Optimization of Window Study Endpoints in Endometrial Cancer.

Sarah J Kitson,Zoe Maskell,Emma J Crosbie,Joseph Shaw,Vanitha N Sivalingam

doi:10.3389/fonc.2019.00428

Abstract

Pre-surgical window studies rely on the accurate quantification of biomarkers as surrogates of disease response. In endometrial cancer, this has traditionally involved comparing immunohistochemical expression in diagnostic endometrial biopsies with the post-treatment hysterectomy specimen. This strategy is at risk of generating erroneous results if significant hypoxia occurs during surgery or delays in fixation of tissues lead to protein loss. Immunohistochemical expression of commonly studied biomarkers in window studies were compared in pre-operative endometrial biopsies and hysterectomy specimens taken on the same day from 75 women with endometrial cancer enrolled in a clinical trial. Differences in expression were correlated with clinico-pathological variables and tissue handling. Expression of Ki-67, markers of the PI3K-Akt-mTOR, and insulin signaling pathways and hormone receptors was significantly lower in the hysterectomy specimen than the corresponding endometrial biopsy (all p < 0.0001). In contrast, expression of the cancer stem cell markers, CD133 and ALDH, were similar in the two specimens. The extent to which protein expression was lost in the hysterectomy specimen was closely correlated with baseline expression in the endometrial biopsy (all p ≤ 0.001). Bisection of the uterus prior to placement in formalin partially preserved protein expression suggesting prompt fixation is critical. These results call into question findings from earlier endometrial cancer window studies which have relied on the hysterectomy specimen for analysis and suggest a post-intervention endometrial biopsy should be included in trials going forward.

Highlights

There is increasing interest in the use of the pre-surgical window study design to determine the efficacy of novel and repurposed cancer therapeutics in a time- and cost-effective manner
In order to investigate the extent to which delays in achieving adequate tissue fixation were responsible for loss of immunohistochemical expression in the hysterectomy specimen, differences in staining were correlated with specimen characteristics and tissue handling (Table 4)
There was a trend toward smaller differences in immunohistochemical expression between endometrial biopsies and the hysterectomy specimen if the uterus had been bisected prior to being placed in formalin, with the exception of p4EBP1, this did not reach statistical significance

Summary

Introduction

There is increasing interest in the use of the pre-surgical window study design to determine the efficacy of novel and repurposed cancer therapeutics in a time- and cost-effective manner. Such a strategy relies on the accurate quantification of biomarkers, which act as surrogates for longer term clinical outcomes and disease response. In endometrial cancer, this has traditionally involved comparing a baseline endometrial biopsy with tumor sampled from the hysterectomy specimen following intervention. Reliance on surgically excised specimens for accurate readouts of tumor biology could, be risky [5]

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Conclusion