P2-12-08: Bcl-2 as a Prognostic Marker in Breast Cancer Patients Receiving Endocrine Therapy.
Authors: Larsen MS , Bjerre KD , Laenkholm A-V , Giobbie-Hurder A , Ejlertsen B , Lykkesfeldt AE , Rasmussen BB 
Published: June 2012

Background: In breast cancer patients with estrogen receptor (ER) positive tumors, endocrine treatment reduces recurrence. However, 30% of patients eventually relapse in spite of therapy. Additional markers to identify this group of therapy resistant, prognostically unfavourable patients are therefore needed. The expression of Bcl-2 has been shown to be a prognostic factor in breast cancer patients regardless of ER-status, but assessment of Bcl-2 by immunohistochemistry (IHC) needs to be standardized since different scoring systems and different cut-points have been used. In a pilot study comprising 258 ER positive tumors from tamoxifen-treated patients, a simple scoring system enabled us to find suitable cut-points, selecting patient-groups with poor prognosis. The aim of the current study was to validate these results in a similar population from a large randomised study.

Material and methods: Bcl-2 was assessed in 1082 (78%) of the 1396 postmenopausal Danish patients who in the BIG 1–98 trial were randomised to 5 years of tamoxifen (N=325), letrozole (N=335) or a sequence of these agents (N=422). Tissue microarrays were made from formalin fixed paraffin embedded primary tumors. An IHC score for expression of cytoplasmic Bcl-2 (clone 124, Dako) was performed according to both the number of positive cells (0%=0, 1–10%=1, 11–50%=2, 51–100%=3) and the intensity of the staining (weak, moderate, strong) as in the pilot study. The associations between Bcl-2 status and clinicopathological variables were assessed. The prognostic value of Bcl-2 according to cut-points determined in the pilot study was analysed by Cox proportional hazards models. The primary endpoint was disease free survival (DFS).

Results: Patients were divided into three subgroups according to predefined cut-points: Bcl-2 low (score 0 or 1 (n= 24)), Bcl-2 intermediate (score 2 or score 3/weak or moderate (n= 216)) and Bcl-2 high (score 3/strong (n= 842)). Bcl-2 expression was significantly associated with ER (P=0.0003) and progesterone receptor (PgR) (P&lt;0.0001), and negatively associated with Ki-67 (P=0.0021) and tumor grade (P=0.005). In univariate analysis patients in the Bcl-2 low group had a bad prognosis compared to the Bcl-2 high group (HR=2.3; 95% CI: 1.2 to 4.1). In the multivariable analysis including ER, PgR, Ki-67, positive lymph nodes, age, tumor size and histological type and grading, association between Bcl-2 and DFS was not statistically significant (P=0.35).

Discussion: We found Bcl-2 to be a prognostic factor in the univariate analysis (P=0.024) but not to be an independent predictor of poor survival of ER positive patients treated with tamoxifen and/or letrozole. In this population a low or absent expression of Bcl-2 was uncommon (2.2 %), as expected since Bcl-2 is an ER regulated protein. The results of the pilot study could not be confirmed in this validation study. However, the strong positive relation to other prognostic factors like tumor grade and high proliferative index indicates that Bcl-2 could contribute to factors characterising a group of tumors with a bad prognosis.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-08.