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Randomized Controlled Trial
. 2021 May 15;27(10):2734-2741.
doi: 10.1158/1078-0432.CCR-20-4618. Epub 2021 Mar 25.

A Surgical Window Trial Evaluating Medroxyprogesterone Acetate with or without Entinostat in Patients with Endometrial Cancer and Validation of Biomarkers of Cellular Response

Linda R Duska  1 , Virginia L Filiaci  2 , Joan L Walker  3 , Laura L Holman  3 , Emily K Hill  4 , Richard G Moore  5 , Kari L Ring  6 , Michael L Pearl  7 , Carolyn Y Muller  8 , Christina L Kushnir  9 , Heather A Lankes  10   11 , Megan I Samuelson  12 , Kelley S Carrick  13 , Anand Rajan  12 , William H Rodgers  14 , Elise C Kohn  15 , Richard Piekarz  15 , Kimberly K Leslie  4
Affiliations
Randomized Controlled Trial

A Surgical Window Trial Evaluating Medroxyprogesterone Acetate with or without Entinostat in Patients with Endometrial Cancer and Validation of Biomarkers of Cellular Response

Linda R Duska et al. Clin Cancer Res. .

Abstract

Purpose: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma.

Patients and methods: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21-24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response.

Results: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008).

Conclusions: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.

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Conflict of interest statement

Conflicts of Interest Statement: The authors declare no potential conflicts of interest specifically with regard to this manuscript.

NCT03018249

Figures

Figure 1:
Figure 1:
Consort diagram tx=treatment, MPA=medroxyprogesterone acetate, N=number
Figure 2
Figure 2
Box Plots for Change in PR expression H-score from pre to post treatment PR=progesterone receptor, Max=maximum, Min=minimum, Std=standard, Nobs=number of observations
See this image and copyright information in PMC

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