Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy

Naoko Honma,Yoshinori Ito,Takuji Iwase,Futoshi Akiyama,Rie Horii,Mamoun Younes,Shigehira Saji

doi:10.1186/s12885-015-1686-y

Naoko Honma, Yoshinori Ito + Show 5 more

Open Access

https://doi.org/10.1186/s12885-015-1686-y

Copy DOI

Abstract

BackgroundBcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. In breast cancer, however, Bcl-2 expression has been reported to be a favorable prognostic factor. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. We constructed a large systematic study to determine whether Bcl-2 has an independent role in breast cancer.MethodsBcl-2 expression was immunohistochemically evaluated and compared with other clinicopathological factors, including clinical outcome, in 1081 breast cancer cases with long follow-up, separately analyzing 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy. The χ2-test for independence using a contingency table, the Kaplan-Meier method with the log-rank test, and a Cox proportional hazards model were used for the comparison of clinicopathological factors, assessment of clinical outcome, and multivariate analyses, respectively.ResultsIn both patient groups, Bcl-2 expression strongly correlated with positive ER/PR status, low grade, negative human epidermal growth factor receptor 2 (HER2) status, and small tumor size, as previously reported. Bcl-2 expression did not independently predict clinical outcome in patients with ER-positive and/or PR-positive tumors or in those who received tamoxifen treatment; however, it was an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative (ER-negative/PR-negative/HER2-negative) tumors who received no adjuvant therapy. The latter was even more evident in postmenopausal women: those with hormone receptor-negative or triple-negative tumors lacking Bcl-2 expression showed a favorable outcome.ConclusionBcl-2 expression is an independent poor prognostic factor in patients with hormone receptor-negative or triple-negative breast cancers, especially in the absence of adjuvant therapy, suggesting that the anti-apoptotic effect of Bcl-2 is clearly exhibited under such conditions. The prognostic value of Bcl-2 was more evident in postmenopausal women. The present findings also highlight Bcl-2 as a potential therapeutic target in breast cancers lacking conventional therapeutic targets such as triple-negative tumors. The favorable prognosis previously associated with Bcl-2-positive breast cancer probably reflects the indirect effect of frequently coexpressed hormone receptors and adjuvant endocrine therapy.

Highlights

Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2
Comparison of Bcl-2 expression with other clinicopathological factors Bcl-2 positivity was significantly correlated with smaller tumor size, lower grade, estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, and human epidermal growth factor receptor 2 (HER2) negativity, in both groups with and without tamoxifen therapy
In the tamoxifen-treated group, Bcl-2 positivity correlated with better Overall survival (OS) in overall patients and in the subgroup with ER-positive and/or PR-positive tumors, but with poor OS in the subgroups with ER-negative and PR-negative tumors or with triple-negative tumors (Fig. 3); Bcl-2 was not an independent predictor of clinical outcome in overall patients or subgroups when ER/PR or HER2 status is taken into consideration (Table 3)

Summary

Introduction

Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. In the case of breast cancer, determining estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression has been routine practice for years. New targets are need to increase treatment options for breast cancer patients, especially with tumors lacking conventional therapeutic targets. Bcl-2 protein, coded by the bcl-2 gene [1], plays an anti-apoptotic role and inhibits cell death [2], resulting in prolonged cell survival [3]. There is increasing evidence to suggest that Bcl-2 targeting therapy may be an effective treatment for many cancers [9,10,11,12,13,14,15]

Methods

Results

Discussion

Conclusion