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

Kathinka E Pitman,Alexandr Kristian,Kine M Bakke,Eirik Malinen

doi:10.1186/s40644-019-0280-y

Kathinka E Pitman, Alexandr Kristian + Show 2 more

Open Access

https://doi.org/10.1186/s40644-019-0280-y

Copy DOI

Abstract

BackgroundDynamic 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.Methods36 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 Ktrans, νe and νB. Treatment effect was evaluated by univariate repeated measures mixed-effects maximum likelihood regression models applied to median tumour data.ResultsWe found no effects of any treatment 24 h post treatment. After 6 days, doxorubicin given as both mono- and combination therapy gave significant increases of ~ 30% in wash-in enhancement (p < 0.011) and Ktrans (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).ConclusionsTwenty-four h after onset of treatment was too early to evaluate treatment effects by DCE-MRI. Early enhancement and Ktrans 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.

Highlights

Obesity and metabolic syndrome are increasingly important risk factors for breast cancer, in particular in post-menopausal women
Cholesterol metabolism is frequently altered in cancer, and is associated with increased proliferation and angiogenesis [1, 2]
Xenograft tumour models 36 female, nude athymic Foxn1nuu mice bilaterally implanted with two different breast cancer xenografts were included; one triple-negative (HBCx39, n = 19) and one oestrogen receptor positive (ER+) invasive ductal carcinoma (HBCx34, n = 17)

Summary

Introduction

Obesity and metabolic syndrome are increasingly important risk factors for breast cancer, in particular in post-menopausal women. Oestrogen receptor (ER) positive breast cancer accounts for roughly 70% of breast cancer cases. Cholesterol metabolism is frequently altered in cancer, and is associated with increased proliferation and angiogenesis [1, 2]. Neoadjuvant chemo- and endocrine therapy is the standard of care for locally advanced breast cancers, aiming to improve patient outcome and maximise breast conserving surgery. Identification of non-responders may allow swift intervention and reassignment to a different treatment regime, improving survival while saving both time and money spent on ineffective therapy. 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

Objectives

Methods

Results

Discussion

Conclusion