title: Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham Prognostic Index.
abstract: OBJECTIVE
  Prognostication of breast cancer using clinicopathologic variables, although useful, remains imperfect. Many reports suggest that gene expression profiling can refine the current approach. Alternatively, it has been shown that panels of proteins assessed by immunohistochemistry might also be useful in this regard. We evaluate the prognostic potential of a panel of markers by immunohistochemistry in a large case series to establish if either a single marker or a panel could improve the prognostic power of the Nottingham Prognostic Index (NPI). We validated the results in an independent series.
  
  
  RESULTS
  The expression of 13 biomarkers was evaluated in 930 breast cancers on a tissue microarray. Eight markers [estrogen receptor (ER), progesterone receptor (PR), Bcl-2, cyclin E, p53, MIB-1, cytokeratin 5/6, and HER2] showed a significant association with survival at 10 years on univariate analysis. On multivariate analysis that included these eight markers and the NPI, only the NPI [hazard ratio (HR), 1.35; 95% confidence interval (95% CI), 1.16-1.56; P = 0.0005], ER (HR, 0.59; 95% CI, 0.39-0.88; P = 0.011), and Bcl-2 (HR, 0.68; 95% CI, 0.46-0.99; P = 0.055) were significant. In a subsequent multivariate analysis that included the NPI, ER, and Bcl-2, only Bcl-2 (HR, 0.62; 95% CI, 0.44-0.87; P = 0.006) remained independent of NPI (HR, 1.50; 95% CI, 1.16-1.56; P = 0.004). In addition, Bcl-2, used as a single marker, was more powerful than the use of a panel of markers. Based on these results, an independent series was used to validate the prognostic significance of Bcl-2. ER and PR were also evaluated in this validation series. Bcl-2 (HR, 0.83; 95% CI, 0.71-0.96; P = 0.018) retained prognostic significance independent of the NPI (HR, 2.04; 95% CI, 1.67-2.51; P < 0.001) with an effect that was maximal in the first 5 years.
  
  
  CONCLUSIONS
  Bcl-2 is an independent predictor of breast cancer outcome and seems to be useful as a prognostic adjunct to the NPI, particularly in the first 5 years after diagnosis.
authors.affiliation: Cancer Genomics Program, Department of Oncology, Hutchison-Medical Research Council Research Centre, University of Cambridge, United Kingdom.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Callagy
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Pinder
authors.forename: Forrest D
authors.initials: FD
authors.lastname: Hsu
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: Joseph
authors.initials: J
authors.lastname: Ragaz
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D016009:Chi-Square Distribution; D019927:Cyclin E / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007633:Keratins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D007633:Keratins; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53