title: Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial.
abstract: OBJECTIVE
  Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA single-nucleotide polymorphisms (SNP) and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here.
  
  
  METHODS
  E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. FISH to assess gene amplification status for VEGFA was conducted on paraffin-embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was conducted.
  
  
  RESULTS
  Estrogen receptor (ER)+ or progesterone receptor (PR)+ tumors were less likely to have VEGFA amplification than ER/PR- tumors (P = 0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; P = 0.013) in univariate analysis with a trend for worse OS in multivariate analysis (P = 0.08). There was a significant interaction between VEGFA amplification, hormone receptor status, and study arm. Patients with VEGFA amplification and triple-negative breast cancers (TNBC) or HER2 amplification had inferior OS (P = 0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior progression-free survival (PFS; P = 0.010) and OS (P = 0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant.
  
  
  CONCLUSIONS
  VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab.
authors: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202, USA. bpschnei@iupui.edu
authors: Bryan P
authors: BP
authors: Schneider
authors: Robert J
authors: RJ
authors: Gray
authors: Milan
authors: M
authors: Radovich
authors: Fei
authors: F
authors: Shen
authors: Gail
authors: G
authors: Vance
authors: Lang
authors: L
authors: Li
authors: Guanglong
authors: G
authors: Jiang
authors: Kathy D
authors: KD
authors: Miller
authors: Julie R
authors: JR
authors: Gralow
authors: Maura N
authors: MN
authors: Dickler
authors: Melody A
authors: MA
authors: Cobleigh
authors: Edith A
authors: EA
authors: Perez
authors: Tamara N
authors: TN
authors: Shenkier
authors: Kirsten
authors: K
authors: Vang Nielsen
authors: Sven
authors: S
authors: Müller
authors: Ann
authors: A
authors: Thor
authors: George W
authors: GW
authors: Sledge
authors: Joseph A
authors: JA
authors: Sparano
authors: Nancy E
authors: NE
authors: Davidson
authors: Sunil S
authors: SS
authors: Badve
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human