Abstract PS3-08-10: Efficacy of LHRHa treatment in luminal type breast cancer and in vivo estrogen-independent breast cancer cell lines

Abstract Hormone receptor-positive (ER+/PR+), HER2-negative (luminal type) breast cancer accounts for 75.6% of all cases. For premenopausal patients, luteinizing hormone-releasing hormone agonists (LHRHa) suppress ovarian estrogen and progesterone production and are often combined with antiestrogen therapies like tamoxifen or aromatase inhibitors. Clinical trials, such as SOFT and TEXT, demonstrate that LHRHa improves outcomes. However, challenges include side effects (e.g., menopausal symptoms, bone density loss) and identifying which patients benefit most. It is important to personalize treatment strategies to optimize LHRHa use.We performed orthotopic injection of MCF7 cells into bilaterally ovariectomized mice (estrogen depleted). After 2-4 months of observation in the estrogen-depleted state, multiple in vivo-estrogen-independent breast cancer cell lines (iEIBCCs) were established. This may be a model that approximates luminal-type recurrent breast cancer under anti-estrogen therapy. Here, we investigated the effects of LHRHa combination therapy in luminal type breast cancer patients and iEIBCC cell lines. The clinicopathological factors and prognosis of patients with Stage I-III Luminal breast cancer from 2016 to 2021 who were treated at Chiba University hospital were analyzed. We selected 152 analytic cohort patients and split them into two groups by treatment with or without LHRHa. Two kinds of iEIBCCs, 1LR and E10, and parental MCF-7 cells were transplanted into ovariectomized SCID mice, LHRHa-treated mice, and wild-type mice. Furthermore, we conducted RNA sequencing to define the differential gene expression between 1LR, E10, and parental MCF-7. The 5-year RFS of the patients treated with LHRHa (N=48) was statistically higher than without LHRHa (N=104) (p = 0.0150). In the parental MCF-7 group, compared to wild-type mice (N=4), the tumor growth was inhibited by both ovariectomize (N=5) and LHRHa-treated (N=7). In 1LR group, the tumor growth was inhibited by LHRHa-treated (N=7) but was not inhibited by ovariectomized (N=4). On the contrary, in E10 group, the tumor growth was inhibited by ovariectomized (N=4) but was not inhibited by LHRHa-treated (N=6). According to RNA sequencing, there are some differential gene expressions between the 1LR, E10, and parental MCF-7 cells. The main differences in GO pathways enrichment are axonogenesis, small GTPase-mediated signal transduction, protein localization, regulation of neuron projection development, and amide metabolic process. Our results suggest that LHRHa treatment is effective in patients with a high risk of recurrence. The differential gene expression between the E10 and 1R, and the resistance and sensitivity in E10, 1LR provide crucial context for interpreting how LHRHa impacts cancer cells. These insights underscore the complexity of cancer cell responses to hormone depletion therapies like LHRHa. Understanding the specific adaptations that confer resistance or sensitivity in these cell lines can guide the development of combination therapies. Citation Format: M. Yu, M. Takada, H. Yamada, T. Nagashima, H. Fujimoto, J. Sakakibara, M. Takaku, M. Otsuka. Efficacy of LHRHa treatment in luminal type breast cancer and in vivo estrogen-independent breast cancer cell lines [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 PS3-08-10.