HER2-low and ultralow breast cancer: interobserver challenges and lessons from a consensus study

Area of Science:

• Oncology
• Pathology
• Biomarker Analysis

Background:

• Trastuzumab deruxtecan approval for HER2-low/ultralow breast cancer necessitates accurate assessment.
• HER2 (human epidermal growth factor receptor 2) expression levels are critical for treatment selection.

Purpose of the Study:

• To evaluate inter-observer variability among pathologists in diagnosing HER2-low and HER2-ultralow breast cancer.
• To assess the consistency of HER2 expression classification in clinical practice.

Main Methods:

• Seven breast pathologists reviewed virtual whole slide images (WSI) of HER2 immunohistochemistry.
• Consensus diagnoses were established through in-depth discussion and real-time WSI visualization.

Main Results:

• Only 33.3% of cases achieved unanimous agreement; 53.3% showed significant disagreement among pathologists.
• All HER2-null cases were reclassified as HER2-ultralow post-consensus, suggesting underclassification.
• Discrepancies highlight challenges in distinguishing HER2-low and HER2-ultralow categories.

Conclusions:

• Significant expert discrepancies exist in interpreting HER2-low/ultralow breast cancer status.
• The clinical necessity of distinguishing HER2-low from HER2-ultralow requires further investigation.
• The existence of true HER2-null breast cancer warrants re-evaluation.