title: Clinical genotyping and efficacy outcomes: exploratory biomarker data from the phase II ABIGAIL study of first-line bevacizumab plus chemotherapy in non-squamous non-small-cell lung cancer.
abstract: OBJECTIVE
  ABIGAIL, a phase II, randomized, open-label, multicenter study evaluated the correlation between biomarkers and best overall response (BOR) to bevacizumab with chemotherapy in patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Exploratory analyses of vascular endothelial growth factor (VEGF) clinical genotyping data are presented.
  
  
  METHODS
  A total of 303 patients with NSCLC were randomized to receive bevacizumab 7.5mg/kg or 15mg/kg until progression or unacceptable toxicity (plus six cycles of chemotherapy). Patients provided blood samples for biomarker analysis. Exploratory analyses were conducted to assess whether genetic variants in VEGF-A or VEGFR-1/-2 act as efficacy or safety biomarkers. Single nucleotide polymorphisms (SNPs) were determined using individual genotyping assays. DNA analysis for 12 SNPs across three genes is reported: VEGF-A (five SNPs), VEGFR-1 (three SNPs), and VEGFR-2 (four SNPs).
  c.+405/c.-634 (CG), VEGF-A: c.-460 >C; c-1498 >C (CT), and
  c.-2578 C>A were associated with >50% higher odds of responding to treatment. VEGFR-1: rs9554316 (GT) was associated with >30% higher risk of progression and >40% higher risk of death.
  c.+936 C>T was associated with higher incidence of hypertension.
  
  
  CONCLUSIONS
  Four genetic variants of VEGF-A and VEGFR-1 were associated with bevacizumab treatment outcome. Three variants in VEGF-A were associated with increased BOR, one variant in VEGFR-1 was associated with worse progression-free survival/overall survival. These associations were not statistically significant after correction for multiple testing. No genetic variant was associated with significantly higher risk of hypertension. Replication in additional studies may provide insight into the use of these variants to predict response to bevacizumab.
authors.affiliation: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Pallaud
authors.affiliation: Department of Thoracic Oncology, LungClinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Wöhrendamm 80, 22927 Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Országos Korányi TBC és Pulmonológiai Intézet, Pihenő str 1, 1121 Budapest, Hungary.
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Juhasz
authors.affiliation: Markusovszky Teaching Hospital, Markusovszky u. 5, 9700 Szombathely, Hungary.
authors.forename: Barna
authors.initials: B
authors.lastname: Szima
authors.affiliation: National Taiwan University Hospital, No. 1, Changde St., Zhongzheng Dist., Taipei City 10048, Taiwan.
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Arkhangelsk Clinical Oncology Dispensary, Obvodny kanal Avenue 145, building 1, Arkhangelsk, Arkhangelsk region, 163045 Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Burdaeva
authors.affiliation: St Petersburg State Medical University, St Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.affiliation: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Magalie
authors.initials: M
authors.lastname: Hilton
authors.affiliation: Roche Products Ltd, Shire Park, 1 Falcon Way, Welwyn Garden City, Hertfordshire AL7 1TW, UK.
authors.forename: Venice
authors.initials: V
authors.lastname: Archer
authors.affiliation: Department of Clinical Oncology, State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. Electronic address: tony@clo.cuhk.edu.hk.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Bevacizumab; Biomarkers; Clinical genotyping; First-line; NSCLC; VEGF