Relative impact of chemotherapy with or without bevacizumab on cytokines and angiogenic factors (CAFs) in metastatic colorectal cancer.

Abstract

401 Background: CAFs were previously shown to be modulated in patients (pts) with metastatic colorectal cancer (mCRC) after bevacizumab-containing chemotherapy. Validation of these prior findings is warranted. In addition, the relative impact of bevacizumab and the cytotoxic chemotherapy components on CAFs has not been previously described. Methods: Plasma samples from 403 mCRC pts were obtained prior to any chemotherapy (Group A) or after progression on a regimen without or with bevacizumab (Group B and C, respectively) between 2002 and 2008. Samples were matched for number of metastatic disease sites (Groups A, B, C) and for prior chemotherapy duration, and time from last chemotherapy dose to sample collection (Groups B, C). Levels of 48 CAFs were measured by suspension bead multiplex assays (BioRad and EMD). Comparisons of Groups A v C (n=169 pairs) and Groups B v C (n=65 pairs) were by the two-sided, nonparametric Wilcoxon paired test, with p<0.05 significance for confirmation of previous CAF results. Results: Prior chemotherapy duration (6.5mo, 6.7mo), and time from last chemotherapy dose to sample collection (1.3mo, 1.2 mo) were similar for Groups B and C, respectively. Results were available for 80% of the samples. Compared to Group A, Group B had reductions in multiple CAFs, including IL-8 (-38%, p<0.0001) and PDGF (-62%, p<0.0001). Commensurate with prior results, PlGF, Eotaxin and TRAIL were increased in Group C by 30% (p<0.0001), 23% (p=0.024) and 19% (p=0.008) respectively. Most CAF changes were attributable to chemotherapy alone. However, PlGF (-31%, p<0.0001) and TRAIL (+26%, p=0.037) significantly differed in Groups B v C. In group C compared to A, multiple changes were seen in the EGFR-axis including decreases in EGF (-52%, p=0.032), epiregulin (-25%, p=0.0023), and HB-EGF (-40%, p<0.0001) as well as an increase in sEGFR (+10%, p=0.004). Conclusions: Most changes in CAFs after treatment with bevacizumab-containing chemotherapy appear to be due to chemotherapy alone and not attributable to anti-VEGF therapy, with several notable exceptions. Chemotherapy-induced changes in the EGFR-axis have not previously been described in mCRC and warrant further investigation. [Table: see text]