title: Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer.
abstract: OBJECTIVE
  Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab.
  
  
  METHODS
  In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizumab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. MVD was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses.
  
  
  RESULTS
  In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22. VEGF or THBS-2 expression and MVD were not significant prognostic factors.
  
  
  CONCLUSIONS
  These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD.
authors.affiliation: Department of Pathology, Genentech Inc, South San Francisco, CA, USA. adrianjubb@gmail.com
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Wei
authors.initials: W
authors.lastname: Bai
authors.forename: Eric B
authors.initials: EB
authors.lastname: Holmgren
authors.forename: Patti
authors.initials: P
authors.lastname: Tobin
authors.forename: A Steven
authors.initials: AS
authors.lastname: Guerrero
authors.forename: Fairooz
authors.initials: F
authors.lastname: Kabbinavar
authors.forename: Scott N
authors.initials: SN
authors.lastname: Holden
authors.forename: William F
authors.initials: WF
authors.lastname: Novotny
authors.forename: Gretchen D
authors.initials: GD
authors.lastname: Frantz
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Hillan
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D019699:Thrombospondins / Q000032:analysis* / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D000099262:Thrombospondin 2
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D012333:RNA, Messenger; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D000099262:Thrombospondin 2; C467484:VEGFA protein, human