Correspondence

Letrozole or Tamoxifen in Early Breast Cancer

N Engl J Med 2006; 354:1528-1530April 6, 2006

Article

To the Editor:

The report on the Breast International Group (BIG) 1-98 trial (Dec. 29 issue)1 highlights apparently statistically nonsignificant data from subgroups (of patients who had received previous chemotherapy and those who had node-positive disease) and contrasts them with the results of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.2 We believe that clinical decisions should not be based on subgroup analyses3 when there are no clear reasons for a differential effect of treatment and no statistical evidence of interaction or heterogeneity. (Such test results were not observed in the ATAC trial2 and not reported in the BIG 1-98 trial, although it is unlikely such tests were performed, given the results shown in Figure 3 of the article.)

We would be interested in knowing the rate of withdrawal due to adverse events in the BIG 1-98 trial. More patients who received letrozole reported at least one adverse event than did patients who received tamoxifen. In the ATAC trial, there were significantly fewer adverse events with anastrozole than with tamoxifen, both overall events and those resulting in withdrawal from the study.2

We agree that the significantly higher risk of cardiac events of grades 3 to 5 and the higher number of deaths from cardiac or cerebrovascular causes in the letrozole group than in the tamoxifen group require further study. However, we do not believe that the evidence indicates an increased risk of cardiovascular events with all aromatase inhibitors. Mature data from the ATAC trial have shown no increased risk of myocardial infarction or deaths from cardiovascular causes among patients receiving anastrozole, as compared with those receiving tamoxifen.2,4

Aman U. Buzdar, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
abuzdar@mdanderson.org

Michael Baum, M.D.
University College London, London WIP 7LD, United Kingdom

Jack Cuzick, Ph.D.
Wolfson Institute of Preventive Medicine, London EC1M 6BQ, United Kingdom

Dr. Buzdar reports having received honoraria and research funding from AstraZeneca and research funding from Eli Lilly, Pfizer, Genentech, and Taiho Pharmaceutical. He reports currently serving as chair of the ATAC Steering Committee, which is partly funded by AstraZeneca. Dr. Baum reports having received honoraria and consulting fees from AstraZeneca and was the founding chair of the ATAC Steering Committee. Dr. Cuzick reports having received honoraria from AstraZeneca and is an independent biostatistician for the ATAC trial.

4 References

1
The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747-57
Full Text | Web of Science | Medline

2
ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60-62
CrossRef | Web of Science | Medline

3
Cuzick J. Forest plots and the interpretation of subgroups. Lancet 2005;365:1308-1308
CrossRef | Web of Science | Medline

4
Howell A. ATAC trial update. Lancet 2005;365:1225-1226
CrossRef | Web of Science

To the Editor:

Prescribing adjuvant hormonal therapy for node-negative invasive breast cancer seems routine, even though the survival benefit of hormonal therapy has not been fully established (for very small, microinvasive cancers, for example). In the BIG 1-98 study, the primary benefit (disease-free survival) at 25.8 months for patients who received letrozole accrued only to patients with node-positive breast cancer, whereas the number of grade 5 cerebrovascular and cardiac adverse events in the letrozole group was 3.3 times that in the tamoxifen group. Other data1 show no survival advantage to date from receiving letrozole among patients with node-negative disease. For these reasons, should the conclusion of the BIG 1-98 study be more narrowly stated? Would it not be more cautious to conclude that adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease in postmenopausal women with node-positive disease and carried a small but statistically significant increase in the risk of serious cardiovascular events?

John K. Erban, M.D.
Tufts–New England Medical Center, Boston, MA 02111
jerban@tufts-nemc.org

1 References

1
Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262-1271
CrossRef | Web of Science | Medline

To the Editor:

With regard to the number of cardiovascular adverse events reported in the BIG 1-98 trial, the initial presentation of these data reported 26 deaths from cardiac causes without a previous cancer-related event in the letrozole group and 13 such deaths in the tamoxifen group.1 The article in the Journal reports 13 deaths from cardiac causes in the letrozole group and 6 in the tamoxifen group. There also appear to be differences in the reporting of various ischemic cardiovascular adverse events between preliminary presentations1,2 and the current article. It would be interesting to learn whether such events have been reclassified and, if so, why.

Rowan T. Chlebowski, Ph.D.
Harbor–UCLA Medical Center, Torrance, CA 90502

Dr. Chlebowski reports having served as a consultant to AstraZeneca, Novartis, and Pfizer.

2 References

1
BIG 1-98 Collaborative Group. BIG 1-98: a prospective randomized double-blind double-dummy phase III study to evaluate letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Breast 2005;14:Suppl 1:S3-S3
CrossRef | Web of Science

2
Thurlimann B, Kesaviah A, Mouridsen H, et al. BIG 1-98: randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. J Clin Oncol 2005;23:6s-6s
Web of Science

Author/Editor Response

Dr. Chlebowski seeks information on the reclassification of fatal adverse events between the various preliminary abstracts and the final publication. The reported number of deaths without breast-cancer recurrence was identical in all presentations. As we stated in our article, all serious adverse events were reviewed before the safety analysis, and several cases of unexpected death were judged to have insufficient evidence of a primary cardiac cause.

There was no significant difference between the two groups in the frequency of withdrawal from therapy because of adverse events. Although no significant excess of cardiac deaths has been reported in large trials of other aromatase inhibitors,1,2 cross-study comparisons are problematic, particularly since adverse events were reported by checking specific boxes on the case-report forms in BIG 1-98, as compared with a nonspecific request to report adverse events in ATAC. Our conclusion remains unchanged and is in accordance with the most recent technical assessment of the American Society of Clinical Oncology3: “Current information is insufficient to determine fully the effect of aromatase inhibitors on cardiovascular disease, especially coronary heart disease.”

Dr. Buzdar and colleagues and Dr. Erban draw attention to treatment effects observed in various subgroups of patients. We performed and reported several preplanned subgroup analyses but drew attention to the contrasting findings in similar subgroups in the ATAC trial1 to reach what we reaffirm as an appropriately conservative conclusion that “these findings highlight the need for caution in interpreting subgroup analyses, even in large trials.”

Alan S. Coates, M.D.
University of Sydney, Sydney NSW 2006, Australia

Henning Mouridsen, M.D.
Rigshospitalet, 2100 Copenhagen, Denmark

Louis Mauriac, M.D.
Institut Bergonié, 33076 Bordeaux, France

for the BIG 1-98 Collaborative Group

3 References

1
Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-9[Erratum, Lancet 2002;360:1520.]
CrossRef | Web of Science | Medline

2
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092[Erratum, N Engl J Med 2004;351: 2461.]
Full Text | Web of Science | Medline

3
Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005;23:619-629
CrossRef | Web of Science | Medline

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