Prognostic potential of automated Ki67 evaluation in breast cancer: different hot spot definitions versus true global score

Abstract

Purpose The proliferation-associated biomarker Ki67 has potential utility in breast cancer, including aiding decisions based on prognosis, but has unacceptable inter-and intralaboratory variability. The aim of this study was to compare the prognostic potential for Ki67 hot spot scoring and global scoring using different digital image analysis (DIA) platforms. Methods An ER+/HER2− breast cancer cohort (n = 139) with whole slide images of sequential sections stained for hematoxylin-eosin, pancytokeratin and Ki67, was analyzed using two DIA platforms. For hot spot analysis virtual dual staining was applied, aligning pancytokeratin and Ki67 images and 22 hot spot algorithms with different features were designed. For global Ki67 scoring an automated QuPath algorithm was applied on Ki67-stained whole slide images. Clinicopathological data included overall survival (OS) and recurrence-free survival (RFS) along with PAM50 molecular subtypes. Results We show significant variations in Ki67 hot spot scoring depending on number of included tumor cells, hot spot size, shape and location. The higher the number of scored tumor cells, the higher the reproducibility of Ki67 proliferation values. Hot spot scoring had greater prognostic potential for RFS in high versus low Ki67 subgroups (hazard ratio (HR) 6.88, CI 2.07-22.87, p = 0.002), compared to global scoring (HR 3.13, CI 1.41-6.96, p = 0.005). Regarding OS, global scoring (HR 7.46, CI 2.46-22.58, p < 0.001) was slightly better than hot spot scoring (HR 6.93, CI 1.61-29.91, p = 0.009). In adjusted multivariate analysis, only global scoring was an independent prognostic marker for both RFS and OS. In addition, global Ki67-based surrogate subtypes reached higher concordance with PAM50 molecular subtype for luminal A and B tumors (66.3% concordance rate, κ = 0.345), than using hot spot scoring (55.8% concordance rate, κ = 0.250). Conclusions We conclude that the automated global Ki67 scoring is feasible and shows clinical validity, which, however, needs to be confirmed in a larger cohort before clinical implementation.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

“… 16 As an effort to overcome some of these concerns, digital image analysis platforms have been developed and validated. 17 , 18 , 19 …”

Reliability of Ki67 visual scoring app compared to eyeball estimate and digital image analysis and its prognostic significance in hormone receptor‐positive breast cancer

“…This recommendation is further supported by their phase‐3 trial, where the global scoring methods showed better interobserver reproducibility compared to scoring hotspots only [5, 13, 18]. Recently, Robertson et al, reported that automated global Ki67 scoring was a more practical method and demonstrated clinical validity when compared to hotspot scoring [19]. In our study, although the visual scoring app had a feature for hotspot scoring, following recent evidence that global scores are superior to hotspot scores, we focussed only on global scoring.…”

Superpixel Image Segmentation of VISTA&nbsp;Expression in Colorectal Cancer: Implications for Immunotherapy

“…Regarding the use of hotspots for image analysis in our study; studies have found that hotspot analysis to outperform global scoring. Robertsona et al found that hotspot scoring had double the potential for predicting recurrence free survival, in the setting of Ki-67 immunohistochemistry and breast cancer 24 .…”