Ultra-early changes in vascular parameters from dynamic contrast enhanced MRI of breast cancer xenografts following systemic therapy with doxorubicin and liver X receptor agonist

Abstract

Background: Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) may be used to depict tumour vascular structure and for therapy response assessment in various tumour sites. The purpose of the current work is to examine whether ultra-early changes in tumour physiology following cytotoxic treatment with doxorubicin and liver X receptor (LXR) agonist GW3965 are detectable by DCE-MRI. Methods: 36 female, athymic nude foxn1nu mice with bilaterally implanted breast cancer xenografts (17 with ER-positive HBCx34, 19 with triple-negative HBCx39) were randomised in the following treatment groups; control, GW3965 (40 mg/kg p.o.), doxorubicin (8 mg/kg i.v.) and a combination therapy of GW3965 and doxorubicin. DCE-MRI (3D FLASH on a 7 T preclinical scanner) was performed at baseline and one and six days after onset of treatment. Wash-in (30 s p.i.) and wash-out (300 s p.i.) enhancement were quantified from dynamic uptake curves, before voxel-by-voxel fitting to the pharmacokinetic Tofts model and generation of maps for the resulting parameters K trans, νe and νB. Treatment effect was evaluated by univariate repeated measures mixed-effects maximum likelihood regression models applied to median tumour data. Results: We found no effects of any treatment 24 h post treatment. After 6 days, doxorubicin given as both mono- A nd combination therapy gave significant increases of ~ 30% in wash-in enhancement (p < 0.011) and K trans (p < 0.017), and 40-50% in νB (p < 0.024) for HBCx34, but not for HBCx39. No effects of GW3965 were observed at any time (p > 0.1). Conclusions: Twenty-four h after onset of treatment was too early to evaluate treatment effects by DCE-MRI. Early enhancement and K trans were approximately equally sensitive metrics to capture treatment effects six days pt. Pharmacokinetic modelling however allowed us to attribute the observed effect to changes in tumour perfusion rather than increased retention.