title: Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients.
abstract: BACKGROUND
  We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS).
  
  
  METHODS
  DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization.
  
  
  RESULTS
  After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes.
  
  
  CONCLUSIONS
  Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00203502.
authors.affiliation: Division of Hematology/Oncology Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Issam
authors.identifier: http://orcid.org/0000-0001-8646-5658
authors.initials: I
authors.lastname: Makhoul
authors.affiliation: Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Valentina K
authors.initials: VK
authors.lastname: Todorova
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Siegel
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Ishwori
authors.initials: I
authors.lastname: Dhakal
authors.affiliation: Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Vinay R
authors.initials: VR
authors.lastname: Raj
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Jeannette Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Orloff
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
authors.affiliation: Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Ronda S
authors.initials: RS
authors.lastname: Henry-Tillman
authors.affiliation: Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.|Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Klimberg
authors.affiliation: Division of Hematology/Oncology Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Hutchins
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Kadlubar
mesh_terms: D000328:Adult; D000368:Aged; D042683:Angiopoietin-1 / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics; D000068258:Bevacizumab / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D017322:Clinical Trials, Phase II as Topic; D005006:Ethnicity; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009389:Neovascularization, Pathologic / Q000235:genetics; D064887:Observational Studies as Topic; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D042787:Receptor, TIE-2 / Q000235:genetics; D012044:Regression Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C467630:ANGPT1 protein, human; C586513:ANGPT2 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000068258:Bevacizumab; D042787:Receptor, TIE-2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9