ArticleEBioMedicine2025
New standards in HER2-low testing: the CASI-01 comparative methods study.
Article in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- HER2-low breast cancer in routine practice: a nationwide study of diagnostic variability across pathology laboratories.Virchows Archiv : an international journal of pathology · 2026Article
- Deep learning-based assessment of HER2-ultralow expression in breast cancer: a multi-center validation study across primary and metastatic lesions.Virchows Archiv : an international journal of pathology · 2026Article
- Repurposing HER2 IHC: Pan-HER2 and Low-HER2.Applied immunohistochemistry & molecular morphology : AIMM · 2026Review
- Reduced folate receptor alpha (FOLR1) protein expression in fallopian tubes from premenopausal women: implications for the FOLR1 CDx assay for mirvetuximab-soravtansine therapy.The journal of pathology. Clinical research · 2026Article
- "HER2-Low" and the Challenge of Repurposing Legacy HER2 IHC Biomarker Assays.Current oncology (Toronto, Ont.) · 2026Article
- HER2 Heterogeneity in Breast Cancer: Biological Basis, Clinical Implications, and Therapeutic Strategies.Breast cancer (Dove Medical Press) · 2026Review
- Liquid Biopsy and Multi-Omic Biomarkers in Breast Cancer: Innovations in Early Detection, Therapy Guidance, and Disease Monitoring.Biomedicines · 2025Review
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24 authors.
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Abstract
backgroundThe introduction of Trastuzumab deruxtecan (T-Dxd) has exposed clinically significant limitations in accurately detecting HER2-low expression testing when using immunohistochemistry (IHC) assays originally developed to detect HER2 over-expression. While HER2 testing is widely used to determine T-Dxd eligibility, no HER2-low assay was ever validated against HER2 protein expression.
methodsTo address this pressing need, the Consortium for Analytic Standardization in Immunohistochemistry (CASI) conducted the CASI-01 study, involving 54 IHC laboratories across Europe and the U.S. The study aimed to identify optimal assay conditions for accurate HER2 testing, differentiating between HER2 overexpression (3+) for Trastuzumab eligibility and HER2-low expression (1+ or ultra-low) for T-Dxd eligibility. The conventional FDA-cleared HER2 assay ("predicate") was compared with higher-sensitivity assays using pathologist versus image analysis readouts. HER2 overexpression was validated against HER2 gene amplification via in situ hybridisation (ISH), while HER2-low accuracy was evaluated using newly introduced HER2 reference standards and a novel IHC parameter-dynamic range.
findingsCASI-01 revealed variability in predicate HER2 assays, with detection thresholds ranging from 30,000 to 60,000 among laboratories. Despite this variability, these assays demonstrated high accuracy for identifying HER2 overexpression (3+), with 85.7% (18/21) sensitivity (95% confidence limits 63.66-96.95%) and 100% (49/49) specificity (95% confidence limits 92.75-100%), though sensitivity may have been limited by the use of older tissue specimens, with loss or reduced expression levels of the HER2 protein. However, these same assays exhibited poor dynamic range for detecting HER2-low scores. Enhanced analytic sensitivity of IHC assays combined with image analysis overcame this limitation with HER2-low scores, achieving a six-fold improvement (p = 0.0017).
interpretationIHC assays with detection thresholds in the range of 30,000-60,000 HER2 molecules per cell yield accurate results for determination of Trastuzumab eligibility (HER2 3+) but fail to demonstrate the dynamic range for accurate HER2-low scores. Enhanced analytic sensitivity of HER2 assays combined with image analysis addresses this critical gap in HER2-low testing. More generally, CASI-01 introduces pivotal advancements in precision medicine: (a) the importance of reporting IHC analytic sensitivity and ability to demonstrate an assay dynamic range, and (b) image analysis can surpass pathologist readout accuracy in specific clinical contexts.
fundingThis work was supported by the National Cancer Institute of the National Institutes of Health under Award Number R44CA268484.
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