Discerning subsets of breast cancer with very low and absent HER2 protein expression

Area of Science:

• Oncology
• Pathology
• Molecular Diagnostics

Background:

• Current anti-HER2 therapies target breast cancers with ERBB2 gene amplification and HER2 protein overexpression.
• Emerging anti-HER2 antibody-drug conjugates show efficacy in low HER2-expressing breast cancers, necessitating better definition of this subgroup.
• The traditional binary HER2 scoring system may be insufficient for stratifying patients with low HER2 expression.

Purpose of the Study:

• To conduct a quality review of HER2 immunohistochemical (IHC) scoring in breast carcinomas with low HER2 expression.
• To assess the feasibility of distinguishing complete absence of HER2 expression from "very low" HER2 expression.
• To evaluate the impact of magnification on HER2 scoring accuracy and identification of low-expressing cases.

Main Methods:

• Quality review of HER2 IHC scoring on 71 core biopsies and 51 excisions from breast carcinomas.
• Rescoring of HER2 status at 200× and 400× magnification.
• Investigation into differentiating complete HER2 absence from "very low" HER2 expression (HER2(1+)).

Main Results:

• Substantial agreement in HER2 rescoring was achieved at 200× magnification, with near-perfect agreement at 400×.
• 400× magnification identified more cases with HER2 expression and facilitated recognition of "very low" expression.
• Complete absence of HER2 protein expression was observed in less than 10% of cases.

Conclusions:

• Enhanced microscopic examination (400×) improves the accuracy and granularity of HER2 scoring in breast carcinomas.
• A "very low" HER2 expression category is feasible to implement in routine pathology workflows.
• Refined HER2 reporting is essential for optimizing patient selection for novel anti-HER2 therapies.