Abstract
PurposeTo 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.MethodsTwo 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.ResultsDW images of MNU-induced mammary tumors were successfully obtained with minimal motion artifact. For group 1, ADC change for 3 days after therapy initiation (ADC3D) was significantly correlated with tumor-volume change until day 11, but the significant correlation between ADC change for 7 days (ADC7D) and the tumor-volume change was observed until day 18. Similarly, for group 2, either ADC7D or ADC3D was significantly correlated with the tumor-volume change, but the higher significance was observed for ADC7D. Furthermore, ADC7D was significantly correlated with apoptotic (TUNEL stained), proliferative (Ki-67 stained), and ERβ-positive cell densities, but ADC3D was not significantly correlated with any of those.ConclusionsADC7D might be a more reliable surrogate imaging biomarker than ADC3D to assess effectiveness of tamoxifen therapy for ER-positive breast cancer, which may enable personalized treatment. The significant correlation between ADC7D and ERβ-positive cell density suggests that ERβ may play an important role as a therapeutic indicator of tamoxifen.
Highlights
Estrogen stimulates cell growth via binding to the estrogen receptor (ER), and approximately 75% of breast cancers in the United States are ER positive
The significant correlation between ADC change for 7 days (ADC7D) and ERb-positive cell density suggests that ERb may play an important role as a therapeutic indicator of tamoxifen
Diffusion weighted images of MNU-induced mammary tumors were successfully obtained with minimal motion artifact
Summary
Estrogen stimulates cell growth via binding to the estrogen receptor (ER), and approximately 75% of breast cancers in the United States are ER positive. Anti-ER drugs like tamoxifen, toremifene, and fulvestrant have been used for treatment of both early and advanced ER positive breast cancers [1,2,3]. Non-invasive imaging is a better approach to address response to therapy. During apoptosis or necrosis induced by effective therapy, water in the extra-cellular space is increased, and this change is detectable prior to visible change of tumor morphology or size. The significant increase of ADC value was detected in breast tumor xenografts at 3 days after anti-DR5 (death receptor 5) therapy, but not at day 6 in our previous study, presumably because water molecules diffused away from the tumor region over time [12]
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