The evolving landscape of breast cancer treatment has exposed significant challenges in the current standards of HER2 testing, with leading pathologists calling for urgent reforms in immunohistochemistry (IHC) testing protocols. As new targeted therapies emerge for various levels of HER2 expression, the accuracy and consistency of diagnostic testing have become increasingly critical for patient care.
"We should not be forced to issue diagnoses that lead to $100,000 therapies that are no more reproducible than the flip of a coin," stated David Rimm, MD, PhD, and colleagues in a January 2023 editorial published in Archives of Pathology and Laboratory Medicine. Rimm serves as the Anthony N. Brady Professor of Pathology at Yale School of Medicine.
Testing Accuracy Challenges
The current classification system for HER2 expression has become increasingly nuanced. While traditionally, IHC scores of 3+ indicated HER2-positive status and scores of 0 or 1+ suggested HER2-negative disease, the introduction of HER2-low categories (IHC 1+ or 2+/ISH-) has complicated the diagnostic landscape. Pathologists now face the additional challenge of distinguishing between HER2-ultralow and HER2-negative cases.
"Being asked to distinguish 0 from 1+ was already [a challenge]. Now, they're asking us to distinguish a 0.5+ from a 0. [This] certainly is not well thought out, because we already couldn't tell 0 from 1. It is baffling to me that they would move in this direction," Rimm explained.
Regulatory Reform Needed
The National Society for Histotechnology (NSH) has endorsed proposals to reform IHC regulations, emphasizing that the current classification of IHC as a "stain" rather than a diagnostic assay is outdated. This classification has led to insufficient quality assurance requirements and inconsistent results across laboratories.
Dr. Barbarajean Magnani of Tufts University School of Medicine emphasized, "Any accrediting organizations should view [IHC] not as a stain, but as an immunoassay, because we're using it differently than we did 40 years ago."
Clinical Implications
The accuracy of HER2 testing has taken on new importance with the approval of targeted therapies like fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). The recent DESTINY-Breast06 trial demonstrated significant benefits of T-DXd in both HER2-low and HER2-ultralow patients, highlighting the critical need for precise testing.
Dr. Ian Krop of Yale Cancer Center noted during the 2024 ASCO Annual Meeting, "Current IHC testing is relatively poor at distinguishing HER2-low and -ultralow cancers from HER2 0 cancers. The original test was designed to distinguish high levels of HER2 [IHC 3+] from all the lower levels."
Moving Toward Solutions
Pathologists are advocating for several key changes:
- Standardization of testing protocols across laboratories
- Implementation of more rigorous quality control measures
- Development of more objective measurement methods
- Updated regulatory framework treating IHC as a diagnostic assay
"We need to have tests be designed in such a way that if they're intended to be read by pathologists, they need to optimize the pathologist's ability to reproduce [the results]," Rimm stated, suggesting a shift from subjective readings to standardized measurements.
The implications of inaccurate testing extend beyond clinical outcomes to include significant financial consequences for patients and healthcare systems. As the field continues to advance with more targeted therapies, the need for precise and reliable HER2 testing becomes increasingly critical for optimal patient care.
