Affiliations of authors: D. F. Archer, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk; T. Bush, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore; L. E. Nachtigall, Department of Obstetrics and Gynecology, New York University School of Medicine, New York.
Correspondence to: Lila E. Nachtigall, M.D., Department of Obstetrics and Gynecology, New York University School of Medicine, 251 E. 33rd St., New York, NY 10016 (e-mail: lilae{at}concentrie.net).
Ross et al. (1) report that women using estrogen and progestin, compared with nonusers, have a 10% higher breast cancer risk for each 5 years of hormone use. They find that women using continuous estrogen and progestin have no increased risk of breast cancer, while women using cyclic estrogen and progestin have a 38% higher risk with each 5 years of hormone use. For women on unopposed estrogen replacement therapy (ERT), they find no increase in risk for the first 15 years of use. The investigators conclude, "the adverse effect [of hormone replacement therapy (HRT)] on the breast may outweigh the beneficial effect on the endometrium, at least in terms of cancer morbidity and mortality."
Nearly one third of all eligible and interviewed case patients (29% or 756 of 2653) and control subjects (33% or 792 of 2429) were excluded from the analysis; most (599 case patients and 537 control subjects) were women who had had a simple hysterectomy before menopause. Ross et al. claim that including these persons would bias the risk estimates. We believe that excluding such a large proportion of participants could also bias the risk estimates.
Another methodologic issue surrounds the simultaneous adjustment for all forms of HRT in a multivariable model [Table 4 in (1)]. This unusual approach raises the question of whether the models used are yielding risk estimates that may be "overadjusted." Given the simultaneous adjustment, interpreting these data in a clinically meaningful way is difficult.
Most important, the risk estimates generated by the regression models and presented as the 5-year risks of hormone therapy appear to be contradicted by the actual data [Table 2 in (1)]. For example, 1015 years of use of any HRT appears to confer a 14% increase in breast cancer risk, not a 20%30% risk, as suggested by the model; 1015 years of use of ERT appears to confer a 7% reduction in risk rather than the 12%18% increased risk suggested by the model. These examples represent the serious problem of using such models to convey risk estimates because their use is dependent on a linear increase in risk, which is often not seen in the actual data. Had Ross et al. provided stratum-specific confidence limits on the odds ratios (ORs) presented in Table 2 in their report (1), the reader would have been able to determine if the ORs presented were statistically significant.
After nearly five decades of considerable research, we still do not know whether there is a causal connection between HRT and breast cancer risk. Many studies, including the Iowa Women's Health Study (2) and the National Health and Nutrition Examination Survey (3), suggest no increased risk for HRT; some, most recently, the study by Schairer et al. (4), find an increased risk only in selected subgroups of women. Despite these serious methodologic questions, the 10% increased relative risk reported by Ross et al. is low, less than half of what one would expect, given the fact that the predicted 5-year increment in breast cancer for women above age 60 years who are not using HRT is 25%. This should be reassuring, rather than a cause for concern.
Physicians must weigh each patient's riskbenefit profile, remembering that treatment also provides a host of benefits. Moreover, any possible small increase in breast cancer risk for women taking HRT is balanced by the fact that, when cancer is found, the histology and prognosis appear favorable. Lack of consistency in results and the weak association between HRT and breast cancer risk should be considered when treatment decisions are made. We will not advise our patients to terminate treatment on the basis of this study.
REFERENCES
1
Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:32832.
2
Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study. JAMA 1999;281:20917.
3 Lando JF, Heck KE, Brett KM. Hormone replacement therapy and breast cancer risk in a nationally representative cohort. Am J Prev Med 1999;17:17680.[Medline]
4
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogenprogestin replacement therapy and breast cancer. JAMA 2000;283:48591.
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |