title: Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer.
abstract: OBJECTIVE
  In recent studies, we showed that TP53 gene mutation or high levels of cytosolic vascular endothelial growth factor (VEGF) in estrogen receptor (ER)-alpha-positive primary breast tumors predict a poor disease outcome for patients treated with first-line tamoxifen for advanced disease. Mutant TP53 may up-regulate VEGF, whereas, on the other hand, wild-type TP53 may decrease VEGF production.
  
  
  METHODS
  In the present study, we aimed to assess the combined predictive value of TP53 gene mutation and VEGF status of 160 advanced breast cancer patients with ER-positive tumors who were treated with tamoxifen (median follow-up from start of tamoxifen treatment, 64 months). To assess TP53 gene mutation status, the entire open reading frame was sequenced; for VEGF status, an ELISA was used.
  
  
  RESULTS
  In univariate analysis, both TP53 gene mutation (28% of the tumors) and a VEGF level above the median value were significantly associated with a short progression-free survival, post-relapse overall survival, and a poor rate of response to tamoxifen. In Cox multivariate regression analysis including the traditional predictive factors, the addition of TP53 gene mutation and VEGF status, alone or in combination, significantly predicted a poor efficacy of tamoxifen treatment. When the two factors were combined, a significantly decreased odds ratio was seen for the rate of response (odds ratio, 0.27). Similarly, an increased hazard ratio (HR) was seen for progression-free survival (HR, 2.32) and post-relapse overall survival (HR, 1.68) in the group with mutant TP53 and high VEGF compared with the group with both risk factors absent.
  
  
  CONCLUSIONS
  Combined TP53 gene mutation status and high VEGF levels of ER-positive primary breast tumors independently predict a poor course of the disease of patients with advanced breast cancer treated with tamoxifen. These patients, having unfavorable tumor characteristics, might benefit more from other types of (individualized) treatment protocols.
authors.affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed, 3000 DR Rotterdam, the Netherlands. pm.j.j.berns@erasmusmc.nl
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Nicolai
authors.initials: N
authors.lastname: Grebenchtchikov
authors.forename: Rolf
authors.initials: R
authors.lastname: Vossen
authors.forename: Harry
authors.initials: H
authors.lastname: Peters
authors.forename: Anneke
authors.initials: A
authors.lastname: Geurts-Moespot
authors.forename: Henk
authors.initials: H
authors.lastname: Portengen
authors.forename: Iris L
authors.initials: IL
authors.lastname: van Staveren
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-van Gelder
authors.forename: Bert
authors.initials: B
authors.lastname: Bakker
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015999:Multivariate Analysis; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D016017:Odds Ratio; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen