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

Background: Circulating angiogenic factors are altered in patients with mCRC receiving bevacizumab. Evaluation of alterations in levels of VEGF ligands may provide insights into possible resistance mechanisms. Methods: PlGF, VEGF-A, VEGF-C, and VEGF-D were measured from two cohorts of patients. Sequential plasma samples were obtained from a discovery cohort of 42 patients treated with chemotherapy and bevacizumab. A validation cohort included plasma samples from a cross-sectional of 403 patients prior to chemotherapy, or after progression on a regimen with or without bevacizumab. Results: In the discovery cohort, VEGF-C was increased prior to progression and at progression (+49% and +95%, respectively, p<0.01), consistent with previously reported elevations in PlGF. Levels of VEGF-D were increased (+23%) at progression (p=0.05). In the validation cohort, samples obtained from patients after progression on a regimen with bevacizumab had higher levels of PlGF and VEGF-D (+43% and +6%, p=0.02, p=0.01, respectively) compared to untreated patients, but failed to validate the increase in VEGF-C seen in the first cohort. Patients who progressed on chemotherapy with bevacizumab had significantly elevated levels of PlGF (+88%) but not VEGF-C and VEGF-D compared to patients treated with chemotherapy alone. Elevations of PlGF and VEGF-D appeared transient and returned to baseline with a half-life of 6 weeks. Conclusions: Increases in PlGF and VEGF-D were observed after progression on chemotherapy with bevacizumab. These changes appear to be reversible after discontinuing therapy. These ligands are associated with resistance to bevacizumab-containing chemotherapy in mCRC, but causation remains to be established.