Correspondence to: Bernard Fisher, M.D., National Surgical Adjuvant Breast and Bowel Project, Four Allegheny Center, Suite 602, Pittsburgh, PA 15212-5234 (e-mail: bernard.fisher{at}nsabp.org).
In their critique of the excellent commentary by Lippman and Brown (1), Rockhill et al. challenge statements that I made in a recent commentary that related to the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT; P-1) (2). In my remarks, I speculated on the consequences of administering tamoxifen to a larger population of eligible women than that which comprised the P-1 study, "even though the vast majority of them would never develop breast cancer and even though not all tumors would be prevented in the women who would have had a tumor" (2). I related the average annual rate (6.76) of occurrence of invasive breast cancer in each 1000 participants in the placebo group of the P-1 study (3) to the approximately 29 million women in the United States comprising 21% of the adult female population who had been estimated by the National Cancer Institute to be potentially eligible for the P-1 trial (4). On the basis of that association, it was estimated that, during a 5-year period, almost 1 million of the 29 million, i.e., about 200000 women per year, would have the potential for being diagnosed with invasive breast cancer. Because the rate was reduced to 3.43 per 1000 women per year in the tamoxifen group of the P-1 study, it was estimated that almost 500000 invasive breast cancers might be prevented in the expanded population over a 5-year period.
The results obtained by extrapolating the findings of the P-1 study to a larger group of similar women demonstrate the potential impact that the more widespread use of tamoxifen could have in lessening the extent of the breast cancer problem. Despite this, in their letter, Rockhill et al. imply that my argument for such a benefit is distorted because it is based on "unrealistic estimates of numbers of cases of breast cancer prevented." The reason for their skepticism is difficult to comprehend. It seems that Rockhill et al. have based much of their concern on the fact that, because only about 180000 new cases of invasive breast cancer are being detected in the United States each year, it would be unrealistic to anticipate that "1.4 million cases of breast cancer might be expected during the course of 5 years," an erroneous estimate that they made.
Rockhill et al. also fail to realize that the number of cases of invasive breast cancer that are being diagnosed each year represents only a fraction of the number of women who are actually at risk for the disease because many of them have undetected molecularbiologic or phenotypic changes in breast cells that put them at increased risk for developing a detectable invasive breast cancer at some future time. It was that concept that led us to conduct the P-1 study.
Although essentially correct, the statement by Rockhill et al. that "Fisher even cited a possible reduction of 1 million cases of breast cancer in 5 years, if 2 million cases were to occur among women eligible for the drug" is misleading because it was taken out of context. In my commentary (2), I presented several hypothetical circumstances to emphasize that the magnitude of benefits observed in the P-1 study was related to the level of breast cancer risk in the women being evaluated. I stated, "If, for example, the 5-year predicted risk in all of the women comprising the 29 million were 5.01%, it would be estimated that almost 2 million invasive cancers would have occurred in the placebo group and 650000 in the tamoxifen group during a 5-year period. Thus, approximately 1.2 million invasive cancers might have been prevented" (2). I then asserted, "if the 5-year predicted risk in all 29 million women were
2.0%, then approximately 500000 tumors might have been prevented" (2). I emphasized further that in none of the circumstances did I imply that all 29 million women should receive tamoxifen.
While the article by Gail et al. (5) may be viewed as a tour de force, using it to diminish the importance of the P-1 trial, as Rockhill et al. have done, is highly inappropriate. Not only have Gail et al. and other investigators (6) provided enough caveats to indicate that many of their "methods are subject to various uncertainties" (5), but also I have emphasized (2) that to estimate the net benefit from tamoxifen by merely subtracting the number of adverse events from the number of cancers prevented and then using the resulting value to formulate conclusions about whether a drug should be given is too simplistic. Such an approach leads to the erroneous assumption that all events are equivalent relative to their significance and, consequently, engenders doubt about the use of tamoxifen, even where appropriate, as a breast cancer preventive agent.
REFERENCES
1
Lippman SM, Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost. J Natl Cancer Inst 1999;91:180919.
2
Fisher B. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial: a reflective commentary. J Clin Oncol 1999;17:16329.
3
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;90:137188.
4 Ford L. Breast Cancer Prevention Trial results. News conference, Washington (DC): April 6, 1998.
5
Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:182946.
6
Taylor AL, Adams-Campbell LL, Wright AT Jr. Risk/benefit assessment of tamoxifen to prevent breast cancerstill a work in progress? [editorial]. J Natl Cancer Inst 1999;91:17923.
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