PLoS ONE (Jan 2013)

The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer.

  • Christopher H Lieu,
  • Hai Tran,
  • Zhi-Qin Jiang,
  • Muling Mao,
  • Michael J Overman,
  • E Lin,
  • Cathy Eng,
  • Jeffrey Morris,
  • Lee Ellis,
  • John V Heymach,
  • Scott Kopetz

DOI
https://doi.org/10.1371/journal.pone.0077117
Journal volume & issue
Vol. 8, no. 10
p. e77117

Abstract

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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.