J Breast Cancer. 2011 Feb;14(Suppl 1):S10-S16. Korean.
Published online Feb 28, 2011.
Copyright © 2011 Korean Breast Cancer Society
Original Article

Different Prognostic Significance of Bcl-2 Based on Cancer Molecular Subtype

Ju-Young Lee, Hyun-Ah Kim, Eun-Kyu Kim, Hoe-Min Yang, Kwan-il Kim, Jong Inn Lee, Jae Soo Koh,1 Eunyoung Ko,2 Nan Mo Moon,2 Min-Suk Kim,3 Nam-Sun Paik,4 and Woo Chul Noh
    • Department of Surgery, Korea Institute of Radiological & Medical Sciences, Korea Cancer Center Hospital, Seoul, Korea.
    • 1Department of Pathology, Korea Institute of Radiological & Medical Sciences, Korea Cancer Center Hospital, Seoul, Korea.
    • 2Department of Surgery, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea.
    • 3Department of Pathology, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea.
    • 4Department of Surgery, Konkuk University College of Medicine, Seoul, Korea.
Received October 29, 2010; Accepted February 14, 2011.

Abstract

Purpose

B-cell lymphoma (bcl)-2 is an anti-apoptotic gene, and it is a poor prognostic factor in various malignant tumors. However, the prognostic significance of bcl-2 expression in breast cancer remains controversial. We investigated the prognostic significance of bcl-2 according to cancer molecular subtype.

Methods

We analyzed 411 patients with primary invasive breast cancer who underwent surgery at our institution between 1999 and 2001. The subtypes were classified as luminal (estrogen receptor [ER]+ and/or progesterone receptor [PR]+, irrespective of human epidermal factor receptor 2 [HER2]), triple-negative (ER-, PR-, and HER2-), or HER2 (ER- ,PR-, and HER2+).

Results

A total of 236 (57.4%) cases were positive for bcl-2, and bcl-2 expression was significantly associated with earlier stage, lower grade, expression of hormone receptor positivity, and HER2 negativity. No difference in disease-free survival (DFS) was observed based on bcl-2 expression. However, the prognostic significance of bcl-2 varied with subtype; bcl-2 was not a prognosticator in patients with the luminal and HER2 subtypes. However, patients with bcl-2(+) tumors of the triple-negative subtype showed significantly worse DFS than those with bcl-2(-) tumors (p=0.048). In a multivariate analysis, bcl-2 expression remained a significant predictor of recurrence in patients with the triple-negative subtype (hazard ratio, 3.26; 95% confidence interval, 1.40-7.59; p=0.006).

Conclusion

The prognostic significance of bcl-2 varied with molecular subtype; bcl-2 expression was a poor prognosticator in patients with the triple-negative subtype, but not in those with the luminal and HER2 subtypes.

Keywords
Bcl-2; Breast neoplasms; Disease-free survival; Prognosis; Triple negative breast cancer

Figures

Figure 1
Disease-free survival according to bcl-2 expression (A) and disease free survival according to hormonal receptor expression (B).

Figure 2
Disease-free survival according to bcl-2 expression in hormonal receptor positive breast cancer (A), in HER2 positive breast cancer (B), in triple negative breast cancer (C).

Tables

Table 1
Clinicopathologic characteristic and treatment details of patients

Table 2
Clinicopathologic characteristic according to bcl-2 expression

Table 3
Clinicopathologic characteristic of triple negative breast cancer patients according to bcl-2 expression

Table 4
Univariated analysis of factors associated with disease-free survival in triple negative breast cancer

Table 5
Multivariated analysis of factors associated with disease-free survival in triple negative breast cancer

References

    1. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418–8423.
    1. Zhou T, Yang L, Ma GM, Li CX, Bai Y, Zhao JA, et al. Clinicopathologic features and prognosis of triple negative breast cancer. Zhonghua Yi Xue Za Zhi 2009;89:2261–2264.
    1. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer-current status and future directions. Ann Oncol 2009;20:1913–1927.
    1. Reed JC, Pellecchia M. Apoptosis-based therapies for hematologic malignancies. Blood 2005;106:408–418.
    1. Lu PJ, Lu QL, Rughetti A, Taylor-Papadimitriou J. Bcl-2 overexpression inhibits cell death and promotes the morphogenesis, but not tumorigenesis of human mammary epithelial cells. J Cell Biol 1995;129:1363–1389.
    1. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992;52:6940–6944.
    1. Pietenpol JA, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B. Paradoxical inhibition of solid tumor cell growth by bcl2. Cancer Res 1994;54:3714–3717.
    1. Chen MK, Yang SF, Lai JC, Yeh KT, Yang JS, Chen LS, et al. Expression of bcl-2 correlates with poor prognosis and modulates migration of nasopharyngeal carcinoma cells. Clin Chim Acta 2010;411:400–405.
    1. O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B, et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 2009;27:5208–5212.
    1. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009;15:1126–1132.
    1. Kroger N, Milde-Langosch K, Riethdorf S, Schmoor C, Schumacher M, Zander AR, et al. Prognostic and predictive effects of immunohistochemical factors in high-risk primary breast cancer patients. Clin Cancer Res 2006;12:159–168.
    1. Zhang GJ, Tsuda H, Adachi I, Fukutomi T, Yamamoto H, Hirohashi S. Prognostic indicators for breast cancer patients with one to three regional lymph node metastases with special reference to alterations in expression levels of bcl-2, p53 and c-erbB-2 proteins. Jpn J Clin Oncol 1997;27:371–377.
    1. Elledge RM, Green S, Howes L, Clark GM, Berardo M, Allred DC, et al. Bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. J Clin Oncol 1997;15:1916–1922.
    1. Hellemans P, van Dam PA, Weyler J, van Oosterom AT, Buytaert P, Van Marck E. Prognostic value of bcl-2 expression in invasive breast cancer. Br J Cancer 1995;72:354–360.
    1. Gurova KV, Kwek SS, Koman IE, Komarov AP, Kandel E, Nikiforov MA, et al. Apoptosis inhibitor as a suppressor of tumor progression: expression of Bcl-2 eliminates selective advantages for p53-deficient cells in the tumor. Cancer Biol Ther 2002;1:39–44.
    1. Lee KH, Im SA, Oh DY, Lee SH, Chie EK, Han W, et al. Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer 2007;7:63.
    1. Lee JH, Lee ES, Kim CH. Expression of bcl-2 and apoptosis and its relationship to clinicopathological prognostic factors in breast cancer: a study with long term follow-up. J Korean Breast Cancer Soc 2004;7:92–97.
    1. Sjostrom J, Krajewski S, Franssila K, Niskanen E, Wasenius VM, Nordling S, et al. A multivariate analysis of tumour biological factors predicting response to cytotoxic treatment in advanced breast cancer. Br J Cancer 1998;78:812–815.
    1. Kim K, Chie EK, Han W, Noh DY, Park IA, Oh DY, et al. Prognostic value of p53 and bcl-2 expression in patients treated with breast conservative therapy. J Korean Med Sci 2010;25:235–239.
    1. Chen HH, Su WC, Guo HR, Chang TW, Lee WY. p53 and c-erbB-2 but not bcl-2 are predictive of metastasis-free survival in breast cancer patients receiving post-mastectomy adjuvant radiotherapy in Taiwan. Jpn J Clin Oncol 2002;32:332–339.
    1. Choi NK, Kim SY, Kim TY, Chae MK, Baek MJ, Lim CW, et al. Clinical correlation of c-erbB-2, p53, bcl-2, and c-myc expression in patients with breast cancer. J Korean Breast Cancer Soc 2002;5:125–134.
    1. Hong YK, Baik SS, Chung MS, Yoon HS. Expression of cyclin D1 and bcl-2 in infiltrative ductal carcinoma of the breast: their correlations and clinical implications. J Breast Cancer 2008;11:172–179.
    1. Costa SD, Lange S, Klinga K, Merkle E, Kaufmann M. Factors influencing the prognostic role of oestrogen and progesterone receptor levels in breast cancer--results of the analysis of 670 patients with 11 years of follow-up. Eur J Cancer 2002;38:1329–1334.
    1. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008;26:2373–2378.
    1. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006;24:4738–4745.
    1. Marcucci G, Moser B, Blum W, Stock W, Wetzler M, Kolitz JE, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy (+/-) oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old; 2007 ASCO Annual Meeting; 2007. pp. 25.
      Abstract #7012.
    1. Manero F, Gautier F, Gallenne T, Cauquil N, Grée D, Cartron PF, et al. The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Cancer Res 2006;66:2757–2764.
    1. Sinicrope FA, Penington RC, Tang XM. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells. Clin Cancer Res 2004;10:8284–8292.
    1. Ray S, Bucur O, Almasan A. Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 family protein inhibitor. Apoptosis 2005;10:1411–1418.

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