Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
Breast Cancer Res Treat. 2024 Aug;207(1):1-12. doi: 10.1007/s10549-024-07352-4. Epub 2024 May 26.
Quantification of Ki67 in breast cancer is a well-established prognostic and predictive marker, but inter-laboratory variability has hampered its clinical usefulness. This study compares the prognostic value and reproducibility of Ki67 scoring using four automated, digital image analysis (DIA) methods and two manual methods.
The study cohort consisted of 367 patients diagnosed between 1990 and 2004, with hormone receptor positive, HER2 negative, lymph node negative breast cancer. Manual scoring of Ki67 was performed using predefined criteria. DIA Ki67 scoring was performed using QuPath and Visiopharm® platforms. Reproducibility was assessed by the intraclass correlation coefficient (ICC). ROC curve survival analysis identified optimal cutoff values in addition to recommendations by the International Ki67 Working Group and Norwegian Guidelines. Kaplan-Meier curves, log-rank test and Cox regression analysis assessed the association between Ki67 scoring and distant metastasis (DM) free survival.
The manual hotspot and global scoring methods showed good agreement when compared to their counterpart DIA methods (ICC > 0.780), and good to excellent agreement between different DIA hotspot scoring platforms (ICC 0.781-0.906). Different Ki67 cutoffs demonstrate significant DM-free survival (p < 0.05). DIA scoring had greater prognostic value for DM-free survival using a 14% cutoff (HR 3.054-4.077) than manual scoring (HR 2.012-2.056). The use of a single cutoff for all scoring methods affected the distribution of prediction outcomes (e.g. false positives and negatives).
This study demonstrates that DIA scoring of Ki67 is superior to manual methods, but further study is required to standardize automated, DIA scoring and definition of a clinical cut-off.
乳腺癌中 Ki67 的定量分析是一种经过充分验证的预后和预测标志物，但由于实验室间的差异，其临床应用受到了阻碍。本研究比较了四种自动化数字图像分析（DIA）方法和两种手动方法评估 Ki67 评分的预后价值和可重复性。
研究队列由 1990 年至 2004 年间诊断的 367 例激素受体阳性、HER2 阴性、淋巴结阴性乳腺癌患者组成。采用预设标准进行 Ki67 手动评分。使用 QuPath 和 Visiopharm®平台进行 DIA Ki67 评分。采用组内相关系数（ICC）评估重复性。ROC 曲线生存分析确定了最佳截止值，此外还参考了国际 Ki67 工作组和挪威指南的建议。Kaplan-Meier 曲线、对数秩检验和 Cox 回归分析评估了 Ki67 评分与远处转移（DM）无复发生存之间的关系。
与对应的 DIA 方法相比，手动热点和全局评分方法显示出良好的一致性（ICC>0.780），不同 DIA 热点评分平台之间显示出良好到极好的一致性（ICC 0.781-0.906）。不同的 Ki67 截止值显示出显著的 DM 无复发生存差异（p<0.05）。使用 14%的截止值（HR 3.054-4.077）进行 DIA 评分对 DM 无复发生存的预测价值大于手动评分（HR 2.012-2.056）。使用所有评分方法的单一截止值会影响预测结果的分布（例如假阳性和假阴性）。
本研究表明，DIA 评分 Ki67 优于手动方法，但需要进一步研究以标准化自动化、DIA 评分和临床截止值的定义。
