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© 2001 American Society for Clinical Oncology
BAG-1 Immunostaining and Survival in Early Breast CancerSouthampton General Hospital, Southampton, United Kingdom To the Editor:We read with interest the article by Turner et al1 in the February 15, 2001, issue describing the association between increased levels of cytosolic, but not nuclear, BAG-1 immunostaining and long-term survival in early breast cancer. There is, however, some difficulty in determining the precise relationship between BAG-1 expression and the biology of breast cancer. A previous report by this group using a monoclonal antibody described a significant positive correlation between high levels of nuclear BAG-1 immunostaining and overall survival,2 whereas a report from a different group described inferior survival in patients with high levels of nuclear BAG-1 staining using a polyclonal antibody.3 From the examples of immunostaining presented in the two articles from Turner and co-workers,1,2 it seems that at least some of the same patients were included in the two series with discrepant results. It would be helpful to know the degree of overlap between the two cohorts and whether any potential selection bias may have influenced the results. In particular, the low proportion of estrogen receptor–positive cases (41% as against an expected level of 70%) suggests that the sample described may not be wholly representative of an early-stage breast cancer population. Tumor grade was not included in the table of patient characteristics, and as correlations have been found between tumor differentiation and BAG-1 status by at least one group,3 it would be instructive to know if BAG-1 was predictive of outcome independent of tumor grade. It is also possible that the discrepant results relate to differences in methodology, such as antigen retrieval techniques, which were not described in the more recent article.1 It is clear that further work is required to properly describe the potential role of BAG-1 expression as a biologic variable, and it would be helpful to other investigators to have these critical details. REFERENCES
1.
Turner BC, Krajewski S, Krajewska M, et al: BAG-1: A novel biomarker predicting long-term survival in early-stage breast cancer. J Clin Oncol 19: 992-1000, 2001 2. Krajewski S, Krajewska M, Turner BC, et al: Prognostic significance of apoptosis regulators in breast cancer. Endocr Rel Cancer 6: 29-40, 1999[Abstract]
3.
Tang SC, Shaheta N, Chernenko G, et al: Expression of BAG-1 in invasive breast carcinomas. J Clin Oncol 17: 1710-1719, 1999
Response
Thomas Jefferson University, Bodine Center for Cancer Treatment, Philadelphia, PA In Reply:The review article published in 1999 by Krajewski et al1 represented an invited report following a scientific meeting where some of our preliminary observations on expression in breast cancer of BAG-1 and several apoptosis-relevant proteins were presented by Stanislaw Krajewski, MD, PhD, in 1998. Of the 116 patients described in that 1999 review (representing patients presenting from 1973 to 1993), 42 were also part of the 122-patient cohort described in the article published in the February 15, 2001, issue of the Journal of Clinical Oncology (JCO) (patients presenting from 1978 to 1993).2 The pilot immunohistochemical data described in the 1999 review1 were obtained using various anti-BAG-1 monoclonal antibodies that we were actively evaluating at that time and collectively involved use of various immunostaining methods and immunoscoring approaches, some of which had not yet been perfected. For the analysis described in our 2001 JCO article, a single monoclonal antibody was used under optimized immunostaining conditions that were quantitated by a pathologist specializing in breast cancer. A detailed protocol describing these immunostaining conditions is available on the Web at http://burnham.org/reedlab/protocols/baglimmunostain./ This monoclonal antibody is now commercially available from Dako, Inc. (Carpentiera, CA) for those wishing to reproduce our immunohistochemical analysis. In Turner et al,2 we revised our immunoscoring methods relative to the 1999 pilot report1 and also enlisted the collaborative input of a highly experienced breast pathologist who performed all of the immunoscoring (as explained in the Patients and Methods of the JCO article). Thus, the preliminary observations reported in 1999 should be viewed strictly as pilot data and do not represent a definitive analysis. In addition to important technical differences in the immunostaining and immunoscoring, data from the 1999 pilot report suggesting a correlation between nuclear BAG-1 staining and patient survival were based on 13 patients (13 of 116 were positive for nuclear BAG-1) and were not reproducible, in as much as the subsequent larger cohort published in 2001 in JCO did not reveal a significant association with survival outcome and nuclear BAG-1 staining. Regarding the question of BAG-1 and tumor histology, we mentioned in the text of Turner et al2 that no correlation was observed between BAG-1 immunostaining data and tumor grade. Tumor grade also was not statistically significantly associated with patient survival in univariate and multivariate analyses of the cohort of patients as described in our JCO article.2 With respect to the question of introduction of bias in the cohort of 122 patients studied in Turner et al,2 of course, one can never entirely exclude this possibility despite best efforts. The percentage of estrogen receptor–positive cases in this cohort was indeed lower than population averages, but this population represented many young breast cancer patients (mean age, 54 years), and these patients are frequently estrogen receptor–negative. Thus, as we stated in the article, our "findings provide preliminary evidence that BAG-1 represents a potential marker of improved survival in early-stage breast cancer patients" and "larger cohorts of patients in prospective trials are needed to firmly establish the overall prognostic utility of BAG-1 testing for women with early-stage breast cancer." Since our anti-BAG-1 monoclonal antibody is publicly available and the immunostaining method has been described in detail, we hope that others will attempt to confirm our findings in larger cohorts of patients. REFERENCES 1. Turner B, Krajewski S, Krajewska M, et al: BAG-1: A novel biomarker predicting long-term survival in early-stage breast cancer. J Clin Oncol 19: 992-1000, 2001 2. Krajewski S, Krajewska M, Turner B, et al: Prognostic significance of apoptosis regulators in breast cancer. Endocr Rel Cancer 6: 29-40, 1999
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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