Background: In vitro and preclinical data indicate that TPA, a selective PR modulator, has activity against hormone-sensitive early breast cancer. We conducted a pre-surgical window trial of oral TPA in Stage 0-II breast cancer to assess the effect of TPA on suppression of cell proliferation (Ki67), and on differential gene expression in responsive and non-responsive tumors.

Methods: We enrolled 70 pre and postmenopausal women into a 1:1 randomized, double-blind, placebo-controlled trial of oral TPA 12mg (Repros Therapeutics Inc.) for 2-10 weeks. The primary endpoint was Ki67 labelling, comparing diagnostic core needle biopsy to post-therapy surgical specimens. Ki67 changes were quantitated by dual immunohistochemistry (Ki67/pan-cytokeratin) and image analysis (Aperio ImageScope and Definiens Tissue Studio®). RNA-sequencing (using RNA extracted from the paraffin blocks) was performed with Illumina TruSeq RNA Coding Access method. Differential gene expression pre-post therapy was assessed, followed by Gene Set Enrichment Analysis for pathway analysis. Ki67 changes from baseline were tested with Paired signed-rank test. For gene expression analysis, p values were calculated by Wald test and adjusted for multiple comparisons by Benjamini-Hochberg method (adjusted p <0.05 and 2-fold gene expression cut-off).

Results: Among 61 evaluable women, (29 placebo and 32 TPA) 97% of tumors were ER or PR positive and 91% were ER and PR positive (balanced across arms). A significant 6% decrease in mean %Ki67 was seen in the TPA arm (p= 0.003). When stratified by menopause, the significance held in premenopausal women (n= 22, p= 0.03) but not in postmenopausal women (n=10, p= 0.08). However, a Ki67 decrease (4%) was also observed in placebo group (p = 0.04); this was non-significant after pre- postmenopausal stratification. Overall, differential gene expression analysis showed no significant modulation of genes in either group. Using a pre-specified response parameter (50% relative reduction in Ki67), we identified 12/32 (38%) “responders” in the TPA, and 9/29 (31%) in the placebo arm. In sub-group analysis of these responders, we found 103 genes to be significantly modulated by treatment in the TPA “responders”, but saw no significant change in any gene expression in placebo “responders”. Gene set enrichment analysis for the 103 genes showed that TPA blocked the progression of cell cycle genes (PTTG1, PLK1, UBE2C, HIST1H3F, PSMD3, and etc.) and suppressed PGR and ERBB2 expression. In a pre-planned pooled analysis, these results will be combined with NCT02314156, reported in SABCS abstract 851790.

Conclusions: An anti-proliferative (Ki67) signal of TPA was observed in early stage breast cancer patients, but interpretation was limited by placebo group changes. The TPA group demonstrated differential suppression of proliferation-related genes among Ki67 responders, but the placebo group did not. Ongoing analysis will examine signatures related to stemness, metastasis, and immune suppression (potentially better endpoints in trials targeting P signaling). These analyses may help us select the right population and the right biomarkers for future trials.

Citation Format: Lee O, Sullivan ME, Xu Y, Shidfar A, Ivancic D, Zeng Z, Singhal H, Helenowski I, Jovanovic B, Hansen N, Bethke K, Gann P, Gradishar WJ, Clare SE, Khan SA. Progesterone receptor (PR) antagonism by telapristone acetate (TPA): A randomized, placebo-controlled phase IIB pre-surgical window trial in women with stage 0-II breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-02.