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

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.

[1]  Robert J. Mayer,et al.  National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. , 2001, Journal of the National Cancer Institute.

[2]  H. Moch,et al.  Tissue microarrays for rapid linking of molecular changes to clinical endpoints. , 2001, The American journal of pathology.

[3]  S. Edge,et al.  Prognostic factors in breast cancer , 2005 .

[4]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[5]  Isabelle Bedrosian,et al.  Cyclin E and survival in patients with breast cancer. , 2002, The New England journal of medicine.

[6]  R. Tibshirani,et al.  Copyright © American Society for Investigative Pathology Short Communication Expression of Cytokeratins 17 and 5 Identifies a Group of Breast Carcinomas with Poor Clinical Outcome , 2022 .

[7]  A. Strasser,et al.  The cell death inhibitor Bcl‐2 and its homologues influence control of cell cycle entry. , 1996, The EMBO journal.

[8]  M. Campbell,et al.  Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. , 1992, Cancer research.

[9]  Michael Peacock,et al.  Hierarchical Clustering Analysis of Tissue Microarray Immunostaining Data Identifies Prognostically Significant Groups of Breast Carcinoma , 2004, Clinical Cancer Research.

[10]  Daniel Birnbaum,et al.  Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. , 2005, Cancer research.

[11]  S. Fox,et al.  Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up. , 1996, Human pathology.

[12]  M. J. van de Vijver,et al.  Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy. , 1996, British Journal of Cancer.

[13]  S. Korsmeyer,et al.  bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation , 1989, Cell.

[14]  Michael A. Gonzalez,et al.  Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  N. Brünner,et al.  S-phase fraction and urokinase plasminogen activator are better markers for distant recurrences than Nottingham Prognostic Index and histologic grade in a prospective study of premenopausal lymph node-negative breast cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[17]  C. Osborne,et al.  bcl‐2 and apoptosis in lymph node positive breast carcinoma , 1998, Cancer.

[18]  I. Ellis,et al.  The Nottingham prognostic index in primary breast cancer , 2005, Breast Cancer Research and Treatment.

[19]  John J Spinelli,et al.  Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. , 2005, Journal of the National Cancer Institute.

[20]  R. Gelber,et al.  Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. , 1995, Journal of the National Cancer Institute.

[21]  L. Norton,et al.  p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  M. Loda,et al.  The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. , 1997, Cancer research.

[23]  I. Ellis,et al.  Prognostic and predictive factors in primary breast cancer and their role in patient management: The Nottingham Breast Team. , 2001, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[24]  M. Salto‐Tellez,et al.  Tissue microarray study for classification of breast tumors. , 2003, Life sciences.

[25]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. , 1999, Critical reviews in oncology/hematology.

[26]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[27]  Douglas G. Altman,et al.  Practical statistics for medical research , 1990 .

[28]  T. McDonnell,et al.  Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18) , 1991, Nature.

[29]  P. Bonnier,et al.  bcl-2 automated and quantitative immunocytochemical assays in breast carcinomas: correlation with 10-year follow-up. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  D. Hockenbery,et al.  Bcl-2 slows in vitro breast cancer growth despite its antiapoptotic effect. , 1998, The Journal of surgical research.

[31]  C. Giardina,et al.  Prognostic factors in breast cancer: the predictive value of the Nottingham Prognostic Index in patients with a long-term follow-up that were treated in a single institution. , 2001, European journal of cancer.

[32]  J. Nesland,et al.  Association between histology grade, expression of HsMCM2, and cyclin A in human invasive breast carcinomas , 2003, Journal of clinical pathology.

[33]  Carlos Caldas,et al.  Molecular Classification of Breast Carcinomas Using Tissue Microarrays , 2003, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[34]  H. Mouridsen,et al.  A modified Nottingham prognostic index for breast cancer patients diagnosed in Denmark 1978-1994. , 2001, Acta oncologica.

[35]  K Vajda,et al.  [Prognostic factors in breast cancer]. , 1998, Orvosi hetilap.

[36]  Michael R. Chernick,et al.  Analysis of Survival Times , 2003 .

[37]  Willi Sauerbrei,et al.  Validation of existing and development of new prognostic classification schemes in node negative breast cancer , 2004, Breast Cancer Research and Treatment.

[38]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  V. Kosma,et al.  Apoptosis suppressing protein bcl‐2 is expressed in well‐differentiated breast carcinomas with favourable prognosis , 1995, The Journal of pathology.

[40]  Harold C. Sox,et al.  National Institutes of Health Consensus Development Conference Statement: Geriatric Assessment Methods for Clinical Decision‐making , 1988 .

[41]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[42]  S. Pinder,et al.  Histological grading of breast carcinomas: a study of interobserver agreement. , 1995, Human pathology.

[43]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[44]  M. Fernö,et al.  "Good Old" clinical markers have similar power in breast cancer prognosis as microarray gene expression profilers. , 2004, European journal of cancer.

[45]  J. Kononen,et al.  Tissue microarrays for high-throughput molecular profiling of tumor specimens , 1998, Nature Medicine.

[46]  N. Le,et al.  Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. , 1997, The New England journal of medicine.

[47]  K. Kinzler,et al.  Paradoxical inhibition of solid tumor cell growth by bcl2. , 1994, Cancer research.

[48]  J. Nesland,et al.  The prognostic value of p53 and c‐erb b‐2 immunostaining is overrated for patients with lymph node negative breast carcinoma , 2000, Cancer.

[49]  J. Foekens,et al.  Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer , 2005, The Lancet.

[50]  R. Blamey,et al.  A prognostic index in primary breast cancer. , 1982, British Journal of Cancer.

[51]  J. Lapointe,et al.  Androgens down-regulate bcl-2 protooncogene expression in ZR-75-1 human breast cancer cells. , 1999, Endocrinology.

[52]  U. Chetty,et al.  Outcome after extended follow-up in a prospective study of operable breast cancer: key factors and a prognostic index , 2002, British Journal of Cancer.

[53]  C. Caldas,et al.  Molecular classification and molecular forecasting of breast cancer: ready for clinical application? , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  John Calvin Reed,et al.  Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. , 1994, Oncogene.