Independent Clinical Validation of the Automated Ki67 Scoring Guideline from the International Ki67 in Breast Cancer Working Group.

Ceren Boyaci,Stephanie Robertson,Wenwen Sun,Johan Hartman,Balazs Acs

doi:10.3390/biom11111612

Ceren Boyaci, Stephanie Robertson + Show 3 more

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https://doi.org/10.3390/biom11111612

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Abstract

Ki67 is an important biomarker with prognostic and potential predictive value in breast cancer. However, the lack of standardization hinders its clinical applicability. In this study, we aimed to investigate the reproducibility among pathologists following the guidelines of the International Ki67 in Breast Cancer Working Group (IKWG) for Ki67 scoring and to evaluate the prognostic potential of this platform in an independent cohort. Four algorithms were independently built by four pathologists based on our study cohort using an open-source digital image analysis (DIA) platform (QuPath) following the detailed guideline of the IKWG. The algorithms were applied on an ER+ breast cancer study cohort of 157 patients with 15 years of follow-up. The reference Ki67 score was obtained by a DIA algorithm trained on a subset of the study cohort. Intraclass correlation coefficient (ICC) was used to measure reproducibility. High interobserver reliability was reached with an ICC of 0.938 (CI: 0.920–0.952) among the algorithms and the reference standard. Comparing each machine-read score against relapse-free survival, the hazard ratios were similar (2.593–4.165) and showed independent prognostic potential (p ≤ 0.018, for all comparisons). In conclusion, we demonstrate high reproducibility and independent prognostic potential using the IKWG DIA instructions to score Ki67 in breast cancer. A prospective study is needed to assess the clinical utility of the IKWG DIA Ki67 instructions.

Highlights

Ki67 is a non-histone protein that plays an important role both in cell division and during interphase, while its localization in the nucleus changes constantly [1]
Twenty-seven tumors were histological the tumortumor diameter was 22was mm.22Twenty-seven tumors were histological grade 1, grade 1, 84 tumors were grade 2 and 46 tumors were grade 3 according to the Nottingham tumors were grade 2 and 46 tumors were grade 3 according to the Nottingham histohistological score
The pathological tumor-node-metastasis classification based on the on the eighth edition of the American Joint Committee on Cancer (AJCC) breast cancer eighth edition of the American Joint Committee on Cancer (AJCC) breast cancer staging staging system showed that 63 cases were pT1, 86 cases were pT2 and 8 cases were pT3

Summary

Introduction

Ki67 is a non-histone protein that plays an important role both in cell division and during interphase, while its localization in the nucleus changes constantly [1]. Ki67 is often used to evaluate cell proliferation by assessment of protein expression in actively dividing cells based on immunohistochemistry, which is an accessible technique. Ki67 is scored by calculating the percentage of positively stained tumor cells, generally referred to as the “Ki67 proliferation index”. The immunohistochemical determination of Ki67 gained increased attention after the proposal from the St. Gallen consensus guideline statement in 2011, where Ki67 was recommended to be used for dividing breast cancers into “surrogate intrinsic subtypes”. The usage of Ki67 in breast cancer management has thereafter been controversial but holds a promising role in the prediction of chemotherapy response [3]

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