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Updated: May 28, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Concordance of conventional two-tier HER2 classification versus three-tier classification (including HER2-low status)
Archita Juneja1,2, Ayushi Sahay3,2, Pooja Padwale1,2
1Homi Bhabha National Institute, Mumbai, Maharashtra, India.
Aim:
To compare changes in HER2 expression status on reassessment across multiple clinical groups using new three-tier versus traditional binary HER2 reporting schemas.
Methods:
Retrospective study of 1107 paired IBC samples wherein HER2 immunohistochemistry (IHC) and, where needed, in-situ hybridisation (ISH) were performed at least twice in four clinical groups: core needle biopsy (CNB)-upfront resection (n=277); CNB-post-chemotherapy resection (n=104); primary (CNB/resection)-recurrence (local/metastatic, n=702); initial and subsequent distant metastasis (n=24). Concordance was noted for HER2-positive (HER2-IHC 3+ or 2+ ISH-amplified), negative (HER2-IHC 0) and low (HER2-IHC 1+ and 2+ ISH-non-amplified) status, and compared with the concordance of binary HER2 status (positive/negative).
Results:
HER2 concordance dropped sharply to 69.7% (k=0.53, 95% CI 0.48 to 0.57) on reassessment after applying the three-tier schema, driven primarily by bidirectional shifts between HER2-negative (IHC 0) and HER2-low. Referral specimens showed poorer concordance than in-house tissue in both binary (p value <0.001, OR: 2.40, 95% CI 1.40 to 4.10) and ternary classification (p value <0.001, OR: 1.72, 95% CI 1.31 to 2.2), emphasising the effects of pre-analytical factors like fixation on HER2 interpretation.
Conclusions:
The three-tier HER2-low classification schema demonstrates poor reproducibility on re-evaluation, with nearly one-third of cases discordant. This fluidity has significant therapeutic implications. We recommend HER2 re-evaluation with careful attention to the 0 versus 1+ distinction, especially in metastatic and post-treatment settings and when pre-analytical factors are suboptimal.