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Low interobserver agreement among subspecialised breast pathologists in evaluating HER2-low breast cancer
  1. Gulisa Turashvili1,
  2. Yuan Gao1,
  3. Di (Andy) Ai1,
  4. Abdulwahab M Ewaz1,
  5. Sandra Gjorgova Gjeorgjievski1,
  6. Qun Wang1,
  7. Thi T A Nguyen1,
  8. Chao Zhang2,
  9. Xiaoxian Li1
  1. 1Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia, USA
  2. 2General Dynamics Information Technology Inc, Falls Church, Virginia, USA
  1. Correspondence to Xiaoxian Li, Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia, USA;{at}


Aims Metastatic HER2-low breast cancer (HLBC) can be treated by trastuzumab deruxtecan. Assessment of low levels of HER2 protein expression suffers from poor interobserver reproducibility. The aim of the study was to evaluate the interobserver agreement among subspecialised breast pathologists and develop a practical algorithm for assessing HLBC.

Methods Six breast pathologists (4 juniors, 2 seniors) evaluated 106 HER2 immunostained slides with 0/1+expression. Two rounds (R1, R2) of ring study were performed before and after training with a modified Ki-67 algorithm, and concordance was assessed.

Results Agreement with 5% increments increased from substantial to almost perfect (R1: 0.796, R2: 0.804), and remained substantial for three categories (<1% vs 1%–10% vs >10%) (R1: 0.768, R2: 0.764). Seniors and juniors had almost perfect agreement with 5% increments (R1: 0.859 and 0.821, R2: 0.872 and 0.813). For the three categories, agreement remained almost perfect among seniors (R1: 0.837, R2: 0.860) and substantial among juniors (R1: 0.792, R2: 0.768). Binary analysis showed suboptimal agreement, decreasing for both juniors and seniors from substantial (R1: 0.650 and 0.620) to moderate (R2: 0.560 and 0.554) using the 1% cut-off, and increasing from moderate to substantial (R1: 0.478, R2: 0.712) among seniors but remaining moderate (R1: 0.576, R2: 0.465) among juniors using the 10% cut-off. The average scoring time per case was higher (72 vs 92 s).

Conclusions Subspecialised breast pathologists have suboptimal agreement for immunohistochemical evaluation of HLBC using the modified Ki-67 methodology. An urgent need remains for a new assay/algorithm to reliably evaluate HLBC.

  • Breast Neoplasms
  • Breast Diseases

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • Handling editor L C Collins.

  • Contributors Conception or design of the work: XL. Assessment of immunohistochemical staining: GT, DAA, AME, SGG, QW and XL. Data collection: YG and TTAN. Statistical analysis: CZ. Data interpretation: GT and XL. Drafting the article: GT and XL. Critical revision of the article: all authors. Final approval of the version to be published: all authors. Author responsible for the overall content as the guarantor: XL.

  • Funding This study was funded by the College of American Pathologists Foundation 2022 Young Investigator HER2 Research Award, sponsored by AstraZeneca and Daiichi Sankyo (XL).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.