The Association of Alternate VEGF Ligands with Resistance to Anti-VEGF Therapy in Metastatic Colorectal Cancer

3533 Background: Circulating angiogenic factors have been previously shown to be altered in patients (pts) with mCRC on bevacizumab (BV)-containing regimens. However, a systematic evaluation of alterations in levels of the VEGF family of ligands may provide insights into resistance mechanisms. METHODS 42 patients (pts) with mCRC were treated on a single arm phase II study with 5-FU, irinotecan, and BV (FOLFIRI+BV), and plasma was collected for cytokine levels. VEGF-C, VEGF-D, and PlGF were measured using ELISA (R&D) or suspension bead multiplex assay (BioRad). Plasma samples were obtained at baseline, prior to radiographic progression, and at the time of radiographic progression. In a retrospective larger cohort used for validation, plasma from 403 matched pts with mCRC were obtained prior to any chemotherapy or after progression on a regimen with or without bevacizumab. Comparisons were done by the two-sided, nonparametric Wilcoxon paired test. RESULTS Following FOLFIRI+BV treatment, VEGF-C was increased prior to progression and at the time of progression (+43% [p=0.045] and +72% [p=0.004], respectively), similar to previously reported changes in PlGF (+67%, p<0.001). Levels of VEGF-D were increased at the time of progression (+39%, p=0.04). In a larger validation cohort, compared with pre-chemotherapy plasma, samples obtained a median of 3 weeks after progression on a regimen with BV had lower levels of VEGF-C but higher levels of VEGF-D (only +6%, p=0.018) and PlGF (+32%, p<0.0001). When compared to pts receiving chemotherapy alone, pts receiving prior BV had significantly elevated levels of PlGF (+72%, p<0.0001) but not VEGF-C and VEGF-D (+5% and +7%, p=NS). Levels of PlGF and VEGF-D were negatively correlated with the time from last chemotherapy dose to sample collection (p<0.0001) suggesting that changes at the time of progression are transient. CONCLUSIONS Increases in VEGF-D and PlGF were consistently observed after progression on chemotherapy and BV, while VEGF-C changes require further validation. These changes may be reversible after discontinuing therapy. VEGF family ligands other than VEGF itself are associated with BV-containing chemotherapy resistance in mCRC.