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.
Background: Early kinetic changes in DCE-MRI are predictive of clinical and pathologic response to neoadjuvant chemotherapy (NAC) in primary breast cancer (BC). Baseline vascular parameters and changes in these parameters with NAC have not been previously correlated with disease-free survival (DFS) and overall survival (OS) in BC.Methods: 73 patients (median age 45, range 26-70) with locally advanced BC due to undergo 4-6 cycles of anthracycline and/or taxotere NAC were imaged with DCE-MRI before and after 2 cycles as part of 2 prospective studies. Quantitative and semi-quantitative kinetic parameters such as Ktrans (inflow transfer constant) and IAUGC60 (initial area under the gadolinium-time curve) were derived from whole tumour regions of interest. Values for both baseline and changes in kinetic parameters as well as known prognostic indicators including age, grade, tumour size, nodal, hormonal and HER2 receptor status, and pathologic complete response were then correlated with DFS and OS using Kaplan-Meier analysis (log-rank test) and the Cox proportional hazards model. Median values for Ktrans and IAUGC60 were used to dichotomise data for survival analysis.Results: DCE-MRIs were performed in 62 patients before treatment (baseline group) and in 56 patients after 2 cycles of NAC. 3 were found to have metastatic disease after enrolment, 8 were not able to undergo both MRIs, 4 did not undergo their second MRI and in 2, the second scan was performed after 3 cycles of NAC. The median follow-up time for DFS was 33.7 months (range 0.3-75.6) and for OS 44.4 months (range 7.6-84.7). There were 21 distant recurrences in the baseline group (3 also had additional local recurrence) and 19 distant recurrences amongst those who were imaged pre and post treatment (2 also had local recurrence). There were 14 deaths in total (13 from BC, 1 from an unknown cause). Baseline DCE-MRI vascular parameters were not significantly associated with DFS or OS.Univariate analysis (n=56) using Cox regression showed age and ER positivity to be significant predictors of DFS & a trend towards a longer DFS with greater reductions in Ktrans (HR 1.94, 95%CI 0.73-5.18; p=0.186) and in IAUGC60 (HR 1.98, 95%CI 0.74-5.28; p=0.172). Multivariate analysis for DFS demonstrated that changes in Ktrans (HR 2.18, 95%CI 0.79-6.05; p=0.133) and IAUGC60 (HR 2.11, 95%CI 0.78-5.74; p=0.142) remain potential prognostic indicators although results did not reach statistical significance. Both age and ER positivity were independent prognostic variables. Changes in DCE-MRI vascular parameters did not predict for OS.Conclusions: These results suggest that changes in DCE-MRI vascular parameters with reductions in Ktrans and IAUGC60, are associated with lower recurrence rates and could be potential prognostic biomarkers for DFS. A larger cohort is currently being studied to explore this further. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1092.
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