© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
RESPONSE: Re: Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study
Affiliations of authors: Department of Surgery (BF), Department of Biostatistics (JPC), University of Pittsburgh, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (BF, JPC)
Correspondence to: Bernard Fisher, MD, 300 Halket St., Suite 350, Pittsburgh, PA 15213 (e-mail: fisherb2{at}upmc.edu).
Cuzick et al. contend that it was inappropriate both to announce the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) prevention trial (P-1) (1,2) and to unblind the participants. They argue that those actions make it difficult to interpret the data from P-1 and that important information has been lost. We disagree.
We question some key points in the authors’ comments. 1) They are uncertain about the reason for the lower incidence of breast cancer in the control group in years 6 and 7. We demonstrated in our update (2) that this finding was the result of the fact that about one-third of women in the placebo group had switched to tamoxifen, providing further evidence that tamoxifen is effective for chemoprevention of breast cancer. In any case, the speculation that another mechanism might have been involved is irrelevant because the rate of breast cancer in the tamoxifen group remained consistently low through 7 years of follow-up. 2) It is not surprising that the British International Breast Cancer Intervention Study (IBIS)-I prevention trial participants agreed to remain blinded in light of the fact that they had been told by their physicians that "neither the Independent Data Monitoring Committee (DMC) nor the Steering Committee felt that the results were sufficient to change clinical practice" and that "blinded continuation was recommended." We could not tell our participants the same thing because our data indicated otherwise. 3) Although Cuzick et al. state that their "open policy (allowing participants to remain blinded) is not possible in the United States," our policy of openness required us to inform women about our findings.
In every aspect of the planning, implementation, and reporting of the P-1 trial, which was conducted with intensive oversight, it was clear that reduction in the incidence of breast cancer was to be the primary endpoint of the study. Because definitive information about mortality was likely to take 15 to 20 years of follow-up, we considered it unrealistic to use mortality as the primary endpoint. The presence of breast cancer is a medical outcome in and of itself, not a surrogate endpoint for death from breast cancer. Only when the DMC had concluded, based on the data, that the primary endpoint of the trial—i.e., an almost 50% reduction in the risk of breast cancer (P = .0000006)—had been attained was it recommended that the findings be disclosed and the study be unblinded so that each woman who received placebo could decide for herself whether or not to take tamoxifen. That action was in keeping with what was in the consent form that each participant had signed before she entered the study.
The decision to unblind the P-1 trial was made judiciously. Unblinding of the participants was not recommended on the first occasion that the interim monitoring boundary was crossed. It was only after the boundary was crossed on three successive interim analyses over 2 years of monitoring that the DMC recommended such an action. At that time, there were sufficient data to provide an understanding of not only the effects of tamoxifen on invasive breast cancer but also of its effects on the other non–breast cancer-related benefits and risks of treating healthy women with the drug (3). Therefore, when the trial was unblinded, a spectrum of benefits and risks from tamoxifen was available to help women make informed decisions about using the drug to lower their risk. In view of these facts, we fail to comprehend why Cuzick et al. would imply that the P-1 DMC did not exercise good judgment.
The P-1 trial was a scientific inquiry aimed at testing the hypothesis that occult pathologic aberrations could be altered so that they failed to become clinically detectable. The evidence obtained via the scientific method that tamoxifen has important health benefits in many women at high risk for breast cancer established proof of that hypothesis.
REFERENCES
(1) Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–88.
(2) Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005;97:1652–62.
(3) Redmond CK, Costantino JP, Colton T. Challenges in monitoring the Breast Cancer Prevention Trial. In: DeMets DI, Furberg CD, Friedman LM, editors. Data monitoring in clinical trials: a case study approach. New York (NY): Springer, 2005.
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J Natl Cancer Inst 2006 98: 643.
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