Graham A. Colditz, M.B., B.S., Susan E. Hankinson, Sc.D., David J. Hunter, M.B., B.S., Walter C. Willett, M.D., JoAnn E. Manson, M.D., Meir J. Stampfer, M.D., Charles Hennekens, M.D., Bernard Rosner, Ph.D., and Frank E. Speizer, M.D.
From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (G.A.C., S.E.H., D.J.H., W.C.W., J.E.M., M.J.S., C.H., B.R., F.E.S.), and the Departments of Epidemiology (G.A.C., S.E.H., D.J.H., W.C.W., M.J.S.), Biostatistics (B.R.), and Nutrition (W.C.W., M.J.S.), Harvard School of Public Health — all in Boston. Address reprint requests to Dr. Colditz at Harvard Medical School, Channing Laboratory, 180 Longwood Ave., Boston, MA 02115.
Supported by a grant (CA 40956) from the National Institutes of Health. The work of Dr. Colditz was supported in part by a grant (FRA-396) from the American Cancer Society.
Presented in part at the meeting of the American Association for the Advancement of Science, San Francisco, February 22, 1994.
Abstract
Background. The effect of adding progestins to estrogen therapy on the risk of breast cancer in postmenopausal women is controversial.
Methods. To quantify the relation between the use of hormones and the risk of breast cancer in postmenopausal women, we extended our follow-up of the participants in the Nurses' Health Study to 1992. The women were asked to complete questionnaires every two years to update information on their menopausal status, use of estrogen and progestin preparations, and any diagnosis of breast cancer. During 725,550 person-years of follow-up, we documented 1935 cases of newly diagnosed invasive breast cancer.
Results: The risk of breast cancer was significantly increased among women who were currently using estrogen alone (relative risk, 1.32; 95 percent confidence interval, 1.14 to 1.54) or estrogen plus progestin (relative risk, 1.41; 95 percent confidence interval, 1.15 to 1.74), as compared with postmenopausal women who had never used hormones. Women currently taking hormones who had used such therapy for 5 to 9 years had an adjusted relative risk of breast cancer of 1.46 (95 percent confidence interval, 1.22 to 1.74), as did those currently using hormones who had done so for a total of 10 or more years (relative risk, 1.46; 95 percent confidence interval, 1.20 to 1.76). The increased risk of breast cancer associated with five or more years of postmenopausal hormone therapy was greater among older women (relative risk for women 60 to 64 years old, 1.71; 95 percent confidence interval, 1.34 to 2.18). The relative risk of death due to breast cancer was 1.45 (95 percent confidence interval, 1.01 to 2.09) among women who had taken estrogen for five or more years.
Conclusions: The addition of progestins to estrogen therapy does not reduce the risk of breast cancer among postmenopausal women. The substantial increase in the risk of breast cancer among older women who take hormones suggests that the trade-offs between risks and benefits should be carefully assessed. (N Engl J Med 1995;332:1589-93.)
Endogenous gonadal hormones have an important role in causing breast cancer. Early age at menarche and late menopause increase the risk of breast cancer.[1,2] The number and timing of deliveries also affect this risk.[3] Furthermore, among postmenopausal women, obesity is positively associated with serum concentrations of endogenous estrogen[4] and with moderate elevations in both the incidence of breast cancer and mortality from the disease.[5,6]
Hormone therapy also increases the risk of breast cancer in postmenopausal women. Meta-analyses and reviews[7] have assessed the relation between the duration of postmenopausal hormone therapy and the risk of breast cancer, but questions remain. Unresolved issues include the risks associated with estrogen plus progestins,[8] the risks with progestins alone, and the variation in risk according to age.[9] To address these issues, we extended the analysis of the participants in the Nurses’ Health Study through 1992, adding 50 percent more prospective data to those in our previous report.[10]
Methods
The Nurses’ Health Study was established in 1976, when 121,700 female registered nurses 30 to 55 years of age completed a mailed questionnaire that included items about known or suspected risk factors for cancer and cardiovascular diseases. Base-line information included details of risk factors for breast cancer,[11,12] the use of oral contraceptives, and the postmenopausal use of hormones. Every two years, we mail follow-up questionnaires to the women and ask them to update the information on risk factors, including whether they currently take hormones, the duration of hormone use, and the type of hormone preparation used (starting in 1978). We used the information on each questionnaire to define the women’s status with respect to hormone therapy for the subsequent two-year period.
Identification of Cases of Breast Cancer
on each questionnaire, we asked whether breast cancer had been diagnosed and, if so, the date of diagnosis. We routinely searched the National Death index for deaths among women who did not respond to the questionnaires. We asked all women who reported breast cancer (or the next of kin, for those who had died) for permission to review the relevant hospital records and confirm the diagnosis. Pathology reports, obtained for 93 percent of the cases, confirmed breast cancer in all but 10 women who reported it. Although hospital records could not be obtained for 7 percent of the cases, we based our analysis on all cases of newly diagnosed breast cancer, because the degree of accuracy of the participants’ reports was extremely high among those for whom records were obtained. We omitted the small number of cases of carcinoma in situ (n= 157) from the primary analysis.
Population for Analysis
We excluded from the analysis all women who had reported breast cancer or other cancer (except nonmelanoma skin cancer) on the 1976 questionnaire and all premenopausal women. We classified a woman as postmenopausal from the time she returned a questionnaire on which she reported natural menopause or hysterectomy with bilateral oophorectomy. We classified women who reported hysterectomy without bilateral oophorectomy as postmenopausal when they reached the age at which natural menopause had occurred in 90 percent of the cohort (54 years for current cigarette smokers and 56 years for nonsmokers).
As reported on the 1976 questionnaire, 23,965 women were postmenopausal; these women entered follow-up in the period from 1976 to 1978. The women’s reported menopausal status was updated every two years, and the study population was expanded to include women in whom menopause occurred. By 1990, the beginning of the final two-year follow-up period for this analysis, 69,586 women were classified as postmenopausal. Follow-up of the cohort for the identification of nonfatal breast cancer by means of questionnaires and telephone interviews was 95 percent complete. For fatal breast cancer, follow-up was more than 98 percent complete.[13]
Statistical Analysis
For each participant, follow-up time was allocated according to the 1976 exposure variables, which were updated at the beginning of each two-year period on the basis of the information provided by the women on follow-up questionnaires. Follow-up terminated with the date of diagnosis of breast cancer, the date of death, or June 1, 1992. Women who reported a diagnosis of cancer other than nonmelanoma skin cancer on any questionnaire were excluded from subsequent follow-up. If no questionnaire was returned for a follow-up cycle and the woman had previously reported current postmenopausal hormone use, her hormone-use status was classified as missing in the updated analysis.
As a measure of association, we used the relative risk, defined as the incidence of breast cancer among women who had taken hormones after menopause divided by the incidence among women who had never used such therapy. We conducted stratified analyses to control for risk factors and to assess the possible influence of other risk factors for breast cancer on the effect of postmenopausal hormone use. We used proportional-hazards models to adjust for multiple risk factors simultaneously.[14]
To assess the relation between postmenopausal hormone therapy and mortality due to breast cancer, we identified all deaths due to breast cancer from 1976 through June 1, 1992, among women who were postmenopausal at the time of the diagnosis (n = 359). For each woman who died of breast cancer, we matched 10 women selected at random from among the women who were free from breast cancer, according to the year of birth and the age at menopause. We defined hormone use for these case patients and their controls as that reported on the questionnaire completed immediately before the diagnosis of breast cancer. To estimate the relative risk of breast cancer according to current and past postmenopausal hormone therapy, we used the odds ratio from a logistic regression in which we controlled for the year of birth and the age at menopause. This approach accounted for changes in estrogen use over time and avoided bias due to the discontinuation of hormone use by women who had received a diagnosis of breast cancer.
Results
During 725,550 person-years of follow-up, we identified 1935 cases of invasive breast cancer among postmenopausal women. Even though progestin use increased in this cohort, it did not add to the risk of breast cancer associated with the use of estrogen alone. Before 1986, few women took progestin. In 1986, 18 percent of postmenopausal women taking hormones used progestin; this proportion rose to 30 percent in 1990. Most women (73 percent) used conjugated estrogens; 77 percent of those who used estrogen omitted taking the drug for one week each month in 1986, and 66 percent did so in 1988. Almost all women receiving progestin took it for 14 or fewer days per month; the most common dose of medroxyprogesterone was 10 mg per day (used by 58 percent of the women who took this drug).
From 1978 to 1992, we observed a significant elevation in the risk of breast cancer among women using conjugated estrogens alone (adjusted relative risk, 1.32; 95 percent confidence interval, 1.14 to 1.54), estrogen plus progestin (adjusted relative risk, 1.41; 95 percent confidence interval, 1.15 to 1.74), and progestins alone (adjusted relative risk, 2.24; 95 percent confidence interval, 1.26 to 3.98) (Table 1). These relative risks did not differ significantly from each other. For each age at menopause, the relative risk of breast cancer was at least as high for women taking estrogen plus progestin as for those taking conjugated estrogens alone. The small number of cases among women taking estrogen plus progestin precluded detailed analysis of the risk according to duration of use and age. However, the similar relative risks for estrogen alone and for estrogen plus progestin suggest that these types of hormone use could be combined in analyses of the duration of therapy.
Table 1. Type of Hormone Currently Used by Postmenopausal Women and Relative Risk of Breast Cancer in the Nurses' Health Study, 1978 to 1992.
Among women currently taking hormones, the relative risk of breast cancer was highest among the oldest women (relative risk, 1.69 for women 65 to 69 years old, 1.42 for women 60 to 64 years old, 1.41 for those 55 to 59 years old, 1.46 for those 50 to 54 years old, and close to 1.0 for women younger than 50). The risk of breast cancer increased significantly only among women currently using hormone therapy who had used such therapy for five or more years. The dose of estrogen among these women did not differ from that received by women who had taken estrogen for less than five years. In contrast, women who had formerly used hormone therapy had no significant increase in risk as compared with women who had never used hormone therapy; this was true even for women who had taken hormones for five or more years in the past (Table 2).
Table 2. Duration of Current and Past Postmenopausal Hormone Therapy and Relative Risk of Breast Cancer in the Nurses' Health Study, 1976 to 1992.
As compared with postmenopausal women who had never taken hormones, and after controlling for the age at menopause, the type of menopause, and family history, the relative risk of breast cancer among postmenopausal women who used hormones was 1.54 (95 percent confidence interval, 1.19 to 2.00) for those 55 to 59 years of age who had taken hormones for five or more years. For women 60 to 64 years of age, the relative risk was 1.71 (95 percent confidence interval, 1.34 to 2.18). A shorter duration of use was not consistently related to the risk of breast cancer (Fig. 1).
Figure 1. Incidence and Relative Risk of Breast Cancer According to Age and the Duration of Current Postmenopausal Hormone Therapy.
Relative risks and 95 percent confidence intervals are shown on the top of the bars; relative risks are expressed in comparison with the risk among women in each age group who never received hormone therapy. Data have been adjusted for age at menopause, type of menopause, and family history of breast cancer in a proportional-hazards analysis.
The multivariate adjusted relative risk for five or more years of past use was 0.92 (95 percent confidence interval, 0.63 to 1.35) among women 55 to 59 years old and 1.13 (95 percent confidence interval, 0.83 to 1.55) among those 60 to 64 years old when these women were compared with those who never took hormones. Women who stopped taking hormones after five or more years of use were at increased risk of breast cancer for a short period after stopping. For those who had stopped taking hormones less than two years earlier, the multivariate adjusted relative risk was 1.44 (95 percent confidence interval, 0.99 to 2.08); for those who had stopped two to four years earlier, the relative risk was 0.80 (95 percent confidence interval, 0.55 to 1.16); and for those with five or more years since their most recent use of hormones, the relative risk was 0.95 (95 percent confidence interval, 0.74 to 1.25).
On the basis of the 359 deaths due to breast cancer among women who were postmenopausal at the time of diagnosis, the overall relative risk of death, adjusted for family history and history of benign breast disease, was 1.14 (95 percent confidence interval, 0.85 to 1.51) for women currently taking hormones and 0.80 (95 percent confidence interval, 0.60 to 1.07) for those who used hormones in the past. The relative risk for women currently taking hormones with less than five years of use at the time of diagnosis was 0.99 (95 percent confidence interval, 0.66 to 1.48), and for women with five or more years of use, the relative risk of death from breast cancer was 1.45 (95 percent confidence interval, 1.01 to 2.09).
Discussion
In this prospective cohort study, we observed an elevated risk of invasive breast cancer among postmenopausal women who were currently taking estrogen alone or both estrogen and progestin. The increase in risk was most pronounced among women over the age of 55 and was largely limited to the women who had used hormone therapy for five or more years. These data on women in the United States thus confirm findings from Europe, where combination therapy with estrogen plus progestins has been associated with an increased risk of breast cancer.[15-17] Because widespread use of progestins is a recent phenomenon, we were unable to examine associations with risk according to the dose or duration of progestin use. Furthermore, we have no data to explain why women in this cohort take hormones after menopause or why they stop.
The addition of progestin to estrogen therapy has been growing more common in the United States, but epidemiologic data on the effects of combination therapy are limited.[18] The initial report by Gambrell et al.[19] (based on 11 cases of breast cancer among women receiving estrogen plus progestin) suggested that combination therapy has a protective effect against breast cancer, but that study did not control for age or other confounding factors. Subsequent studies have found an elevated risk of breast cancer among Danish women who took sequential estrogen plus progestin (62 cases; relative risk, 1.4) and among Swedish women with a history of long-term use of combined hormone therapy (10 cases; relative risk, 4.4). In a British study, the risk of breast cancer was similar among women taking estrogen alone and among those taking estrogen plus progestin. Among three U.S. case-control studies[20-22] (a total of 48 cases in women who took hormones), two found an increased risk in association with combined therapy (as compared with no use of hormones),[20,22] and one found no association.[21] The multivariate adjusted relative risk of breast cancer that we observed (1.41) is compatible with the confidence intervals in all previous studies (except that of Gambrell et al.) and is based on 111 cases in women taking estrogen plus progestin. These data clearly indicate that the addition of progestin does not reduce the risk of breast cancer that is associated with estrogen use in postmenopausal women. Ductal cells of the breast therefore respond differently from the endometrium, where the addition of a progestin counters the adverse effect of estrogen. Hence, these data do not support the use of progestin by women who have undergone hysterectomy.
Estrogens increase serum hormone concentrations to approximate those in premenopausal women,[23-26] and 1.25 mg of conjugated estrogens has a greater effect than 0.625 mg.[26] There is evidence that progestins, when added to estrogen, may enhance the proliferation of epithelial cells in the breast.[27]
One potential source of bias in our study is the differences in the rates of participation in mammographic screening. We addressed this problem in several ways. First, because mammography detects a larger proportion of in situ breast cancers than other methods, we excluded such cases from this analysis. As expected, current use of hormones was somewhat more strongly associated with in situ disease (age-adjusted relative risk, 1.95), a finding that is consistent with the slightly higher frequency of screening mammography among postmenopausal women taking hormones. However, the age-standardized rate of screening mammography was only about 14 percent higher among women currently using hormones and 8 percent higher among past users of hormones than among postmenopausal women who never used hormones. Furthermore, from 1988 to 1992, only 9 percent of women who never used hormones, 6 percent of past users, and 3 percent of those currently using hormones did not undergo at least one mammogram. This difference is proportionately much smaller than the increase in risk for current users of hormones, and the large majority of women had been screened previously. Thus, it is unlikely that differences in the frequency of mammographic studies can explain the elevation in the risk of breast cancer among current postmenopausal recipients of hormone therapy. Moreover, postmenopausal women who received hormone therapy in the past and those who had been taking such hormones for less than five years were not at increased risk for breast cancer despite a higher rate of screening mammography. Finally, the higher risk of death due to breast cancer among women who had taken hormone therapy for five or more years at the time of diagnosis adds further weight to the causal association, because analyses based on mortality overcome problems of lead time and selective detection of tumors.[28]
In this analysis, we confirmed our earlier finding of a greater increase in the risk of breast cancer among older women taking hormones after menopause. This finding is consistent with data from several case-control studies that suggested an increased risk among older women, independent of the duration of hormone use.[21,29,30] This effect was stronger among women with five or more years of current use of hormones. The lack of association between current estrogen therapy and breast cancer among younger women may be due at least in part to the short time since menopause. Our data and those from several case-control studies suggest that the use of hormones at older ages after menopause may have a particularly deleterious effect on the risk of breast cancer.
These findings suggest that women over 55 years of age should carefully consider the risks and benefits of estrogen therapy, especially if they have used estrogen for five or more years. It is not clear that benefits outweigh risks for all women, particularly women with few risk factors for heart disease. Furthermore, short-term estrogen therapy — for up to seven years — in the decade after menopause cannot be expected to protect against osteoporotic fractures many years later.[31,32] Our data indicate that the addition of progestins to postmenopausal estrogen therapy does not reduce the risk of breast cancer. Estrogen alone, estrogen plus progestin, and progestins alone all appear to raise the risk of breast cancer. The significant increase in the risks of breast cancer and of death due to breast cancer among postmenopausal women over 55 who are currently taking hormones and who have used this therapy for five or more years suggests that the risks and benefits of hormone therapy among older women should be carefully assessed.
Correction. Breast Cancer and Hormone-Replacement Therapy
To the Editor: The data from the Nurses’ Health Study, reported by Colditz et al. (June 15 issue),[1] show a significant increase in the risk of breast cancer with hormone-replacement therapy. I am at a loss, however, about howto counsel my patients on the basis of these data. The relative risks are presented, but there is no mention of the absolute risk, which would be of much value to patients facing a decision about taking hormones. The use of patient-years is confusing and counterintuitive for clinical purposes.
In an attempt to obtain an overview of the data, I have calculated the absolute risk of breast cancer on the basis of 1935 cases of cancer among 69,586 postmenopausal women, as reported by the authors. Simple arithmetic puts the absolute risk at 2.78 percent. Since the cohort includes both treatment and control groups, this figure is an overestimate of the risk for the controls. On the basis of the reported relative risk (1.71) among older women taking hormones, the absolute risk would then be 4.75 percent (95 percent confidence interval, 3.73 to 6.06 percent). For patient and doctor, a crucial decision based on a 71 percent increase in the relative risk of a disease is quite different from a decision based on a 1.97 percentage point increase in the absolute risk.
My numbers are necessarily imperfect for the reasons stated above, and I would welcome similar calculations by the authors based on their original data. Relative risks are all well and good, but for most patients, the bottom line is the overall likelihood of disease.
Thomas Brunoski, M.D.
4 Ivy Knoll Westport, CT06880.
References:
1. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589-1593.
To the Editor: Menopausal women deciding whether to use hormone therapy face a difficult choice: a possibly reduced risk of coronary disease and osteoporosis in exchange for a possibly increased risk of breast cancer and cancers of the reproductive system. Colditz et al. missed their opportunity to help women with this choice by determining whether the increased risk of breast cancer among hormone users occurred primarily in the women with family histories of breast cancer. What is needed is stratification according to family history, not statistical adjustment for it.
Lynda H. Powell, Ph.D.
Rush-Presbyterian-St. Luke’s Medical Center Chicago, IL 60612.
To the Editor: After a careful reading of the article by Colditz et al., we are troubled that potential biases, including those noted in previous studies by this group, have not been addressed.[1,2,3,4] Of particular concern is the previously reported absence of an association between the use of hormone-replacement therapy and breast cancer among nondrinkers,[3] since an increased risk of death from breast cancer with heavier drinking has been reported in the same cohort.[5] If the association between hormone-replacement therapy and breast cancer is modified by alcohol consumption, then any risk of breast cancer associated with hormone-replacement therapy should be reported separately for drinkers and nondrinkers.
To our knowledge, none of the analyses in the Nurses’ Health Study have accounted for the racial or ethnic composition of the cohort.[1,2,3,4] It is possible that the reported association between hormone-replacement therapy and breast cancer is confounded by race, since black women, as compared with white women, are both less likely to use hormone-replacement therapy and at lower risk for postmenopausal breast cancer. That is, a higher incidence of breast cancer among women using hormone-replacement therapy would be expected simply because the risk of postmenopausal breast cancer is higher among white women.
It is also possible that the elevated risk among the women using hormone-replacement therapy in the Nurses’ Health Study reflects a lower-than-expected occurrence among nonusers rather than an increased risk among users. We compared the incidence of invasive breast cancer reported by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program for white women in the United states (from 1986 through 1990) with the incidence reported in the Nurses’ Health Study according to age.[3] The incidence of breast cancer in the Nurses’ Health Study was 0.8 times that expected (0.7 among the women who never used hormones, 0.7 among past users, and 1.0 among current users). An additional concern is the generalizability of risk estimates reported for long-term users, since nurses with very early menopause or bilateral oophorectomy (or both) may be overrepresented in this cohort.
Finally, Colditz et al. did not present any information on the relation between mortality from all causes and the use of hormonereplacement therapy It is not implausible, given the cardioprotective effects of hormone-replacement therapy in the Nurses’ Health Study, that mortality from all causes may be reduced by 20 percent or more among current users, even though the risk of breast cancer may be elevated. In our opinion, published analyses of the disease-specific effects of hormone-replacement therapy should be accompanied by information on mortality from all causes, since this information is necessary to help women and physicians make decisions about using hormone-replacement therapy.
Janine A. Blackman, M.S.
Trudy L. Bush, Ph.D., M.H.S.
University of Maryland School of Medicine Baltimore, MD 21201.
References:
1. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589-1593.
2. Buring JE, Hennekens CH, Lipnick RJ, et al. A prospective cohort study of postmenopausal hormone use and risk of breast cancer in US women. Am J Epidemiol 1987;125:939-947.
3. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 1990;264:2648-2653.
4. Colditz GA, Stampfer MJ, Willett WC, et al. Type of postmenopausal hormone use and risk of breast cancer: 12-year follow-up from the Nurses’ Health Study. Cancer Causes Control 1992;3:433-439.
5. Fuchs CS, Stampfer MJ, Colditz GA, et al. Alcohol consumption and mortality among women. N Engl J Med 1995;332:1245-1250.
To the Editor: The Nurses’ Health Study involves a follow-up of postmenopausal women for two years after assessment of their exposure status. Exposure status is updated every two years, and person-time data for each two-year segment are cumulated. The contrasted categories (users and nonusers) are a consequence of indications diagnosed by physicians and adherence by patients, not random assignment. Interestingly, medical practice with regard to postmenopausal estrogen therapy changed during the study period. The changes are manifest in the study cohort; 28 percent of the person-time accrued in the first four years was among current users, whereas this proportion fell to 19 percent in the next six years.[1]
It is intriguing that the results from the early part of the follow-up differ somewhat from those obtained subsequently. The earliest report (after four years of follow-up, with no updating of exposure[2]) showed relative risks of 1.0 and 1.3 for current and past use of hormonereplacement therapy, respectively. The current article reports relative risks ranging from 1.14 to 1.46 for current use and from 0.90 to 1.03 for past use. The relative risk of coronary disease also appears to have changed. Early follow-up yielded a relative risk of 0.30 among current users and 0.59 among past users.[3] After 10 years of data accrual, the estimated relative risk for current users had almost doubled, to 0.56, and the relative risk for past users had also increased, to 0.83.[4] Note that the cumulative nature of the data tends to blur differences in results between early and subsequent periods.
The implications of observing simultaneous changes in clinical practice and drug effects (as assessed through nonexperimental methods) have been discussed previously.[1] Such time trends suggest that nonexperimental quantification of drug effects may be confounded by changes in clinical practice. Perhaps a better insight into these issues would be obtained if the study investigators provided results stratified according to calendar time (e.g., two-year segments of data accrual) for the relative risks of both breast cancer and coronary disease. Nevertheless, the design feature relating exposure status to outcome within a two-year period, although probably relevant for coronary events, does not appear to be appropriate for studying breast cancer.
K.S. Joseph, M.D., Ph.D.
Royal Victoria Hospital Montreal, QC H3A 1A1, Canada.
References:
1. Joseph KS. The evolution of clinical practice and time trends in drug effects. J Clin Epidemiol 1994;47:593-598.
2. Buring JE, Hennekens CH, Lipnick RJ, et al. A prospective cohort study of postmenopausal hormone use and risk of breast cancer in US women. Am J Epidemiol 1987;125:939-947.
3. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985;313:1044-1049.
4. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease ten-year follow-up from the Nurses’ Health Study N Engl J Med 1991;325:756-762.
To the Editor: Colditz et al. present evidence that hormonal therapy of at least five years’ duration among current users is associated with a 45 percent increase in mortality from breast cancer.[1,2] Since the increase in mortality cannot be due to a detection bias, this result strongly supports the hypothesis of a causal association. This evidence deserves careful consideration, but the method used to derive the result reduces its credibility. The most straightforward and statistically powerful approach to analyzing cohort data such as those in the Nurses’ Health Study is survival analysis. This is precisely the approach that Colditz et al.[1] have taken in assessing the risk of breast cancer. For their analysis of mortality, however, they chose a matched, nested, case-control design that is inadequately described and hence difficult to evaluate. Their stated reason for this approach is that it "avoided bias due to the discontinuation of hormone use by women who had received a diagnosis of breast cancer." Such a bias can be readily avoided in survival analyses by delaying the start of follow-up until all the subjects have had the opportunity to undergo the exposure of interest. For example, when assessing the risk associated with five years of hormone therapy, follow-up should start five years after the menopause; women in whom breast cancer develops before this time should be excluded, since they did not have the opportunity to be exposed for five years. It would also be of great interest to know how many women received at least five years of therapy and to compare the survival curves for these women with the curves for the women who did not receive estrogens.
Editor’s note: Dr. Dupont has been a paid consultant to Wyeth-Ayerst Laboratories.
William D. Dupont, Ph.D.
Vanderbilt University School of Medicine Nashville, TN 37232-2637.
References:
1. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 1990;264:2648-2653.
2. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589-1593.
To the Editor: Colditz et al. conclude that the addition of progestins to estrogen therapy does not reduce the risk of breast cancer in postmenopausal women and that there is a substantial increase in the risk of breast cancer among older women who take hormones.
From experimental studies, it has been concluded that the period between the initial development of a breast tumor and its growth to 1 cm in diameter is approximately 16 to 20 years, with a mean of 18 years.[1,2] Given this very long latent period, it is likely that a considerable but unknown proportion of the women had undetected breast cancer throughout the study period.
The authors did not state whether screening for breast cancer was the same for the women receiving hormone treatment and those not taking hormones. It may be that the detection rates were higher in the groups of women who used hormones because they were screened more diligently — for example, by mammography.
What the authors are reporting is an increased detection rate among the women treated with hormones, not an increased incidence of cancer. It is by no means certain that this is a bad thing, since breast cancer is a curable disease and the proportion of women who are cured is dependent on the stage of the cancer at the time of its detection.[3] Provided the metastatic potential of breast cancer is not increased by hormone treatment and provided concern about the effects of hormone treatment results in improved screening, the potential risk may be lower than anticipated.
D.R. Wigg, M.B., B.S., M.D.
Royal Adelaide Hospital Adelaide, SA 5000, Australia.
References:
1. von Fournier D, Weber E, Hoeffken W, Bauer M, Kubli F, Barth V. Growth rate of 147 mammary carcinomas. Cancer 1980;45:21982207.
2. Koscielny S, Tubiana M, Valleron AJ. A simulation model of the natural history of human breast cancer. Br J Cancer 1985;52:515524.
3. Pearlman AW. Breast cancer influence of growth rate on prognosis and treatment evaluation: a study based on mastectomy scar recurrences. Cancer 1976;38:1826-1833.
To the Editor: If the hypothesis tested by the recently updated Nurses’ Health Study was that estrogen-replacement therapy is associated with an increased risk of breast cancer, it was not supported by the data presented. The relative risk for all the women who ever used estrogen-replacement therapy (as compared with the women who never used hormones) was 1.06. The duration of treatment did not increase the risk of breast cancer among the past and current users (even among those using hormones for more than 10 years), and there was no increase in the incidence of death from breast cancer among the users, as compared with the nonusers. These findings are in accord with the results of the majority of previously published studies examining the association between estrogen-replacement therapy and the development of breast cancer and mortality.[1]
Rather than discuss this absence of an association, the article by Colditz et al. deals almost exclusively with a minority of the women who have ever used hormones, categorized as current users. The authors report that the adjusted relative risk of breast cancer among current users who had taken hormones for five or more years (as compared with the nonusers) was 1.46. What hypothesis is accepted or rejected by these results? The authors’ conclusion appears to be related more to statistical manipulation than to any known biologic determinant of breast cancer.
AvrumZ. Bluming, M.D.
University of Southern California Los Angeles, CA 90033.
References:
1. Bluming AZ. Hormone replacement therapy: benefits and risks for the general postmenopausal female population and for women with a history of previously treated breast cancer. Semin Oncol 1993;20:662-674.
The authors reply:
To the Editor: Dr. Bluming asks what hypothesis we address and implies that there is no known biologic determinant of breast cancer in our analysis. However, estrogen is clearly a key determinant of risk. Breast cancer develops in women at much higher rates than in men. Women with earlier menopause have a lower risk of breast cancer than those with later menopause. Longer-term use of postmenopausal hormones increases the risk of breast cancer, an effect similar to that of a delay in menopause. The key question is not whether a woman who has ever used hormones has an increased risk of breast cancer, but rather how long a woman can use hormones before the risk is appreciably elevated and how rapidly any excess risk decreases after she stops using hormones. Pooling data from previous studies that included predominantly short-term use (typically less than two years) gives the false impression that all use is safe.
To respond to Ms. Blackman, Dr. Bush, and Dr. Powell, the relative risk associated with current use of postmenopausal hormones was similar among women with family histories of breast cancer and those without family histories and among those who consumed alcohol and those who did not. In sum, there was no important variation in relative risk for women with these important risk factors.
Dr. Brunoski asks about the absolute risk of breast cancer. It is small, although the disease is a major cause of death, in middleaged women. However, the lifetime risk of breast cancer is substantial. For a 60-year-old woman who has never used hormones after menopause, for example, the risk of receiving a diagnosis of breast cancer during the next five years is 1.8 percent. If she has taken hormones for five years and continues to take them, the risk is 3 percent. Alternatively, for every 80 women taking hormones for five years from the age of 60 to 65, 1 will receive a diagnosis of breast cancer.
Ms. Blackman and Dr. Bush compare our incidence rates with the SEER data from 1986 through 1990. This comparison is inappropriate, because the incidence of breast cancer has risen significantly overtime.[1] A comparison of the incidence of breast cancer from 1976 to 1990 with the SEER data from 1976 shows that our observed number of cases is within 3 percent of the expected number.2 Furthermore, the cohort is more than 95 percent white, so race cannot materially confound this result.
Dr. Dupont asks for a survival analysis; such an analysis is possible but complex. Sampling by risk group is essentially equivalent to the analysis suggested by Dr. Dupont. We are currently undertaking an analysis of hormone use and total mortality.
As we noted, the rates of mammography did not differ substantially between hormone users and nonusers, so biased detection cannot explain the results, particularly the increased mortality due to breast cancer among women using hormones for more than five years.
During further analysis of the data on postmenopausal hormone use and screening histories, we identified a minor programming error. A total of 1411 women previously categorized as past users in 1982 were actually current users. With this correction, there is a 7 percent increase in person-years of follow-up among current users (with 33 additional cases of cancer in this category), and a 2.8 percent reduction in person-years of follow-up among past users (with 10 fewer cases in this category).
The analysis of the relation between the type of hormone and the risk of breast cancer is not affected by these corrections. Repeated analyses of the data presented in Table 2 and Figure 1 in our article show no material difference in the results; all previously significant results remain significant. In Figure 1, the relative risks associated with nonuse, current use for less than five years, and current use for five or more years are as follows: for women between 50 and 54 years of age: 1.0, 1.41 (95 percent confidence interval, 0.95 to 2.10), and 1.53 (95 percent confidence interval, 0.97 to 2.42), respectively; for those between 55 and 59: 1.0, 1.30 (95 percent confidence interval, 1.03 to 1.67), and 1.45 (95 percent confidence interval, 1.12 to 1.87), respectively; and for those between 60 and 64: 1.0, 1.06 (95 percent confidence interval, 0.75 to 1.51), and 1.63 (95 percent confidence interval, 1.28 to 2.07), respectively. The largest change is in the group of current users who took hormones for 60 to 119 months; the relative risk in this group changes from 1.46 (95 percent confidence interval, 1.22 to 1.74) to 1.36 (95 percent confidence interval, 1.15 to 1.61) (Table 1).
Although a modest increase in the risk of breast cancer should be taken into consideration when making a decision about long-term use of hormones after menopause, our data should reassure women who are considering short-term use of estrogens for the relief of symptoms during menopause.
Table 1. Duration of Current and Past Postmenopausal Hormone Therapy and Relative Risk of Breast Cancer in the Nurses’ Health Study, 1976 to 1992.
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Graham A. Colditz, M.B., B.S.
Walter C. Willett, M.D.
Frank E. Speizer, M.D.
Brigham and Women’s Hospital Boston, MA 02115.
References:
1. Miller BA, Ries LA, Hankey BF, et al., eds. SEER cancer statistics review, 1973-1990. Bethesda, Md.: National Cancer Institute, 1993. (NIH publication no. 93-2789.)
2. Spiegelman D, Colditz GA, Hunter D, Hertzmark E. Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 1994;86:600-607.
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