Proellex (telapristone)

Conversely, one study using telapristone acetate showed Ki67d only in premenopausal pts. Higher body mass index (BMI) was reported to be associated with Ki67d, in one of the studies together with metformin...Higher Ki67d was reported when pictilisib or enzalutamide were added to NET in luminal B or luminal A tumors, respectively...The effect of this mutation was reverted in these studies by the addition of targeted therapy to NET (pictilisib, everolimus, or lapatinib). Conclusions We summarize baseline characteristics associated with Ki67d after NET in pts with eBC. These characteristics are important to inform clinical trial design and pts selection in clinical practice.

P2, N=67, Completed, Northwestern University | Unknown status --> Completed

PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention.

We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.

One group was treated was estradiol and progesterone (EP) while the other was treated with EP and the PR antagonist telapristone acetate (TPA) to identify PR-mediated effects...CD44 , associated with cellular proliferation and migration, NCOR2 associated with tamoxifen resistance, and AKR1C2 associated with progesterone metabolism all showed significant skipped exon (SE) events...We hypothesize that the skipping of Exon 4 of AKR1C2 in BRCA1 mut results in a structural alteration that decreases protein activity, leading to increased concentrations of P4 and 5α-pregnane-3,20-dione. This may explain the previously reported high median luteal phase serum P levels (p=0.00034) in BRCA1 mut /BRCA2 mut (PMID: 24140203).

TPA-treated patients whose Ki67 decreased by ≥30% demonstrated a selective anti-proliferative 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.

These data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system.