title: First application of the Automated QUantitative Analysis (AQUA) technique to quantify PTEN protein expression in ovarian cancer: A correlative study of NCIC CTG OV.16.
abstract: BACKGROUND
  Platinum resistance is a dominant cause of poor outcomes in advanced ovarian cancer (OC). A mechanism of platinum resistance is the inhibition of apoptosis through phosphatidylinositol 3 kinase (PI3K) pathway activation. The role of phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, as a tumor biomarker is unclear. Quantitative analysis of PTEN expression as an alternative to immunohistochemistry has not been considered.
  
  
  METHODS
  In 238 patient tumors from the NCIC-CTG trial OV.16, PTEN protein expression was quantified by Automated QUantitative Analysis (AQUA). Cox model was used to study the association between PTEN expression and clinical outcomes using a minimum p-value approach in univariate analysis. Multivariate analysis was used to adjust for clinical and pathological parameters.
  
  
  RESULTS
  PTEN scores (range 13.9-192.3) of the 202 samples that passed quality control were analyzed. In univariate analysis, there was a trend suggesting an association between PTEN expression by AQUA as a binary variable (low ≤61 vs high >61) and progression free survival (HR=0.77, p=0.083), and in multivariate analysis, this association approached significance (HR=0.74, p=0.059). The relationship between quantitative PTEN expression and PFS differed (p=0.01 for interaction) by the extent of surgical debulking (residual disease (RD) <1cm or ≥1cm), with a numerically superior PFS in patients with high PTEN (23.5 vs 14.9m) only when RD<1cm (p=0.19). There was no association between PTEN levels and overall survival.
  
  
  CONCLUSIONS
  AQUA is a novel method to measure PTEN expression. Further study of PTEN as a biomarker in OC is warranted.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada; Division of Gynecologic Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address: jweberpals@ottawahospital.on.ca.
authors.forename: J I
authors.initials: JI
authors.lastname: Weberpals
authors.affiliation: Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Amin
authors.affiliation: NCIC-CTG, Kingston, Ontario, Canada.
authors.forename: B E
authors.initials: BE
authors.lastname: Chen
authors.affiliation: NCIC-CTG, Kingston, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Tu
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
authors.forename: J N
authors.initials: JN
authors.lastname: Spaans
authors.affiliation: Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: J A
authors.initials: JA
authors.lastname: Squire
authors.affiliation: NCIC-CTG, Kingston, Ontario, Canada; Department of Oncology, Queen's University, Kingston, Ontario, Canada.
authors.forename: E A
authors.initials: EA
authors.lastname: Eisenhauer
authors.affiliation: NCIC-CTG, Kingston, Ontario, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Virk
authors.affiliation: Department of Mathematics and Statistics, Queen's University, Kingston, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Ma
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Duciaume
authors.affiliation: BC Cancer Centre, Vancouver, British Columbia, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Hoskins
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: D P
authors.initials: DP
authors.lastname: LeBrun
mesh_terms: D000368:Aged; D001331:Automation; D014408:Biomarkers, Tumor / Q000032:analysis*; D065426:Cytoreduction Surgical Procedures; D018572:Disease-Free Survival; D005187:Fallopian Tubes / Q000737:chemistry; D005260:Female; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D018365:Neoplasm, Residual; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000601:surgery*; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: AQUA; BRCA1; Ovarian carcinoma; PTEN