Abstract PS3-03-23: Effects of hormonal contraceptive on tamoxifen efficacy to prevent chemically induced invasive cancers in rats

Abstract Background: Tamoxifen (TAM) is the only anti-estrogen approved for women with functioning ovaries who are advised to avoid pregnancy due to risk to the fetus but are cautioned against using hormonal contraceptives (HCs). This reluctance is based on concerns that HCs may counteract the efficacy of TAM and increase adverse effects when used concomitantly. However, these concerns lack direct supporting evidence, and the possibility of a neutral or even beneficial interaction has not been explored. We hypothesized that the most widely used combined hormonal contraceptive (17α-ethinylestradiol + levonorgestrel) would not reduce the tumor-preventive efficacy of oral TAM in a hormonally sensitive, ER-positive mammary tumorigenesis model in rats. Methods: Female Sprague Dawley rats (4-5 weeks old) received N-Methyl nitrosourea (50 mg/kg i.p.) to induce mammary tumors. Three weeks later, they were randomized (n=12-13 per group) to control, HC alone, TAM alone, or TAM+HC. HC pellets (17α-ethinylestradiol 0.06 mg + levonorgestrel 0.28 mg, 90-day release; Innovative Research of America) were implanted subcutaneously in the dorsal area and replaced at 90 days. TAM was incorporated into the diet (1.03 mg/kg/day in rats, equivalent to daily 7 mg in humans; Inotiv Inc.). Rats were monitored for 6 months for tumor formation. Tumor incidence, latency, weights, and volumes were measured. Wet uterine weight was recorded, adjusted for body weight, and processed for histology. Tumor-free survival was analyzed with the log-rank test; other comparisons used Kruskal-Wallis with Dunn’s post hoc tests. Results: In the control group, median tumor latency was 3 months with a final incidence of 92%, consistent with published studies. Tumor incidence was higher in the HC alone group (46%) than in the TAM alone (17%) and TAM+HC (15%) groups. Tumor weights and volumes were significantly lower in both TAM-treated groups compared to controls (all adjusted p < 0.003). These findings indicate that HC co-administration did not reduce TAM’s cancer-preventive efficacy. HC alone had no significant impact on body weight (adjusted p > 0.99). TAM significantly reduced body weight versus control (median difference = 30 g, adjusted p = 0.001), with no difference between TAM alone and TAM+HC groups (median difference = 16 g, adjusted p = 0.73). HC alone had no significant effect on uterine weight (adjusted p > 0.99). TAM significantly reduced uterine weight relative to controls (adjusted p < 0.001), with no difference between TAM alone and TAM+HC groups (adjusted p = 0.97). Histopathological assessment of mammary glands, uterus, and endometrial thickness is ongoing. Conclusions: Combined HC did not reduce the tumor-preventive efficacy of oral TAM in this ER-positive mammary tumorigenesis model. Ongoing analyses will assess uterine safety with this combination. Citation Format: O. Lee, A. Eremin, S. A. Khan. Effects of hormonal contraceptive on tamoxifen efficacy to prevent chemically induced invasive cancers in rats [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-23.