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

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.References: 1. Ah-See, M-L. W et al. Early Changes in Functional Dynamic Magnetic Resonance Imaging Predict for Pathologic Response to Neoadjuvant Chemotherapy in Primary Breast Cancer. Clinical Cancer Research 2008;14(20):6580-6589. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5013.

Assessment of early treatment response to neoadjuvant chemotherapy in breast cancer using non-mono-exponential diffusion models: a feasibility study comparing the baseline and mid-treatment MRI examinations

“…Neoadjuvant chemotherapy regimens used in the treatment of breast cancer commonly consist of an anthracycline in combination or sequentially administered with taxanes. The mechanism of action of anthracyclines is mainly attributed to the inhibition of DNA synthesis, preventing the replication of rapidly dividing cells [ 34 ] , whereas taxanes have been reported to have an anti-angiogenic effect with selective shutdown of microvessel formation [ 35 , 36 ]. This is supported by the significant increase in DDC seen on mid-treatment ( p = 0.04), suggesting a change in the distribution of diffusion compartments resulting from the early breakdown of the vascular endothelial cells.…”

Amide proton transfer imaging of the breast at 3 T: Establishing reproducibility and possible feasibility assessing chemotherapy response

“…Salhotra et al (9) attributed this to an increase in cellular proliferation and subsequent accumulation of defective proteins. Application in human brain cancer has further indicated the sensitivity of CEST MRI, particularly APT, for the delineation of neoplasia in vivo (5, 10, 34, 35). Treatment effects have been explored by Zhou et al using a radiation necrosis model in rats (10), demonstrating the ability to detect viable malignancy from radiation necrosis and predicting tumor response to targeted radiation therapy.…”

“…Specifically, the peak pulse amplitude was swept between 0.25 and 1.25 μT in increments of 0.25 μT, whereas the number of pulse elements and duty cycle were held constant at 35 and 90%, respectively. In addition, the effects of duty cycle were examined at values of 50%, 60%, 70%, and 80% with the number of pulses per pulse repetition time (35) and pulse duration (25 ms) held constant. Finally, the total duration of saturation was examined at 440, 600, and 907 ms, both while holding the peak pulse amplitude (0.5 μT) and pulse duration (25 ms) constant.…”

Evaluation of the treatment response to neoadjuvant chemotherapy in locally advanced breast cancer using combined magnetic resonance vascular maps and apparent diffusion coefficient

“…Taxanes have been reported to have greater antiangiogenic activity compared to anthracyclines, and selectivity for the inhibition of endothelial cell migration and/or microvessel formation . In our study, significant differences were found in the early reduction of the VMs of the patients with LABC between those treated with taxane‐containing regimens and those treated with regimens not containing taxanes, consistent with the prior observation.…”

“…The neoadjuvant chemotherapy regimens were mainly anthracycline or taxane‐based, and a few patients received vinorelbine or cisplatin‐based chemotherapy regimens. Taxanes have been reported to have greater antiangiogenic activity compared to anthracyclines in the neoadjuvant treatment of breast cancer, and preclinical studies have reported that taxanes have strong antiangiogenic activity via inhibition of the proliferation and differentiation of the endothelial cells . Therefore, the treatment response between the patients receiving regimens containing and not containing taxanes was also evaluated separately.…”