Discordance between Immunohistochemistry and ERBB2 mRNA to Determine HER2 Low Status for Breast Cancer

Novel HER2-directed antibody-drug conjugates (ADC) have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with IHC scores of 1+ or 2+ with a negative ISH assay. However, current HER2 testing methods are designed to identify HER2 amplified tumors with “high” expression levels. The true definition of “HER2-low” expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. ERBB2 mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI: 0.36,0.57), 0.58 (95% CI: 0.26,0.70), and 0.32 (95% CI: -0.12,0.75) when comparing IHC 0+ without staining vs IHC 0+ with some staining, IHC 0+ with some staining vs IHC 1+, and IHC 1+ vs IHC 2+/FISH-ve, respectively. The results showed that immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggest that a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response need to be further evaluated by prospective clinical trials.