title: Quantitative analysis of breast cancer tissue microarrays shows high cox-2 expression is associated with poor outcome.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Maciej P
authors.initials: MP
authors.lastname: Zerkowski
authors.forename: Robert L
authors.initials: RL
authors.lastname: Camp
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Burtness
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Gina G
authors.initials: GG
authors.lastname: Chung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human