BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received - PubMed (original) (raw)

. 2010 Aug 24;103(5):668-75.

doi: 10.1038/sj.bjc.6605736. Epub 2010 Jul 27.

N Makretsov, F M Blows, K E Driver, E Provenzano, J Le Quesne, L Baglietto, G Severi, G G Giles, C A McLean, G Callagy, A R Green, I Ellis, K Gelmon, G Turashvili, S Leung, S Aparicio, D Huntsman, C Caldas, P Pharoah

Affiliations

BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received

S-J Dawson et al. Br J Cancer. 2010.

Erratum in

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.

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Figures

Figure 1

Figure 1

Prognostic significance of BCL2 according to the level of BCL2 expression. (A) Immunohistochemical evaluation of BCL2 staining intensity. Immunohistochemical analysis of BCL2 from the SEARCH series (BCL2 antibody, Dako clone 124, 1 : 200). (B) Kaplan–Meier curve of cumulative survival according to BCL2 staining intensity. 0=no BCL2 staining: _n_=1646, HR=1.00; 1=weak BCL2 staining intensity: _n_=1100, HR=0.76, 95% CI 0.66–0.88, P<0.001; 2=moderate BCL2 staining intensity: _n_=1921, HR=0.55, 95% CI 0.49–0.63, P<0.001; 3=strong BCL2 staining intensity: _n_=3022, HR=0.45, 95% CI 0.40–0.51, P<0.001.

Figure 2

Figure 2

Prognostic significance of BCL2 according to study, tumour characteristics and type of adjuvant therapy. Plot showing the hazard ratio and 95% confidence intervals for BCL2 positivity according to the individual study, tumour characteristics (ER, HER2, TNP (triple-negative phenotype), tumour grade, lymph node status, tumour size) and the type of adjuvant therapy received.

Figure 3

Figure 3

Prognostic significance of BCL2 according to hormonal status, HER2 status and adjuvant therapy. Kaplan–Meier curves of cumulative survival according to (A) BCL2 status: (i) BCL2−, HR=1.00; (ii) BCL2+, HR=0.76, 95% CI 0.66–0.88, P<0.001. (B) Oestrogen receptor and BCL2 status: (i) ER−/BCL2−, HR=1.00; (ii) ER+/BCL2−, HR=0.81, 95% CI 0.69–0.96, _P_=0.012; (iii) ER−/BCL2+, HR=0.62, 95% CI 0.53–0.71, P<0.001; (iv) ER+/BCL2+, HR=0.46, 95% CI 0.42–0.51, P<0.001. (C) Human epidermal growth factor receptor 2 and BCL2 status: (i) HER2−/BCL2−, HR=1.00; (ii) HER2+/BCL2−, HR=1.36, 95% CI 1.17–1.59, P<0.001; (iii) HER2−/BCL2+, HR=0.55, 95% CI 0.49–0.61, P<0.001; (iv) HER2+/BCL2+ _n_=399, HR=0.94, 95% CI 0.78–1.13, _P_=0.52. (D) Triple-negative phenotype (TNP) and BCL2 status: (i) non-TNP/BCL2−, HR=1.00; (ii) TNP/BCL2−, HR=1.43, 95% CI 1.18–1.74, P<0.001; (iii) non-TNP/BCL2+, HR=0.56, 95% CI 0.49–0.65, P<0.001; (iv) TNP/BCL2+, HR=1.19, 95% CI 0.83–1.73, _P_=0.34. (E) Adjuvant chemotherapy and BCL2 status: (i) adjuvant chemotherapy/BCL2−, HR=1.00; (ii) adjuvant chemotherapy/BCL2+, HR=0.76, 95% CI 0.71–0.82, P<0.001. (F) Adjuvant endocrine therapy and BCL2 status: (i) adjuvant endocrine therapy/BCL2−, HR=1.00; (ii) adjuvant endocrine therapy/BCL2+, HR=0.69, 95% CI 0.64–0.75, P<0.001.

Figure 4

Figure 4

BCL2 as a prognostic marker for risk prediction. Relative utility curves comparing the performance of the risk prediction algorithm used by Adjuvant! Online (AOL) with the performance of AOL in combination with BCL2.

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