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

Honma N, Horii R, Ito Y, Saji S, Younes M, Iwase T, Akiyama F - BMC Cancer (2015)

Bottom Line: Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2.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.The prognostic value of Bcl-2 was more evident in postmenopausal women.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan. naoko.honma@med.toho-u.ac.jp.

ABSTRACT

Background: Bcl-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.

Methods: Bcl-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 χ (2)-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.

Results: In 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.

Conclusion: Bcl-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.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier disease-free (a, c, e, g) and overall survival (b, d, f, h) curves among patients with tamoxifen monotherapy. Bold lines, Bcl-2-positive; thin lines, Bcl-2-negative. Total patients (a, b), patients with ER-positive and/or PR-positive tumors (c, d), patients with ER-negative and PR-negative tumors (e, f), and patients with triple-negative tumors (g, h). The P-value was determined by the log-rank test. *Significant, P <0.05
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Fig3: Kaplan-Meier disease-free (a, c, e, g) and overall survival (b, d, f, h) curves among patients with tamoxifen monotherapy. Bold lines, Bcl-2-positive; thin lines, Bcl-2-negative. Total patients (a, b), patients with ER-positive and/or PR-positive tumors (c, d), patients with ER-negative and PR-negative tumors (e, f), and patients with triple-negative tumors (g, h). The P-value was determined by the log-rank test. *Significant, P <0.05

Mentions: The DFS/OS according to Bcl-2 status in all patients and in subgroups stratified by ER/PR (and HER2) status is shown separately for groups with no adjuvant therapy (Fig. 2) and adjuvant tamoxifen monotherapy (Fig. 3). In patients with no adjuvant therapy, there was no difference in clinical outcome according to Bcl-2 status (Fig. 2a, b) even in the subgroup with ER-positive and/or PR-positive tumors (Fig. 2c, d). By contrast, Bcl-2 positivity was significantly associated with poor clinical outcome in the subgroups with ER-negative and PR-negative tumors (Fig. 2e, f) or with triple-negative tumors (Fig. 2g, h). In patients with adjuvant tamoxifen monotherapy, Bcl-2 positivity was significantly associated with favorable OS (Fig. 3b), including the subgroup with ER-positive and/or PR-positive tumors (Fig. 3d), whereas it was significantly associated with poor OS in the subgroups with ER-negative and PR-negative tumors (Fig. 3f) or triple-negative tumors (Fig. 3h).Fig. 2


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

Honma N, Horii R, Ito Y, Saji S, Younes M, Iwase T, Akiyama F - BMC Cancer (2015)

Kaplan-Meier disease-free (a, c, e, g) and overall survival (b, d, f, h) curves among patients with tamoxifen monotherapy. Bold lines, Bcl-2-positive; thin lines, Bcl-2-negative. Total patients (a, b), patients with ER-positive and/or PR-positive tumors (c, d), patients with ER-negative and PR-negative tumors (e, f), and patients with triple-negative tumors (g, h). The P-value was determined by the log-rank test. *Significant, P <0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4607008&req=5

Fig3: Kaplan-Meier disease-free (a, c, e, g) and overall survival (b, d, f, h) curves among patients with tamoxifen monotherapy. Bold lines, Bcl-2-positive; thin lines, Bcl-2-negative. Total patients (a, b), patients with ER-positive and/or PR-positive tumors (c, d), patients with ER-negative and PR-negative tumors (e, f), and patients with triple-negative tumors (g, h). The P-value was determined by the log-rank test. *Significant, P <0.05
Mentions: The DFS/OS according to Bcl-2 status in all patients and in subgroups stratified by ER/PR (and HER2) status is shown separately for groups with no adjuvant therapy (Fig. 2) and adjuvant tamoxifen monotherapy (Fig. 3). In patients with no adjuvant therapy, there was no difference in clinical outcome according to Bcl-2 status (Fig. 2a, b) even in the subgroup with ER-positive and/or PR-positive tumors (Fig. 2c, d). By contrast, Bcl-2 positivity was significantly associated with poor clinical outcome in the subgroups with ER-negative and PR-negative tumors (Fig. 2e, f) or with triple-negative tumors (Fig. 2g, h). In patients with adjuvant tamoxifen monotherapy, Bcl-2 positivity was significantly associated with favorable OS (Fig. 3b), including the subgroup with ER-positive and/or PR-positive tumors (Fig. 3d), whereas it was significantly associated with poor OS in the subgroups with ER-negative and PR-negative tumors (Fig. 3f) or triple-negative tumors (Fig. 3h).Fig. 2

Bottom Line: Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2.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.The prognostic value of Bcl-2 was more evident in postmenopausal women.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan. naoko.honma@med.toho-u.ac.jp.

ABSTRACT

Background: Bcl-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.

Methods: Bcl-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 χ (2)-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.

Results: In 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.

Conclusion: Bcl-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.

No MeSH data available.


Related in: MedlinePlus