Diffusion Weighted Imaging Evaluated the Early Therapy Effect of Tamoxifen in an MNU-Induced Mammary Cancer Rat Model

PURPOSE: To assess the optimal time point of diffusion-weighted imaging (DWI) for early prognosis of breast cancer following tamoxifen therapy using a methylnitrosourea (MNU)-induced ER-positive breast-cancer model. METHODS: Two groups of Sprague-Dawley rats (n = 15 for group 1; n = 10 for group 2) were used. All animals (50 days old) were intravenously injected with MNU (50 mg/kg body weight) to induce ER-positive mammary tumors. When tumors were approximately 2 cm in diameter, DWI was performed on days 0, 3, and 7, and intratumoral apparent diffusion coefficient (ADC) values were measured. Therapy started on day 0 with tamoxifen (10 mg/kg diet) and continued for 4 weeks for group 1, but only 1 week for group 2, while tumor volume was measured by caliper twice weekly. All animals of group 2 were euthanized on day 7 after imaging, and Ki-67, TUNEL, ERα, and ERβ staining were performed on tumor tissue. RESULTS: DW images of MNU-induced mammary tumors were successfully obtained with minimal motion artifact. For group 1, ADC change for 3 days after therapy initiation (ADC(3D)) was significantly correlated with tumor-volume change until day 11, but the significant correlation between ADC change for 7 days (ADC(7D)) and the tumor-volume change was observed until day 18. Similarly, for group 2, either ADC(7D) or ADC(3D) was significantly correlated with the tumor-volume change, but the higher significance was observed for ADC(7D). Furthermore, ADC(7D) was significantly correlated with apoptotic (TUNEL stained), proliferative (Ki-67 stained), and ERβ-positive cell densities, but ADC(3D) was not significantly correlated with any of those. CONCLUSIONS: ADC(7D) might be a more reliable surrogate imaging biomarker than ADC(3D) to assess effectiveness of tamoxifen therapy for ER-positive breast cancer, which may enable personalized treatment. The significant correlation between ADC(7D) and ERβ-positive cell density suggests that ERβ may play an important role as a therapeutic indicator of tamoxifen.