The Ki67 dilemma: investigating prognostic cut-offs and reproducibility for automated Ki67 scoring in breast cancer
Adult
Aged, 80 and over
0301 basic medicine
Research
Reproducibility of Results
Breast Neoplasms
Kaplan-Meier Estimate
Middle Aged
Prognosis
Ki-67 Antigen
0302 clinical medicine
ROC Curve
Biomarkers, Tumor
Humans
Female
Aged
DOI:
10.1007/s10549-024-07352-4
Publication Date:
2024-05-26T19:01:26Z
AUTHORS (6)
ABSTRACT
Abstract
Purpose
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.
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.
Results
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).
Conclusion
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.
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