassification can lead to under-treatment or unnecessary exposure to potential toxicities without benefit. Therefore, ongoing research and clinical trials continue to refine the therapeutic indices that optimize patient outcomes while balancing safety and efficacy.
In conclusion, the evolution of HER2 testing epitomizes the dynamic interplay between diagnostic innovation and targeted therapy development. Moving forward, the adoption of fully quantitative and multiplexed assays promises to revolutionize the companion diagnostic landscape, facilitating tailored treatment strategies that are attuned to the nuanced biology of HER2 expression. As the oncology field embraces these advancements, the precision of HER2 status determination will be pivotal in unlocking the full potential of next-generation HER2-targeted therapies, ultimately enhancing the prognosis and quality of life for patients across a broad array of cancer types.
Subject of Research: HER2 testing evolution and its role as a companion diagnostic assay in guiding targeted therapies across various solid tumors.
Article Title: HER2 testing: evolution and update for a companion diagnostic assay
Article References:
Robbins, C.J., Bates, K.M. & Rimm, D.L. HER2 testing: evolution and update for a companion diagnostic assay.
Nat Rev Clin Oncol 22, 408–423 (2025). https://doi.org/10.1038/s41571-025-01016-y
Image Credits: AI Generated
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