title: The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer.
abstract: 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.
authors.affiliation: Division of Medical Oncology, University of Colorado, Denver, Colorado, United States of America.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lieu
authors.forename: Hai
authors.initials: H
authors.lastname: Tran
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Jiang
authors.forename: Muling
authors.initials: M
authors.lastname: Mao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.forename: E
authors.initials: E
authors.lastname: Lin
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Morris
authors.forename: Lee
authors.initials: L
authors.lastname: Ellis
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008024:Ligands; D008565:Membrane Proteins; C098069:PIGF protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab