Ehsani, Sima

TPS655 Background: Early (14-28 day) on-treatment suppression of tumor proliferation during neoadjuvant endocrine therapy (NET) is strongly associated with favorable long-term outcomes in estrogen receptor–positive (ER+) HER2– breast cancer. In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. (Z)-endoxifen (ENDX), the active metabolite of tamoxifen, dually inhibits ER signaling and PKCβ1-mediated AKT activation, supporting its evaluation as an alternative NET strategy in this population. Methods: EVANGELINE (NCT05607004) is an ongoing, multicenter, open-label Phase 2 study evaluating daily 40 mg ENDX plus goserelin administered every 28 days as neoadjuvant therapy in premenopausal women with ER+/HER2–, cT2–3, cN0–1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 ≤10% after 4 weeks of therapy. A Simon two-stage design is used to test whether the Week 4 Ki-67 ≤10% rate is at least 65%, with 20 patients enrolled into the first stage and, if promising, another 25 patients enrolled into the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 ≤10% (cohort B) is enrolled to assess objective response rate (ORR) at 24 weeks per RECIST v1.1. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers. Clinical trial information: NCT05607004 .

Abstract Text While the importance of estrogen in driving ER+ breast cancer progression is clear, data from pre-clinical studies exploring the role of tumoral progesterone (PR) and androgen (AR) receptors are conflicting, likely due in part to the promiscuity of steroid receptor ligands, as well as relative levels of steroid hormone receptor expression and of steroid hormones within the tumor milieu. While bone is usually the first site of metastases in ER+ metastatic breast cancer, the roles of tumoral PR and AR (present in 58 percent and 86 percent of clinical ER+ bone metastases [BMET], respectively) in ER+ breast cancer progression at this site have not been well studied. Studies were undertaken to examine the effects of ovariectomy (OVX), a model of surgical menopause that significantly reduces endogenous progesterone and androgen levels, in a pre-clinical model of human ER+ bone metastases that is dependent on exogenous 17ß-estradiol (E2) supplementation. Effects of OVX (at 9-weeks of age) were ascertained using skeletally mature female nude mice supplemented with a modest dose of E2 (0.36 mg 60 day pellets) prior to intracardiac inoculation (at 10 weeks of age) with bone metastasis-derived MCF7 cells (43.4M cells) that form robust E2- and TGFß-dependent osteolytic metastasis in vivo, and express PR and AR in vitro. Osteolytic bone metastatic lesions in E2-supplemented mice were reduced in both incidence and size in OVX (vs ovary intact) mice. Anti-tumoral effects of OVX were not limited to bone; E2-driven orthotopic tumor progression was similarly reduced. Histologic assessment of cytokeratin-positive breast cancer tumor cells within bone revealed a small but statistically significant reduction in Ki67-positivity in OVX (vs ovary -intact) mice that correlated with osteolytic lesion size. In addition, PR and AR expression in BMET lesions, which was readily detected by IHC in ovary-intact mice, was markedly reduced in OVX mice. While additional experiments are underway to query possible roles of specific reproductive hormones altered in OVX mice, these results are consistent with the postulate that tumoral AR and PR signaling may promote ER+ bone metastases progression in this model. In addition, while ovariectomy is a common pre-clinical means of reducing estrogen to model natural menopause in women, resultant changes in steroid receptor signaling are clearly much more complex. Funding: NIH 5R25CA275753, 5P30CA023074 Date of Presentation October 17, 2024

Abstract Text While the importance of estrogen in driving ER+ breast cancer progression is clear, data from pre-clinical studies exploring the role of tumoral progesterone (PR) and androgen (AR) receptors are conflicting, likely due in part to the promiscuity of steroid receptor ligands, as well as relative levels of steroid hormone receptor expression and of steroid hormones within the tumor milieu. While bone is usually the first site of metastases in ER+ metastatic breast cancer, the roles of tumoral PR and AR (present in 58 percent and 86 percent of clinical ER+ bone metastases [BMET], respectively) in ER+ breast cancer progression at this site have not been well studied. Studies were undertaken to examine the effects of ovariectomy (OVX), a model of surgical menopause that significantly reduces endogenous progesterone and androgen levels, in a pre-clinical model of human ER+ bone metastases that is dependent on exogenous 17ß-estradiol (E2) supplementation. Effects of OVX (at 9-weeks of age) were ascertained using skeletally mature female nude mice supplemented with a modest dose of E2 (0.36 mg 60 day pellets) prior to intracardiac inoculation (at 10 weeks of age) with bone metastasis-derived MCF7 cells (43.4M cells) that form robust E2- and TGFß-dependent osteolytic metastasis in vivo, and express PR and AR in vitro. Osteolytic bone metastatic lesions in E2-supplemented mice were reduced in both incidence and size in OVX (vs ovary intact) mice. Anti-tumoral effects of OVX were not limited to bone; E2-driven orthotopic tumor progression was similarly reduced. Histologic assessment of cytokeratin-positive breast cancer tumor cells within bone revealed a small but statistically significant reduction in Ki67-positivity in OVX (vs ovary -intact) mice that correlated with osteolytic lesion size. In addition, PR and AR expression in BMET lesions, which was readily detected by IHC in ovary-intact mice, was markedly reduced in OVX mice. While additional experiments are underway to query possible roles of specific reproductive hormones altered in OVX mice, these results are consistent with the postulate that tumoral AR and PR signaling may promote ER+ bone metastases progression in this model. In addition, while ovariectomy is a common pre-clinical means of reducing estrogen to model natural menopause in women, resultant changes in steroid receptor signaling are clearly much more complex. Funding: NIH 5R25CA275753, 5P30CA023074 Date of Presentation October 17, 2024