Abstract
This work evaluates quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI) parameters as early biomarkers of response in a preclinical model of triple negative breast cancer (TNBC). The standard Tofts' model of DCE-MRI returns estimates of the volume transfer constant (Ktrans ) and the extravascular extracellular volume fraction (ve ). DW-MRI returns estimates of the apparent diffusion coefficient (ADC). Mice (n=38) were injected subcutaneously with MDA-MB-231. Tumors were grown to approximately 275mm3 and sorted into the following groups: saline controls, low-dose Abraxane (15mg/kg) and high-dose Abraxane (25mg/kg). Animals were imaged at days zero, one and three. On day three, tumors were extracted for immunohistochemistry. The positive percentage change in ADC on day one was significantly higher in both treatment groups relative to the control group (p<0.05). In addition, the positive percentage change in Ktrans was significantly higher than controls (p<0.05) on day one for the high-dose group and on days one and three for the low-dose group. The percentage change in tumor volume was significantly different between the high-dose and control groups on day three (p=0.006). Histology confirmed differences at day three through reduced numbers of proliferating cells (Ki67 staining) in the high-dose group (p=0.03) and low-dose group (p=0.052) compared with the control group. Co-immunofluorescent staining of vascular maturity [using von Willebrand Factor (vWF) and α-smooth muscle actin (α-SMA)] indicated significantly higher vascular maturation in the low-dose group compared with the controls on day three (p=0.03), and trending towards significance in the high-dose group compared with controls on day three (p=0.052). These results from quantitative imaging with histological validation indicate that ADC and Ktrans have the potential to serve as early biomarkers of treatment response in murine studies of TNBC.
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