Correspondence to: Jack Cuzick, Ph.D., Imperial Cancer Research Fund, 61 Lincoln's Inn Fields, London WC2A 3PX, U.K. (e-mail: cuzick{at}icrf.icnet.uk).
The fundamental role of estrogens in the development of breast cancer is now well recognized. This role can be seen most clearly in the postmenopausal age range, where several studies have found that serum levels of endogenous estradiol are higher in women who develop breast cancer [reviewed in (1)]. Also, obesity, which is associated with increased postmenopausal estrogen production, is a clearly established risk factor for postmenopausal breast cancer. Likewise, the continuance of premenopausal status is a strong risk factor for breast cancer, and the risk is increased by about 2.8% for each additional year that a woman remains premenopausal (2). Thus, it is not surprising that hormone replacement therapy (HRT) has been found to increase the risk of developing breast cancer. This increase in risk is smaller than the risk associated with remaining premenopausal [being about 2.3% per year for current users, but disappearing soon after stopping HRT use (2)] and reflects the intermediate level of estrogenic stimulus compared with that in premenopausal or postmenopausal women [typically, 170 pmol/L for a 50-µg estradiol patch versus 500 pmol/L for premenopausal women or 25 pmol/L for postmenopausal women (3)].
On the other hand, breast cancer that develops in HRT users has a better prognosis than breast cancer that develops in postmenopausal nonusers. Tumors are more often small, well differentiated, and lymph node negative, and survival is better (4,5). These facts could reflect surveillance bias to some extent because HRT users are screened more actively by mammography, but factors such as a lower S-phase fraction (6) suggest that these tumors may be intrinsically more benign. Thus, the overall effect of HRT on breast cancer mortality in the general population remains uncertain.
For women at increased risk of breast cancer, because of a family history of breast cancer or other risk factors, there is no evidence for a positive interaction with exogenous estrogen use (2), so this group of women gives little insight into the appropriate use for women with breast cancer. However, even in the absence of such an interaction, because of the high risk of new cancers and the possibility of promoting existing cancers, the same relative risk for HRT use would lead to a higher absolute risk.
Yet, women with breast cancer are particularly in need of relief from menopausal symptoms. The disease has a high incidence around age 50 years, when menopausal symptoms are most common, and, in addition, the therapies used for treatment of breast cancer are well known to exacerbate these symptoms. The most common side effect of tamoxifen is hot flushes, and placebo-controlled trials (7,8) have shown that the incidence of hot flushes is increased by about 20% with tamoxifen. The use of chemotherapy produces amenorrhea in about half of the premenopausal patients, and the use of luteinizing hormone-releasing hormone agonists produces amenorrhea in all premenopausal patients, leading to a profound increase in menopausal symptoms.
Use of estrogen replacement is often avoided in women with breast cancer. However, the better survival of women whose cancers were diagnosed while taking HRT has raised some doubt about this policy, and the observation in the report by O'Meara et al. (9) in this issue of the Journal of apparently better survival for women who have taken HRT after the diagnosis of breast cancer raises even greater doubts about the wisdom of this practice. On the surface, the results obtained by O'Meara et al. appear very clear-cuta halving of breast cancer recurrence and a two-thirds reduction in breast cancer mortality rates, both of which are highly statistically significant. These results [which have been observed before (10)] were adjusted for confounding factors by using matched control subjects and appeared to be little affected by other possible confounding factors in multivariate analyses. The evaluation was performed by a sophisticated use of casecontrol methodology involving the proportional hazards model, in which HRT use after breast cancer diagnosis was modeled as a time-varying covariate. This complicated approach makes the analysis less transparent but has been properly employed. It is the best method available for this type of observational study, and every effort to minimize bias has been undertaken. However, there must always remain some concern about residual biases because the main exposure is a lifestyle variable under direct control of the subjects. In particular, the importance of HRT use before breast cancer diagnosis is a concern because of its independent effect on prognosis and association with subsequent use, even though adjustment for this prior use did not materially affect the results. Also, the follow-up was relatively short, being less than 4 years for recurrence, and the improved prognosis appeared to be related only to the earliest follow-up period and shorter exposures, raising concern about a "healthy user" effect.
Despite the limitations of observational studies, the results reported by O'Meara et al. (9) cannot be dismissed on methodologic grounds. At no stage of follow-up or for any subgroup was there evidence of a poorer prognosis in HRT users. These results must still be considered preliminary; in particular, any suggestion that use of HRT might improve survival remains unproven. However, the results do give added support and urgency for the conduct of randomized trials of HRT use in symptomatic women with breast cancer, such as the HABITS trial in Sweden (11) and a similar trial in the U.K. (12).
Even if HRT turns out to have no effect on the prognosis of breast cancer, this knowledge would be a major step forward in terms of lowering morbidity and improving quality of life. One hardly dares speculate on the possibility that HRT might be beneficial; however, should this beneficial effect be confirmed in randomized studies, the hormonal treatment of breast cancer will require very major reevaluation.
REFERENCES
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4
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8
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.
9
O'Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001;93:75462.
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