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.

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

“…This is consistent with the results obtained previously (Park et al, 2002;Neri et al, 2006), which indicate that the expression of Bcl-2 is a marker of breast cancer with reduced capability of distant colonization even in presence of lymphovascular invasion (Neri et al, 2006). On the contrary, Nadler et al (2008), found no association between expression of Bcl-2 and nodal status and Dawson et al (2010), verified the prognostic impact of Bcl-2 positivity regardless of lymph node status.…”

“…This is not surprising because a recent study proved that Bcl-2 is a prognostic factor in women with both ER positive and ER negative disease and also in women with both Her2 negative and Her2 positive disease and its positivity is maintained across various molecular subtypes of breast cancer (Dawson et al, 2010). Although the frequency of Bcl-2 expression ranged from 69-73% in previous studies (Dawson et al, 2010;Kallel-Bayoudh et al, 2011), a controversy exists because they found that TNBC tend commonly to have lower Bcl-2 expression compared to non-TNBC (Tawfik et al, 2010;de Ruijter et al, 2011), moreover, Bcl-2 oncogene expression was found to be statistically greater in the ER positive breast tumors compared to ER negative tumors (dos Santos et al, 2008). Such discrepancies between the studies are likely to be due to the wide variation between the methodologies and types of cases studied (Cecka et al, 2008).…”

“…In this study, immunohistochemistry was used to measure protein expression levels of several biomarkers including Bcl-2, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2) in 77 cases of breast cancer who were divided into two groups triple-negative (TNBC) and non-triple-negative (non-TNBC). In contrast gene expression signatures, immunohistochemical analysis of Bcl-2 protein expression is a simple, well-validated, inexpensive and widely available test (used routinely in diagnostic pathology of low-grade lymphoproliferative disorders) (Dawson et al, 2010).…”

“…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).…”

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

“…It was previously reported that GATA-3 functions as a critical regulator of commitment and maturation of cancer cells in the luminal A epithelial lineage, i.e., the expression of GATA-3 regulates luminal differentiation (37). The anti-apoptotic marker Bcl-2 has been proven to be an independent molecular signature, alone or in combination with Ki-67 as a marker pair, in the luminal type of breast cancer (38)(39)(40)(41)(42).…”