Approval For The Proliferative Marker Ki-67 As An Integrated Biomarker For Endometrial Cancer In Nrg Study Gy011.

Introduction: NRG Study GY011 is a surgical window trial of medroxy-progesterone acetate (MPA) +/- entinostat (E), a histone deacetylase inhibitor hypothesized to upregulate PR levels through epigenetic modifications. The principal goal of this trial was to determine the impact of treatment on the level as well as the activity of progesterone receptors (PR) in women with endometrial cancer. However, a reliable marker for PR activity was needed, and the most promising choice was Ki-67. To be approved for inclusion in the study as an integrated biomarker, Ki-67 had to first undergo rigorous evaluation by the participating pathologists with oversight by the NIH Biomarker Review Committee. Methods: Fifty patients were enrolled on GY011, and specimen collection was planned by biopsy prior to receiving study drugs and by tissue sample at the time of the hysterectomy. There were 42 pre-drug administration specimens with tumor for analysis and 1 without and 43 hysterectomy specimens with tumor. Ki-67 immunohistochemistry performed on pre and post drug specimens was evaluated by three experienced reviewers (MS, KC and AR) using a qualitative approach, blinded to treatment arm. Pre and post-drug samples for each individual patient were compared and scored as increased, decreased, or unchanged. The Fleiss kappa statistic was chosen as the measure of concordance as it allows for more than two reviewers and more than two categories. Percent agreement and standard weighted kappa statistics were calculated for individual pairs of reviewers. Results: There was very good concordance between reviewers using the qualitative comparison of post to pre-drug Ki-67 staining with Fleiss’ Kappa of 0.91 and weighted Kappa’s ranging between 0.85 and 0.95. Reviewers 1 and 2 had the highest level of concordance. Reviewer agreement ranged from 0.92 to 0.98. The reviewer-specific (marginal) score distributions were similar. Each reviewer scored about 80% (79.5%-82.5%) of pairs as decreasing, with the remainder split similarly between no change (7.5%-10%) and increasing (10%-12.8%). Conclusion: Based upon the high concordance between reviewers, the NIH Biomarker Review Committee approved Ki-67 as an integrated biomarker for GY011, setting the stage for its use as an approved biomarker of therapeutic effectiveness in future endometrial cancer trials. Citation Format: Megan I. Samuelson, Virginia Filiaci, Kelley Carrick, Anand Rajan KD, William H. Rodgers, Kristina W. Thiel, Linda R. Duska, Kimberly K. Leslie. Approval for the proliferative marker Ki-67 as an integrated biomarker for endometrial cancer in NRG study GY011 [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO020.