Abstract PD11-08: Low dose endoxifen represses mouse mammary tumorigenesis: A preclinical study of monotherapy and combination with ulipristal acetate

Abstract Background: Endoxifen (ENX), a major active metabolite of the selective estrogen receptor (ER) modulator tamoxifen (TAM), has been shown to inhibit the growth of ER+ cancer. However, it has not been evaluated for prevention of mammary cancer. We report here the cancer prevention efficacy of ENX as monotherapy and in combination with ulipristal acetate (UPA), a selective progesterone receptor (PR) modulator. We compare these to TAM using the SV40 C3 T-antigen (C3-TAg) mouse, a well-documented mammary cancer prevention model. Methods: C3-TAg female virgin mice aged 7-8 weeks were randomized to no-treatment control or to drug treatment groups (TAM, ENX, UPA and ENX+UPA). Drug pellets were subcutaneously implanted on backside of mice. The doses of drug pellet were 12.5mg/30d for TAM, 9mg/90d for ENX, 10mg/30d for UPA, and combination of ENX (9mg/90d) + UPA (10mg/30d). The dose of ENX was equivalent to the exposure resulting from 20 mg/day, the lowest dose used in a recent Phase I human trial. Pellets were replaced every 30 days or 90 days. Mammary tumor formation was monitored twice weekly by palpation. Tumor latency, multiplicity, and tumor volume were recorded; animals are euthanized at 23 weeks of age, or earlier if tumors reach > 1 cm2. Tumors and mammary glands were formalin fixed and paraffin embedded for histology evaluation by a rodent pathologist. The primary endpoint was a reduction in tumor incidence in drug treated versus control groups. Secondary endpoints included prolongation of latency, reduction in tumor multiplicity, and tumor burden. Statistical significance between groups was calculated with Wilcoxon log-rank test for % tumor-free survival and Mann Whitney test for tumor multiplicity and burden.Results: All mice in the control group developed tumors by 18 weeks of age. Tumor-free survival % of ENX, UPA, and ENX+UPA treated groups were significantly higher than control animals, with the greatest increase in the ENX group (p=0.02). TAM had no effect on tumor-free survival (p=0.32). Median tumor latencies were similar in three treated groups: ENX (112 days), UPA (114 days), and ENX+UPA (111 days) groups, and were significantly delayed compared to the control or TAM group (100 days in both) (p<0.05). Median tumor multiplicity (invasive adenocarcinoma) per animal was significantly lower in ENX group compared to control group (3 vs. 7, p=0.02). UPA and TAM did not significantly reduce tumor multiplicity (4 for TAM and 6 for UPA). We observed non-significant 32% and 23% reduction in median tumor weight of ENX+UPA group and ENX group, respectively compared to control group. Histology evaluation for ENX+UPA group and pathologic size of invasive carcinoma is ongoing, along with the expression of Ki67, ERα and PR of mammary tumors and mammary gland by immunohistochemistry.Conclusions: TAM showed no significant effect on delaying tumorigenesis, consistent with a previous study. However, low dose of ENX (equivalent to 24 mg/day in human) effectively repressed tumor development and growth than TAM or UPA treatment. Our data suggest that ENX is promising for prevention of ER+ mammary tumorigenesis and warrant a dose optimization study for improving efficacy. Citation Format: Oukseub Lee, Minhua Wang, Maarten C. Bosland, Omid Hosseini, Irene Helenowski, Seema A. Khan. Low dose endoxifen represses mouse mammary tumorigenesis: A preclinical study of monotherapy and combination with ulipristal acetate [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-08.