title: Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival.
abstract: BACKGROUND
  The development of targeted therapies has undoubtedly broadened therapeutic options for patients with colorectal cancer (CRC). The use of bevacizumab to reduce angiogenesis has been associated with improved clinical outcomes. However, an urgent need for prognostic/predictive biomarkers for anti-angiogenic therapies still exists.
  
  
  METHODS
  Clinical data of 105 CRC patients treated with bevacizumab in conjunction with chemotherapy were analyzed. The expression of vascular endothelial growth factor (VEGF) receptors, NOTCH1 receptor and its ligand DLL4 were determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. The association between protein expression and clinicopathological characteristics and outcomes was determined.
  
  
  RESULTS
  Bevacizumab was administered as a first-line of treatment in 70.5 % of our cases. The median progression-free survival (PFS) was 10.2 months. The median overall survival (OS) of the total cohort was 24.4 months. Bevacizumab, as the first-line of treatment, and the presence of liver metastasis were independently associated with objective response rate. Membrane VEGFR1 and VEGFR3 expressions were associated with the presence of lung metastasis; interestingly, VEGFR3 was associated with less liver metastasis. NOTCH1 expression was associated with lymph node metastasis. There was a trend toward association between improved PFS and lower NOTCH1 expression (p = 0.06). Improved OS was significantly associated with lower NOTCH1 expression (p = 0.01). In a multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status, liver metastasis, histological grade, and NOTCH1 expression were independently associated with OS.
  
  
  CONCLUSIONS
  Our findings illustrated the expression profile of angiogenesis-related proteins and their association with clinicopathological characteristics and outcomes. NOTCH1 expression is a detrimental prognostic factor in metastatic CRC patients treated with chemotherapy plus bevacizumab.
authors.affiliation: Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil. tadeufpaivajr@hotmail.com.
authors.forename: Tadeu Ferreira
authors.initials: TF
authors.lastname: Paiva
authors.affiliation: Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil. victorhugoba@gmail.com.
authors.forename: Victor Hugo Fonseca
authors.initials: VH
authors.lastname: de Jesus
authors.affiliation: Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil. raulmarques81@yahoo.com.br.
authors.forename: Raul Amorim
authors.initials: RA
authors.lastname: Marques
authors.affiliation: Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil. alexandreandredacosta@gmail.com.
authors.forename: Alexandre André Balieiro Anastácio
authors.initials: AA
authors.lastname: da Costa
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil. maripetaccia@gmail.com.
authors.forename: Mariana Petaccia
authors.initials: MP
authors.lastname: de Macedo
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil. patricia_peresi@hotmail.com.
authors.forename: Patricia Maria
authors.initials: PM
authors.lastname: Peresi
authors.affiliation: Department of Statistics, Centro Internacional de Pesquisa e Ensino - Fundação Antônio Prudente, São Paulo, Brazil. damascena@cipe.accamargo.org.br.
authors.forename: Aline
authors.initials: A
authors.lastname: Damascena
authors.affiliation: PhD/MSc Program, Hospital Sírio-Libanês, São Paulo, Brazil. nmrossi@me.com.
authors.forename: Benedito Mauro
authors.initials: BM
authors.lastname: Rossi
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil. mariadirlei@gmail.com.
authors.forename: Maria Dirlei
authors.initials: MD
authors.lastname: Begnami
authors.affiliation: Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil. vladcclima@gmail.com.|Department of Clinical Oncology, 1° Subsolo, Edifício Hilda Jacob R. Prof. Antônio Prudente, 211, São Paulo, ZC 01509-900, Brazil. vladcclima@gmail.com.
authors.forename: Vladmir Cláudio Cordeiro
authors.initials: VC
authors.lastname: de Lima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000068258:Bevacizumab; C581309:FLT4 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3