TY - JOUR
T1 - Selective progesterone receptor modulators in early-stage breast cancer
T2 - A randomized, placebo-controlled phase II window-of-opportunity trial using telapristone acetate
AU - Lee, Oukseub
AU - Sullivan, Megan E
AU - Xu, Yanfei
AU - Rogers, Chiara
AU - Muzzio, Miguel
AU - Helenowski, Irene
AU - Shidfar, Ali
AU - Zeng, Zexian
AU - Singhal, Hari
AU - Jovanovic, Borko
AU - Hansen, Nora
AU - Bethke, Kevin P.
AU - Gann, Peter H.
AU - Gradishar, William
AU - Kim, J. Julie
AU - Clare, Susan E.
AU - Khan, Seema A.
N1 - Funding Information:
This study was funded by the Breast Cancer Research Foundation (to S.A. Khan) and NIH R01CA192124 (to S.A. Khan and J.J. Kim). Telapristone and placebo were supplied by Repros Therapeutics, who also supported the drug concentration assays. We thank Xiaoling Xuei and Yunlong Liu at the Center for Medical Genomics at Indiana University School of Medicine, for performing the RNA-seq study and Ryan Deaton, Rami Hayajneh, and the Research Histology and Tissue Imaging Core at the University of Illinois at Chicago, for performing the Ki67 study.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Purpose: Selective progesterone receptor modulators (SPRMs) show preclinical activity against hormone-sensitive breast cancer, but have not been tested in patients with early, treatment-naïve tumors. Patients and Methods: In a double-blind presurgical window trial of oral telapristone acetate (TPA) 12 mg daily versus placebo, 70 patients with early-stage breast cancer were randomized 1:1 (stratified by menopause) and treated for 2 to 10 weeks. The primary endpoint was change in Ki67 between diagnostic biopsy and surgical specimens. Gene expression pre- and posttherapy was assessed using RNA-sequencing and gene set enrichment analysis was performed to determine pathways enriched in response to TPA and placebo treatments. Results: Among 61 evaluable women (29 placebo and 32 telapristone acetate), 91% of tumors were ER/PR positive. The mean Ki67 declined by 5.5% in all women treated with telapristone acetate (P = 0.003), and by 4.2% in all women treated with placebo (P = 0.04). After menopausal stratification, the Ki67 decline remained significant in 22 telapristone acetate–treated premenopausal women (P = 0.03). Differential gene expression analysis showed no significant modulation overall. However, in a subset of tumors that demonstrated ≥30% relative reduction in Ki67 in the telapristone acetate group, genes related to cell-cycle progression, and those in the HER2 amplicon were significantly downregulated. In contrast, no significantly enriched pathways were identified in the placebo group. Conclusions: Patients treated with telapristone acetate whose Ki67 decreased by ≥30% demonstrated a selective antiproliferative signal, with a potentially important effect on HER2 amplicon genes. Evaluation of SPRMs in a neoadjuvant trial is merited, with attention to predictors of response to SPRM therapy, and inclusion of pre- and postmenopausal women.
AB - Purpose: Selective progesterone receptor modulators (SPRMs) show preclinical activity against hormone-sensitive breast cancer, but have not been tested in patients with early, treatment-naïve tumors. Patients and Methods: In a double-blind presurgical window trial of oral telapristone acetate (TPA) 12 mg daily versus placebo, 70 patients with early-stage breast cancer were randomized 1:1 (stratified by menopause) and treated for 2 to 10 weeks. The primary endpoint was change in Ki67 between diagnostic biopsy and surgical specimens. Gene expression pre- and posttherapy was assessed using RNA-sequencing and gene set enrichment analysis was performed to determine pathways enriched in response to TPA and placebo treatments. Results: Among 61 evaluable women (29 placebo and 32 telapristone acetate), 91% of tumors were ER/PR positive. The mean Ki67 declined by 5.5% in all women treated with telapristone acetate (P = 0.003), and by 4.2% in all women treated with placebo (P = 0.04). After menopausal stratification, the Ki67 decline remained significant in 22 telapristone acetate–treated premenopausal women (P = 0.03). Differential gene expression analysis showed no significant modulation overall. However, in a subset of tumors that demonstrated ≥30% relative reduction in Ki67 in the telapristone acetate group, genes related to cell-cycle progression, and those in the HER2 amplicon were significantly downregulated. In contrast, no significantly enriched pathways were identified in the placebo group. Conclusions: Patients treated with telapristone acetate whose Ki67 decreased by ≥30% demonstrated a selective antiproliferative signal, with a potentially important effect on HER2 amplicon genes. Evaluation of SPRMs in a neoadjuvant trial is merited, with attention to predictors of response to SPRM therapy, and inclusion of pre- and postmenopausal women.
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U2 - 10.1158/1078-0432.CCR-19-0443
DO - 10.1158/1078-0432.CCR-19-0443
M3 - Article
C2 - 31570566
AN - SCOPUS:85077476912
SN - 1078-0432
VL - 26
SP - 25
EP - 34
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -
