title: BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received.
abstract: BACKGROUND
  Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker.
  
  
  METHODS
  Five studies of 11 212 women with early-stage breast cancer were analysed. Individual patient data included tumour size, grade, lymph node status, endocrine therapy, chemotherapy and mortality. BCL2, ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) levels were determined in all tumours. A Cox model incorporating the time-dependent effects of each variable was used to explore the prognostic significance of BCL2.
  
  
  RESULTS
  In univariate analysis, ER, PR and BCL2 positivity was associated with improved survival and HER2 positivity with inferior survival. For ER and PR this effect was time dependent, whereas for BCL2 and HER2 the effect persisted over time. In multivariate analysis, BCL2 positivity retained independent prognostic significance (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.66-0.88, P<0.001). BCL2 was a powerful prognostic marker in ER- (HR 0.63, 95% CI 0.54-0.74, P<0.001) and ER+ disease (HR 0.56, 95% CI 0.48-0.65, P<0.001), and in HER2- (HR 0.55, 95% CI 0.49-0.61, P<0.001) and HER2+ disease (HR 0.70, 95% CI 0.57-0.85, P<0.001), irrespective of the type of adjuvant therapy received. Addition of BCL2 to the Adjuvant! Online prognostic model, for a subset of cases with a 10-year follow-up, improved the survival prediction (P=0.0039).
  
  
  CONCLUSIONS
  BCL2 is an independent indicator of favourable prognosis for all types of early-stage breast cancer. This study establishes the rationale for introduction of BCL2 immunohistochemistry to improve prognostic stratification. Further work is now needed to ascertain the exact way to apply BCL2 testing for risk stratification and to standardise BCL2 immunohistochemistry for this application.
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge CB1 9RN, UK.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Dawson
authors.forename: N
authors.initials: N
authors.lastname: Makretsov
authors.forename: F M
authors.initials: FM
authors.lastname: Blows
authors.forename: K E
authors.initials: KE
authors.lastname: Driver
authors.forename: E
authors.initials: E
authors.lastname: Provenzano
authors.forename: J
authors.initials: J
authors.lastname: Le Quesne
authors.forename: L
authors.initials: L
authors.lastname: Baglietto
authors.forename: G
authors.initials: G
authors.lastname: Severi
authors.forename: G G
authors.initials: GG
authors.lastname: Giles
authors.forename: C A
authors.initials: CA
authors.lastname: McLean
authors.forename: G
authors.initials: G
authors.lastname: Callagy
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.forename: I
authors.initials: I
authors.lastname: Ellis
authors.forename: K
authors.initials: K
authors.lastname: Gelmon
authors.forename: G
authors.initials: G
authors.lastname: Turashvili
authors.forename: S
authors.initials: S
authors.lastname: Leung
authors.forename: S
authors.initials: S
authors.lastname: Aparicio
authors.forename: D
authors.initials: D
authors.lastname: Huntsman
authors.forename: C
authors.initials: C
authors.lastname: Caldas
authors.forename: P
authors.initials: P
authors.lastname: Pharoah
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2