The Future of HER2 Testing: Why Accurate ‘HER2-Low’ Detection is Crucial for Targeted Breast Cancer Therapy
Nearly 70% of breast cancers exhibit HER2 alterations, but a growing challenge lies in accurately identifying those with low levels of the protein. A recent study, CASI-01, reveals that current immunohistochemistry (IHC) assays, while reliable for detecting HER2-positive tumors, struggle with the nuances of HER2-low expression – a critical distinction now that therapies like trastuzumab deruxtecan (T-DXd, Enhertu) are proving effective in this patient population. This isn’t just a technical issue; it’s a matter of ensuring the right patients receive potentially life-saving treatment.
Understanding the HER2 Landscape: Beyond Positive and Negative
For years, HER2 status in breast cancer was largely categorized as positive or negative. HER2-positive cancers have an overabundance of the HER2 protein, driving aggressive growth. HER2-negative cancers, conversely, have low expression. However, the landscape is far more complex. We now recognize four distinct subtypes: HER2-positive, HER2-negative, HER2-low, and HER2 ultra-low. The emergence of HER2-low as a clinically relevant category, particularly with the success of T-DXd, has exposed limitations in existing diagnostic methods.
The Challenge of Detecting Low HER2 Expression
Traditional IHC assays were designed to identify high levels of HER2 protein. Detecting subtle variations in HER2 expression – the hallmark of HER2-low and ultra-low cancers – requires significantly greater sensitivity. The CASI-01 study highlighted substantial variability in assay sensitivity across 54 laboratories, with detection thresholds ranging from 30,000 to 60,000 HER2 molecules per cell. This wide range means a patient’s HER2 status, and therefore their eligibility for targeted therapies, could depend on where their test is performed.
CASI-01: A Wake-Up Call for Standardization
The Consortium for Analytic Standardization in Immunohistochemistry (CASI) launched the CASI-01 trial to address this critical issue. Researchers compared standard FDA-cleared IHC assays with more sensitive tests, utilizing both pathologist assessment and cutting-edge image analysis. The findings were stark: while current assays maintain high sensitivity (85.7%) and specificity (100%) for HER2-positive cases, their performance falters significantly when classifying HER2-low tumors due to a limited dynamic range.
However, the study also offered a path forward. Higher-sensitivity assays, coupled with image analysis, demonstrated a six-fold improvement in accurate HER2-low detection (P = .0017). This suggests that technological advancements can bridge the gap and ensure more patients benefit from targeted therapies.
The Role of Image Analysis in Precision Diagnostics
The CASI-01 results underscore the potential of image analysis to move beyond traditional pathologist scoring. Objective, quantitative analysis of IHC slides can provide a more precise and reproducible assessment of HER2 expression levels. This is particularly crucial for HER2-low cancers, where subtle differences in protein expression can significantly impact treatment decisions. As Emina Torlakovic, MD, PhD, a study co-author, noted, “Whereas current methods of IHC assay validation are insufficient to support the needs of precision medicine, by enabling an objective quantification of analytical sensitivity, we can now reliably evaluate the accuracy and precision of IHC assays for targeted therapies.”
Looking Ahead: The Future of HER2 Testing
The era of HER2-low therapies demands a new standard in diagnostic accuracy. Simply reporting a HER2 status is no longer sufficient. Laboratories must also report their assay’s analytic sensitivity and dynamic range, providing clinicians with the information they need to interpret results with confidence. Furthermore, the integration of image analysis into routine IHC workflows is poised to become increasingly prevalent.
Beyond technological advancements, a broader shift towards standardized protocols and quality control measures is essential. As Steve Bogen, MD, PhD, emphasized, “A patient’s treatment options should not depend on which lab performs their test.” This requires collaborative efforts across the diagnostic community to ensure consistent and reliable HER2 testing, regardless of location.
The future of HER2 testing isn’t just about identifying more HER2-low cancers; it’s about delivering truly personalized breast cancer care. By embracing innovation and prioritizing standardization, we can unlock the full potential of targeted therapies and improve outcomes for countless patients. What advancements in precision medicine do you foresee impacting breast cancer diagnostics in the next five years? Share your thoughts in the comments below!
