Quantitative analysis of breast cancer tissue microarrays shows high cox-2 expression is associated with poor outcome

Cancer Invest. 2007 Feb;25(1):19-26. doi: 10.1080/07357900601128825.

Abstract

Epidemiologic and preclinical studies suggest that cyclooxygenase-2 (Cox-2) may promote tumor growth and spread by affecting angiogenesis and apoptosis in breast cancer. Using a tissue microarray (TMA), we analyzed the expression and subcellular localization of Cox-2 by AQUA and X-tile, our algorithms for quantitative analysis of protein expression and determination of optimal cutpoints. Our TMA consisted of 669 Stage I-III primary breast cancers. The total tumor and subcellular expression of Cox-2 were then correlated with clinicopathologic factors and with survival. Cox-2 expression appeared higher in malignant than in benign tissue and was predominantly membrane/cytoplasmic (i.e. non-nuclear). X-tile determines an optimum cutpoint on a training set then uses this cutpoint on a validation set. This cutpoint was 19.3 (top 44 percent defined as positive) with high nonnuclear Cox-2 expressers having significantly worse survival. Cox-2 expression also was inversely associated with estrogen receptor (ER) and progesterone receptor (PR), and directly associated with nuclear grade. Multivariate analysis showed that Cox-2 remained a significant prognostic factor for survival independent of tumor size, nodal status, ER, Her2/neu, and grade. In summary, Cox-2 is overexpressed in breast neoplasms, is associated with other markers of poor prognosis, and is significantly associated with worse survival independent of known prognostic factors. Furthermore, AQUA and X-tile analysis suggest an optimal cutpoint that may be helpful in future investigations of Cox-2 and specifically, in studies looking at its expression as a predictive biomarker in clinical trials of Cox-2 inhibitors in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cyclooxygenase 2 / biosynthesis*
  • Female
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Membrane Proteins / biosynthesis*
  • Middle Aged
  • Prognosis
  • Tissue Array Analysis

Substances

  • Biomarkers, Tumor
  • Membrane Proteins
  • Cyclooxygenase 2
  • PTGS2 protein, human