Greater Anti-Angiogenic Effects with Docetaxel Compared with Anthracyclines in the Neoadjuvant Treatment of Breast Cancer.

Abstract

Abstract Background: Dynamic contrast-enhanced MRI (DCE-MRI) allows for the functional assessment of tumour permeability and perfusion and has been previously shown to predict for clinical and pathologic response in women with breast cancer undergoing neoadjuvant anthracycline based chemotherapy1. Changes in DCE-MRI kinetic parameters after 2 cycles of neoadjuvant chemotherapy (NAC) predicts clinical and pathological benefit, with transfer constant Ktrans being the best predictive biomarker. This study examines (1) whether DCE-MRI can predict for final clinical response in women undergoing neoadjuvant docetaxel and (2) whether taxanes demonstrate greater anti-angiogenic activity over anthracyclines in the NAC setting.Methods: 30 patients with histologically proven primary breast cancer (T2-4, N0-1, M0) due to receive neoadjuvant docetaxel chemotherapy underwent DCE-MRI before and after 2 cycles of NAC as part of a prospective study. Whole tumour regions of interest were outlined and values for inflow transfer constant (Ktrans), outflow rate constant (kep), leakage space (ve), initial area under gadolinium-time curve (IAUGC60), relative blood volume (rBV), Mean Transit Time (MTT) and relative blood flow (rBF) calculated. Both baseline and changes in DCE-MRI kinetic parameters were correlated with final clinical response using the Mann-Whitney U test. DCE-MRI results of the docetaxel NAC cohort were compared with a previously analysed cohort of 28 patients who received neoadjuvant FEC chemotherapy1. MRI data acquisition and pharmacokinetic modelling analysis for both cohorts were identical.Results: 25 docetaxel patients were assessable (median age 42, range 26-62; docetaxel 100mg/m2; median number of cycles 4, range 2-6). 1 patient received 1 cycle of docetaxel only and 4 were not able to complete their imaging. There were 21 clinical responders (CR)(9 complete and 12 partial responders) and 4 non-responders (NR)(3 with SD, 1 with PD). There was no significant difference in pretreatment parameters between CR and NR. The median reduction in Ktrans in CR was -58.1% vs -8.9% in NR (95% CI -81.1 to -19.8, p=0.011) and in IAUGC60, -57.6% vs -3.7% (95% CI -79.9 to -14.7, p=0.011). ROC analysis revealed that both Ktrans and IAUGC60 changes were good predictors of clinical response (Ktrans: sensitivity 81%, specificity 100%, area under ROC curve 0.89; IAUGC60: sensitivity 76%, specificity 100%, area under ROC curve 0.89). Comparison of docetaxel versus FEC cohorts showed greater reductions in kinetic parameters in clinical responders in the docetaxel group (Ktrans: -58.1% vs -29.5%, p=0.022; IAUGC60 values: -57.5% vs -20.4%, p=0.006).Discussion: Early changes in DCE-MRI biomarkers depicting tumour vascularity can predict clinical benefit from docetaxel NAC in breast cancer, similar to a finding previously shown for anthracyclines. Significantly larger changes in DCE-MRI biomarkers related to tumour perfusion and permeability in responding patients suggest a greater anti-angiogenic effect with docetaxel.