Affiliation of authors: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
Correspondence to: Michael D. Radmacher, Ph.D., National Institutes of Health, 7550 Wisconsin Ave., Rm. 3C06, MS 9015, Bethesda, MD 208929015 (e-mail: mdradmac{at}helix.nih.gov).
Ménard et al. report that, in their mouse model, early treatment (before spontaneous tumor formation) with tamoxifen prevented both estrogen receptor-negative (ER-) and ER-positive (ER+) tumor formation, while late treatment was effective only against ER+ tumors. Since only ER+ tumor incidence was reduced in the National Surgical Adjuvant Breast and Bowel Project's BCPT (1), they conclude that the protective effect of tamoxifen in the trial was limited to treatment of occult disease. We disagree with this conclusion, since the small number of ER- tumors detected during the trial and the potential opposing effects of tamoxifen on occult and new ER- tumors made it difficult to detect a reduction in ER- tumor incidence, even if one existed.
Although no reductionand, in fact, a slight increasein the incidence of ER- tumors were observed in the treatment arm of the BCPT (1), some evidence of time-dependent effects exists. As shown in Table 1, an excess of ER- tumors (i.e., 22) was detected in the tamoxifen group during the first 2 years of the trial when compared with the number that occurred in the placebo group (i.e., nine). However, in each year after the second year, the number of ER- tumors detected in the tamoxifen group was less than the number detected in the placebo group. As indicated by the various breast tumor growth models that we considered in our analysis of the BCPT (2), we would expect that the vast majority of tumors detected within the first 2 years of study entry were occult at entry. The increase in incidence of ER- tumors in the tamoxifen group during the first 2 years of the trial, if indeed it is not just a statistical fluctuation, is likely due to some effect on occult disease. This observation is consistent with the finding by Ménard et al. (3) of an acceleration in estrogen-independent tumor development in mice treated with tamoxifen after the appearance of subclinical disease. The suggested decrease in ER- tumor incidence in later years of the BCPT (as new tumors become more prevalent) may be indicative of a preventive effect of tamoxifen on new ER- tumor formation.
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In conclusion, rejecting our inference (that both a treatment and preventive effect reduced ER+ tumor incidence in the BCPT) based on the lack of a similar reduction for ER- tumors is inappropriate for at least two reasons. First, only total (occult plus new) tumor incidence is observable. Thus, an acceleration of occult ER- disease may have masked a preventive effect on new ER- tumor formation in the BCPT. Second, many fewer ER- than ER+ tumors were detected during the BCPT and, therefore, the power to detect a preventive effect on ER- tumors was greatly diminished.
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;90:137188.
2
Radmacher MD, Simon R. Estimation of tamoxifen's efficacy for preventing the formation and growth of breast tumors. J Natl Cancer Inst 2000;92:4853.
3
Menard S, Aiello P, Tagliabue E, Rumio C, Lollini PL, Colnaghi MI, et al. Tamoxifen chemoprevention of a hormone-independent tumor in the proto-neu transgenic mice model. Cancer Res 2000;60:2735.
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