Bcl-2 Is a Prognostic Marker in Breast Cancer Independently of the Nottingham Prognostic Index

Abstract

Purpose: 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. Experimental Design and 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. Conclusion: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.

Different Prognostic Factors Correlate with Bcl-2 Expression among Triple Negative and Non-Triple Negative Breast Cancers

“…A cutoff value was applied to each marker to indicate positive or negative staining (Callagy et al, 2006). For hormone receptors, tumors were considered positive if at least 1% of the tumor cells showed unequivocal nuclear staining (Kreike et al, 2007).…”

“…For Her2/neu, membranous staining was scored for as follows: 0, no staining or faint incomplete staining in <10% cells; 1, faint incomplete staining in >10% cells; 2, weak to moderate complete staining in >10% cells; 3, strong complete staining in >10% cells. Score 3 was considered as positive (Callagy et al, 2006;Kreike et al, 2007). Cytoplasmic staining was scored for Bcl-2.…”

“…To identify additional prognostic markers and improve risk stratification for breast cancer, further studies suggested combining protein markers used to define these molecular subtypes (Callagy et al, 2006;Nadler et al, 2008;Dawson et al, 2010). Indeed, they showed that only Bcl-2 added prognostic information independent of the other accepted prognostic factors (Callagy et al, 2006).…”

“…Indeed, they showed that only Bcl-2 added prognostic information independent of the other accepted prognostic factors (Callagy et al, 2006). Bcl-2 (acronym for the B-cell lymphoma/leukemia-2 gene) was first discovered in B-cell malignancies (Tsujimoto and Croce, 1986).…”

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

“…However, other studies suggest a paradoxical relationship between oncogenesis and the Bcl-2 family. Bcl-2 expression delays tumor formation in animal models [4,5] and high expression of Bcl-2 is a favorable, independent prognostic factor in breast cancer [6]. Other studies link high expression of pro-apoptotic Bax to accelerated cancer formation and to unfavorable prognosis [4,7].…”