Sequencing ADCs in HER2-Low and -Ultralow mBC: Clinical Considerations and Emerging Evidence

HER2 Testing Evolution and Clinical Implementation

HER2 testing has evolved significantly with the introduction of HER2-ultralow categories, requiring updated pathology protocols and clinical team coordination. The transition from traditional HER2 0/1+/2+/3+ reporting to include ultralow designation necessitated immediate communication between oncology and pathology departments following regulatory approvals. Practical implementation involves requesting pathologists to reexamine archived tissue specimens for any HER2 membrane staining in patients previously reported as HER2 0.

Tumor heterogeneity presents ongoing challenges in HER2 assessment, with documented spatial and temporal variation in HER2 expression within individual patients and even within single organs. Results from autopsy studies demonstrate significant heterogeneity within liver metastases, highlighting the limitations of single-site biopsies for comprehensive tumor characterization. Clinical practice adapts by maximizing use of available tissue rather than subjecting patients to additional biopsies when possible.

Recent College of American Pathologists guideline updates provide standardized reporting frameworks for HER2-ultralow designation, with pathologists now specifically noting presence or absence of membrane staining in HER2 0 cases. This enhanced reporting enables oncologists to identify patients eligible for HER2-targeted antibody-drug conjugate therapy without requiring repeat biopsies. The evolution toward more nuanced HER2 reporting reflects the expanding therapeutic relevance of subtle HER2 expression differences.