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Selective Progesterone Receptor Modulators in Early-Stage Breast Cancer: A Randomized, Placebo-Controlled Phase II
Oukseub Lee1, Megan E Sullivan2, Yanfei Xu1
1Department of Surgery, University of Illinois at Chicago, Chicago, Illinois.
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.
Insights
Selective progesterone receptor modulators (SPRMs) like telapristone acetate show antiproliferative effects in early breast cancer. A subset of patients experienced significant Ki67 reduction, suggesting potential for SPRMs in neoadjuvant therapy.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Selective progesterone receptor modulators (SPRMs) demonstrate preclinical efficacy in hormone-sensitive breast cancer.
- SPRMs have not been previously evaluated in treatment-naïve, early-stage breast cancer patients.
Purpose of the Study:
- To assess the presurgical efficacy of oral telapristone acetate (TPA) in early-stage breast cancer.
- To evaluate the impact of TPA on Ki67 proliferation index and gene expression in treatment-naïve tumors.
Main Methods:
- A double-blind, placebo-controlled presurgical window trial involving 70 early-stage breast cancer patients randomized to TPA or placebo.
- Treatment duration ranged from 2 to 10 weeks, with Ki67 changes assessed pre- and post-therapy.
- RNA-sequencing was used to analyze gene expression changes and identify enriched pathways.
Main Results:
- Telapristone acetate significantly reduced mean Ki67 by 5.5% (P=0.003), while placebo showed a 4.2% reduction (P=0.04).
- A significant Ki67 decline was observed in premenopausal women treated with TPA (P=0.03).
- In a subset with ≥30% Ki67 reduction, TPA downregulated cell-cycle and HER2 amplicon genes; no pathways were enriched in the placebo group.
Conclusions:
- Telapristone acetate exhibits a selective antiproliferative signal in a subset of early breast cancer patients, impacting HER2 amplicon genes.
- Further evaluation of SPRMs in neoadjuvant settings is warranted, focusing on response predictors and including diverse menopausal populations.
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