title: Morphologic complexity of epithelial architecture for predicting invasive breast cancer survival.
abstract: BACKGROUND
  Precise criteria for optimal patient selection for adjuvant chemotherapy remain controversial and include subjective components such as tumour morphometry (pathological grade). There is a need to replace subjective criteria with objective measurements to improve risk assessment and therapeutic decisions. We assessed the prognostic value of fractal dimension (an objective measure of morphologic complexity) for invasive ductal carcinoma of the breast.
  
  
  METHODS
  We applied fractal analysis to pan-cytokeratin stained tissue microarray (TMA) cores derived from 379 patients. Patients were categorized according to low (<1.56, N = 141), intermediate (1.56-1.75, N = 148), and high (>1.75, N = 90) fractal dimension. Cox proportional-hazards regression was used to assess the relationship between disease-specific and overall survival and fractal dimension, tumour size, grade, nodal status, estrogen receptor status, and HER-2/neu status.
  
  
  RESULTS
  Patients with higher fractal score had significantly lower disease-specific 10-year survival (25.0%, 56.4%, and 69.4% for high, intermediate, and low fractal dimension, respectively, p < 0.001). Overall 10-year survival showed a similar association. Fractal dimension, nodal status, and grade were the only significant (P < 0.05) independent predictors for both disease-specific and overall survival. Among all of the prognosticators, the fractal dimension hazard ratio for disease-specific survival, 2.6 (95% confidence interval (CI) = 1.4,4.8; P = 0.002), was second only to the slightly higher hazard ratio of 3.1 (95% CI = 1.9,5.1; P < 0.001) for nodal status. As for overall survival, fractal dimension had the highest hazard ratio, 2.7 (95% CI = 1.6,4.7); P < 0.001). Split-sample cross-validation analysis suggests these results are generalizable.
  
  
  CONCLUSIONS
  Except for nodal status, morphologic complexity of breast epithelium as measured quantitatively by fractal dimension was more strongly and significantly associated with disease-specific and overall survival than standard prognosticators.
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Canada. mtambasc@ucalgary.ca
authors.forename: Mauro
authors.initials: M
authors.lastname: Tambasco
authors.forename: Misha
authors.initials: M
authors.lastname: Eliasziw
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000473:pathology*; D004848:Epithelium / Q000473:pathology*; D005260:Female; D017709:Fractals; D006801:Humans; D053208:Kaplan-Meier Estimate; D007633:Keratins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D007633:Keratins