A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers

Abstract

Purpose: Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors. This randomized phase II trial was designed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel.

Experimental design: Patients with inoperable breast cancer were randomized to either 2 cycles of preoperative docetaxel (D) 35 mg/m(2) i.v. weekly for 6 weeks, followed by a 2-week break; or docetaxel with bevacizumab 10 mg/kg i.v. every other week for a total of 16 weeks (DB). Plasma and serum markers of endothelial damage, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle.

Results: Forty-nine patients were randomized (DB, 24; D, 25). There was no difference in overall clinical response, progression-free survival, or overall survival. Vascular endothelial growth factor increased during treatment; more so with DB (P < 0.0001). Vascular cell adhesion molecule-1 (VCAM-1) also increased (P < 0.0001); more so with DB (P = 0.069). Intercellular adhesion molecule increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB (P = 0.024). DCE-MRI also showed an overall decrease in tumor volume (P = 0.012).

Conclusion: Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin.

Figure 1. Kaplan-Meier Outcome Curves

Panel A shows the Kaplan-Meier estimation of progression-free survival (PFS) in months demonstrated by the two treatment groups: docetaxel (D) vs. docetaxel + bevacizumab (DB). The probability of PFS with DB treatment was consistently larger up to 3 years than with D treatment, though the difference was not statistically significant. Panel B shows the Kaplan-Meier estimation of overall survival (OS) in months demonstrated by the two treatment groups: docetaxel (D) vs. docetaxel + bevacizumab (DB). The median OS has not been reached in either treatment group, but again, there was no statistically significant difference in OS.

Figure 2. Changes In Levels Of Angiogenic And Endothelial Markers Over Time

All figures demonstrate a scatter plot of angiogenic and endothelial markers vs. time (days on study), superimposed with lowess smoother (locally weighted scatterplot smoothing) by treatment group; docetaxel (D) vs. docetaxel + bevacizumab (DB). The arrow in all figures denotes the end of Cycle 2 (C2). Figure 2A - Overall, vascular endothelial growth factor (VEGF) levels increased with pre-operative treatment. There was no difference in VEGF levels pre-treatment, but at the end of C2, VEGF levels with DB were significantly larger than VEGF levels with D. Figure 2B - Overall, there was a gradual increase in vascular cell adhesion molecule-1 (VCAM-1) levels with treatment. There was no difference in VCAM-1 levels pre-treatment, and only marginally different at the end of C2. Figure 2C - Overall, there was an increase in intracellular adhesion molecule-1 (ICAM-1) with treatment. There was no difference in ICAM-1 levels pre-treatment or after C2. Figure 2D - Overall, there was a decrease in E-selectin levels with treatment. There was no difference in E-selectin levels pre-treatment or at the end of C2.

Figure 3. Changes In DCE-MRI Analysis Of Tumor Volume And Tumor Perfusion

Figure 3A: Bar plot of tumor volume (number of ROI voxel×individual voxel volume) by treatment; docetaxel (D) vs. docetaxel + bevacizumab (DB). Top figure demonstrates the mean ± SEM of all patients treated at baseline, end of cycle 1 (C1) and end of cycle 2 (C2). There was a significant decrease in tumor volume compared with baseline at both C1 and C2. Bottom figure demonstrates the mean ± SEM by treatment; D vs. DB, at baseline, C1 and C2. There was no difference in tumor volume between the two treatments at any time point. Figure 3B: Bar plot of tumor IAUC₉₀ (initial area under the curve for the first 90 seconds post-contrast) by treatment; D vs. DB. Top figure demonstrates all patients treated at baseline, end of C1 and end of C2. Compared with baseline, there was a significant decrease in IAUC₉₀ at C1 and C2. Bottom figure demonstrates the mean ± SEM by treatment; D vs. DB, at baseline, C1, and C2. There was no difference in IAUC₉₀ at baseline, DB had a significant low level of IAUC₉₀ at C1 compared with D, and no significant difference at C2.