title: Proangiogenic tumor proteins as potential predictive or prognostic biomarkers for bevacizumab therapy in metastatic colorectal cancer.
abstract: Tumor biomarkers to more accurately predict a patient's response to a given therapy are much needed in oncology practice. For metastatic colorectal cancer the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab is now commonly included in first-line therapy regimens and has led to modest but significant improvements in patient outcomes compared with chemotherapy. Given the modest gains there is a pressing need for predictive biomarkers to better identify patients who would benefit from this targeted therapy. We used a multiplex protein assay to determine the tumor expression levels of the proangiogenic proteins IL-6, IL-8, bFGF, PDGF-BB and VEGF-A in formalin-fixed paraffin-embedded tumors from the MAX clinical trial patients with available tissue samples. Patients were dichotomized into "low" vs. "high" expression subgroups based on median baseline levels to correlate with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). "Low" tumor VEGF-A level was predictive of better ORR for bevacizumab [ORR (low) 53% vs. (high) 19%, interaction p = 0.03] but not for PFS [hazard ratio, HR (low) 0.73 vs. (high) 0.62, interaction p = 0.68] in the comparison of capecitabine (C) versus C and bevacizumab (CB) and CB plus mitomycin (M). When analyzed as a dichotomized variable, "high" VEGF-A was prognostic for shorter PFS (unadjusted HR 1.34, p = 0.06; adjusted HR 1.55, p = 0.008). The other four proteins were neither predictive of bevacizumab benefits nor prognostic for ORR, PFS or OS. "Low" tumor VEGF-A was associated with longer PFS after adjustment for other baseline factors. Proangiogenic proteins were not predictive of benefit with bevacizumab for PFS.
authors.affiliation: Haematology-Oncology Department, Basil Hetzel Institute,The Queen Elizabeth Hospital, Woodville, SA, Australia.
authors.forename: Maressa A
authors.initials: MA
authors.lastname: Bruhn
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Townsend
authors.forename: Chee
authors.initials: C
authors.lastname: Khoon Lee
authors.forename: Aravind
authors.initials: A
authors.lastname: Shivasami
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Price
authors.forename: Joe
authors.initials: J
authors.lastname: Wrin
authors.forename: Georgia
authors.initials: G
authors.lastname: Arentz
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: Christopher
authors.initials: C
authors.lastname: Hocking
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Hardingham
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D042501:Angiogenic Proteins / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000077214:Becaplermin; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D016209:Interleukin-8; D020574:Proto-Oncogene Proteins c-sis; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D000068258:Bevacizumab
keywords: angiogenic proteins; bevacizumab therapy; predictive biomarkers