Ki-67 in endometrial cancer: scoring optimization and prognostic relevance for window studies

Sarah Kitson,Vanitha N Sivalingam,James Bolton,Rhona Mcvey,Mashid Nickkho-Amiry,Melanie E Powell,Alexandra Leary,Hans W Nijman,Remi A Nout,Tjalling Bosse,Andrew G Renehan,Henry C Kitchener,Richard J Edmondson,Emma J Crosbie

doi:10.1038/modpathol.2016.203

Abstract

Ki-67, a marker of cellular proliferation, is increasingly being used in pre-surgical window studies in endometrial cancer as a primary outcome measure. Unlike in breast cancer, however, there are no guidelines standardizing its measurement and its clinical relevance as a response biomarker is undetermined. It is, therefore, imperative that Ki-67 scoring protocols are optimized and its association with patient survival rigorously evaluated, in order to be able to clinically interpret the results of these studies. Using the International Ki-67 in Breast Cancer Working Group guidelines as a basis, whole slide, hot spot and invasive edge scoring protocols were evaluated using endometrial biopsies and hysterectomy specimens from 179 women. Whole sections and tissue microarrays, manual and semi-automated scoring using Definiens Developer software were additionally compared. Ki-67 scores were related to clinicopathological variables and cancer-specific survival in uni- and multivariate analysis. Against criteria of time efficiency, intra- and inter-observer variability and consistency, semi-automated hot spot scoring was the preferred method. Ki-67 scores positively correlated with grade, stage and depth of myometrial invasion (P-values all <0.03). By univariate analysis, higher Ki-67 scores were associated with a significant reduction in cancer-specific survival (P≤0.05); however, this effect was substantially attenuated in the multivariate model. In conclusion, hot spot scoring of whole sections using Definiens is an optimal method to quantify Ki-67 in endometrial cancer window study specimens. Measured this way, it is a clinically relevant marker, though further work is required to determine whether reductions in Ki-67 in neoadjuvant intervention studies translate into improved patient outcome.

Highlights

Despite the rising incidence and corresponding increase in deaths from endometrial cancer, there is Clinical trials require large numbers of participants over long follow-up periods to demonstrate the superiority of one treatment over another on www.modernpathology.org clinically important outcomes, such as overall and cancer-free survival
In cancer types that are amenable to diagnostic sampling, novel interventions can be screened for efficiently using the pre-surgical window study design, whereby tissue endpoints are compared before and after treatment using biomarkers as surrogates for clinical endpoints
The aims of this study were three-fold: to identify the most reliable, reproducible and time efficient method of Ki-67 scoring using the recommendations of the International Ki-67 in Breast Cancer Working Group as a guide;[8] to determine the correlation between Ki-67 and known pathological prognostic variables; and to investigate whether higher Ki-67 expression is associated with a shorter cancerspecific survival and, has clinical value as a biomarker in endometrial cancer trials

Summary

Introduction

Despite the rising incidence and corresponding increase in deaths from endometrial cancer, there is Clinical trials require large numbers of participants over long follow-up periods to demonstrate the superiority of one treatment over another on www.modernpathology.org clinically important outcomes, such as overall and cancer-free survival. Despite ambiguity in the literature about the value of Ki-67 as a biomarker in endometrial cancer, presurgical window studies using a change in Ki-67 as their primary endpoint have begun in earnest.[9,10,11,12,13] Ki-67 expression has been shown to positively correlate with tumor grade,[12,14,15,16] there is a lack of consensus as to whether it has prognostic value.[14,15,16,17,18] Heterogeneity of staining, scoring, and analysis protocols, including the use of studyspecific cut-off values, have hampered the validation of findings in other cohorts and, by extension, hindered the clinical interpretation of results from the aforementioned window studies. Most previous studies were published over 10 years ago, using the superseded FIGO 1988 staging criteria, limiting their applicability to modern clinical research.[17,18]

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