Rosenberg L, Palmer JR, Wise LA, Adams-Campbell LL. A Prospective Study of Female Hormone Use and Breast Cancer Among Black Women. Arch Intern Med. 2006;166(7):760-765. doi:10.1001/archinte.166.7.760
Epidemiologic studies, largely of white women, have found that recent long-term female hormone use, particularly use of estrogen with progestin, is associated with an increased risk of breast cancer. Some studies suggest that the increase is greater among leaner women. Our aim was to assess the relation of female hormone use to incidence of breast cancer in black women, with attention to differences in effect according to body mass index.
Data on female hormone use, breast cancer risk factors, and the occurrence of breast cancer were collected through biennial questionnaires from 1995 through 2003 in the Black Women's Health Study, a follow-up study of US black women. During 182 629 person-years of follow-up of 32 559 women 40 years or older, 615 cases of breast cancer were reported.
The incidence rate ratio for breast cancer in women recently using female hormone supplements relative to those who had never used female hormones, with control for confounding factors, increased with duration of use and was 1.58 (95% confidence interval [CI], 1.12-2.23) for 10 or more years of use; the incidence rate ratios were 1.41 (95% CI, 0.95-2.10) for 10 or more years of use of estrogen alone, and 1.45 (95% CI, 0.94-2.23) for 5 or more years of use of estrogen with progestin. The association of breast cancer with female hormone use was stronger among leaner women (body mass index [calculated as weight in kilograms divided by the square of height in meters] <25) than among heavier women. Among the leaner women who recently used female hormone supplements for durations of 10 or more years, the incidence rate ratio was 3.08 (95% CI, 1.70-5.56); the corresponding estimates among women with body mass indexes of 25 to 29 and 30 or greater were 1.43 and 0.91, respectively, and neither was statistically significant.
These results based on data from US black women strengthen the evidence that use of estrogen alone and estrogen with progestin increases the risk of breast cancer and that the association is stronger among leaner women.
Many observational studies suggest that the risk of breast cancer is increased by the long-term use of female hormone supplements, particularly the use of estrogen with progestin; the associations have been strongest for recent use, variously defined as current use or use within the previous 1 to 5 years.1- 14 In the largest randomized trial to date, the Women's Health Initiative (WHI),15 the relative risk of breast cancer for women randomized to use of estrogen with progestin was 1.26 after 5 years of follow-up, and the increase among users was larger among those who had taken female hormone supplements before the trial. Breast cancer risk was not increased among women using estrogen alone in the WHI.16
Belief that an association represents cause and effect is strengthened when similar results are obtained across different populations. Black women take female hormone supplements less frequently compared with white women, and the distribution of risk factors for breast cancer also differs between these ethnic groups.17- 21 Most of the women included in previous studies of female hormone use and breast cancer have been white, and there is little information on the effect of female hormone use on breast cancer risk in black women specifically. A case-control study that included 1870 black women with breast cancer reported that continuous use of combined estrogen and progestin was associated with an increased risk of breast cancer for all ethnic groups combined and that the association was not significantly modified by ethnic group.10 In a combined reanalysis of data from many observational studies that included 52 705 women with breast cancer and 108 411 women without breast cancer, 2% of the subjects were of races other than white; breast cancer risk was increased among those taking female hormone supplements in both white and nonwhite women, but the confidence interval among the latter group was too wide to be informative.2 In the WHI, in which approximately 10% of the women were of races other than white, the associations of breast cancer with female hormone use were not modified by racial/ethnic group.15,16 In the present study, we assessed the relation of female hormone use to breast cancer incidence in black women, with data obtained in a nationwide follow-up study, the Black Women's Health Study (BWHS).
Some studies have found that the association of female hormone use with breast cancer risk differs according to body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), with greater increases in breast cancer risk for leaner female hormone users.2- 6 The distribution of BMI among US black women differs markedly from that among US white women, with a greater prevalence of overweight and obesity among black women.22 We thought it would be of particular interest to assess whether the effect of female hormone use varied according to BMI among BWHS participants.
Female hormone use declined dramatically after the release of the WHI results,23 and selective changes in use associated with breast cancer risk could lead to bias in future observational studies. Therefore, we assessed the relation of female hormone use to breast cancer incidence in the BWHS using female hormone data collected before the WHI results were published.
The BWHS began in 1995, when 64 500 black women aged 21 to 69 years were enrolled through postal health questionnaires. Most of the enrollees were subscribers to Essence magazine, a popular magazine targeted to black women, and small numbers were members of selected professional organizations or friends or relatives of early respondents. Of the enrollees, 27% lived in the Northeast, 29% in the South, 23% in the Midwest, and 21% in the West. The 59 000 participants whose addresses were judged to be valid 1 year after entry have been followed through biennial postal questionnaires.24 Follow-up questionnaires were completed by 91% of the original cohort in 1997, 88% in 1999, 83% in 2001, and 80% in 2003; during the 8 years of follow-up, 2% of the cohort died. The institutional review boards of Boston University Medical Center, Boston, Mass, and Howard University Cancer Center, Washington, DC, approved the BWHS.
The baseline questionnaire included questions about the use of female hormones (recency of use, duration, and type of preparation last used), menopausal status, and medical history. The follow-up questionnaires asked about these factors and the occurrence of breast cancer in the previous 2 years. The present analyses used data from baseline in 1995 through the 2003 follow-up cycle.
Review of medical records of incident cases of breast cancer for validation of self-report is an ongoing process in the BWHS. To date, 65% of the women approached who reported breast cancer have agreed to release their medical records for review; the reasons cited by most women who did not sign a release were mistrust of the medical establishment and concern about confidentiality. We have thus far obtained medical records for 299 women who reported breast cancer during follow-up; 296 cases (98%) were confirmed to be breast cancer (88% invasive and 12% in situ). The 3 unconfirmed cases were excluded. Female hormone use and menopausal status among women who consented to release their records were similar to those among women who refused, allaying concern that women's willingness to release their records was associated with female hormone use.
We defined recent use of female hormones as use within the previous 2 years of any oral medications or patches containing female hormones and past use as use that had ceased more than 2 years previously. Because most female hormone use reported was of pills (88%-90% of use in each of the 4 follow-up cycles), it was not possible to informatively assess the use of patches or injections separately (they accounted for 8%-11% and <1% of use, respectively).
Breast cancer occurring in a particular follow-up cycle was assessed in relation to exposure data from the previous cycle (eg, breast cancer reported on the 1999 questionnaire in relation to female hormone use reported on the 1997 questionnaire). Women contributed person-years of female hormone use or nonuse during each follow-up cycle. Over the course of follow-up, a woman could contribute person-years of use of estrogen alone, estrogen with progestin, progestin alone, and nonuse.
After excluding women who had breast cancer at baseline, were currently taking oral contraceptives, had unknown menopausal status, or did not complete the female hormone questions, 32 559 women were followed up for breast cancer incidence. Because women younger than 40 years rarely take female hormone supplements, the analysis was confined to women 40 years or older at baseline (23 191 women) or who reached age 40 years during follow-up (9368 women).
We used age-stratified Cox regression models (SAS version 8.2; SAS Institute Inc, Cary, NC) to derive incidence rate ratios (IRRs) for breast cancer in relation to female hormone use, with control for confounding factors. Women contributed person-years from baseline to the time of diagnosis of breast cancer, loss to follow-up, death, or the end of follow-up (March 2003), whichever came first. The Anderson-Gill data structure was used to handle time-varying covariates.25,26
As shown in Table 1, among 23 191 women 40 years or older at baseline, female hormone use was associated positively with being postmenopausal (particularly because of bilateral oophorectomy), menopause before age 50 years, menarche at 14 years or older, benign breast disease, living in the West, and having had a mammogram in the previous 2 years.
We controlled for menopausal status (premenopausal, naturally menopausal, bilateral oophorectomy, and hysterectomy) and age at menopause in the final Cox regression models; for women with a simple hysterectomy (hysterectomy without removal of both ovaries), the age at hysterectomy was used as the age at menopause. We carried out a secondary analysis confined to women who had not had a simple hysterectomy (ie, premenopausal women and women who were postmenopausal owing to bilateral oophorectomy or natural causes). With respect to potential confounding factors other than age, menopausal status, and age at menopause, the IRRs changed less than 10% after control for age at menarche, age at first birth, parity, oral contraceptive use, BMI, vigorous exercise, benign breast disease, alcohol use, family history of breast cancer, years of education, and geographic region. The IRRs presented in the “Results” section are adjusted for age, menopausal status, and age at menopause only. Information on the use of mammography in the previous 2 years was obtained on each follow-up questionnaire. To assess whether having undergone mammography affected the association between female hormone use and breast cancer risk, we conducted a secondary analysis that excluded noncases who had not had a mammogram in the previous 2 years.
During 182 629 person-years of follow-up of 23 304 BWHS participants during 1995 through 2003, 615 cases of breast cancer were reported (Table 2). The IRR point estimate was greater for recent (1.15) than for past (0.94) use and also greater for recent use of estrogen with progestin (1.28) than for recent use of estrogen alone (1.10), but all of these estimates were compatible with 1.0 and each other. The IRR increased with increasing duration of recent female hormone use and was 1.58 (95% confidence interval [CI], 1.12-2.23) for 10 or more years of use (P = .08, test for trend); the IRR was 1.23 (95% CI, 0.82-1.84) for 5 to 9 years of estrogen use alone, 1.41 (95% CI, 0.95-2.10) for 10 or more years of use of estrogen alone, and 1.45 (95% CI, 0.94-2.23) for 5 or more years of use of estrogen with progestin. There were too few users of progestin alone for informative results on this hormone. The results were closely similar when we excluded women who had not had a mammogram in the previous 2 years (data not shown).
As shown in Table 3, almost all of the IRRs were highest among the leanest women, those with a BMI less than 25. Among the leanest women, the IRR was 1.54 (95% CI, 1.06-2.26) for recent female hormone use, 1.41 (95% CI, 0.85-2.33) for recent use of estrogen alone, and 1.65 (95% CI, 1.02-2.68) for recent use of estrogen with progestin. The IRR for recent users increased with duration of use and was 3.08 (95% CI, 1.70-5.56) for 10 or more years of female hormone use (P = .02, test for trend). Among women with a BMI of 25 to 29, the IRRs for longer-duration use were elevated but less so than among women with a BMI of less than 25: the IRR was 1.43 for 10 or more years of female hormone use among recent users, 1.37 for recent users with 10 or more years of use of estrogen only, and 1.38 for recent users with 5 or more years of use of estrogen with progestin, but the 95% CIs for all of the IRR estimates included 1.0. Among women with a BMI of 30 or greater, all of the IRR point estimates were close to 1.0 and all of the 95% CIs included 1.0.
We examined IRRs among strata of other risk factors for breast cancer, including alcohol consumption, benign breast disease, parity, and oral contraceptive use. The associations of female hormone use with breast cancer risk did not vary materially across strata of these factors, but strata-specific numbers of users tended to be small. Numbers were too small to assess modification by family history of breast cancer.
To assess whether the association of female hormone use with breast cancer risk was consistent across socioeconomic strata, we examined IRRs among subgroups of educational attainment. The IRRs were similar across the strata: for 10 or more years of recent female hormone use, the IRR estimates among women with 12 or less, 13 to 15, and 16 or more years of education were 1.63 (95% CI, 0.83-3.21), 1.66 (95% CI, 0.87-3.15), and 1.54 (95% CI, 0.92-2.59), respectively.
Because it is not possible to accurately determine and fully control age at menopause for women with a simple hysterectomy,27 we carried out a secondary analysis among the 26 470 women remaining after exclusion of those women. The results were closely similar to those presented.
The present results suggest that recent long-term female hormone use increases the risk of breast cancer among US black women. The findings apply to female hormone pills, which accounted for most of the use among women in the BWHS. About 10% of the women used transdermal hormones. In a large British follow-up study, the Million Women Study, the relative risks did not differ between those taking oral and transdermal estrogen supplements.4
In the present study, risk of breast cancer increased with increasing duration of female hormone use; the overall IRR was 1.41 (95% CI, 0.95-2.10) for 10 or more years of estrogen use and 1.45 (95% CI, 0.94-2.23) for 5 or more years of use of estrogen with progestin. Most previous studies, largely of white women, have found an increased risk of breast cancer associated with use of estrogen with progestin and that risk increases with duration of use.2- 17,28 In the WHI, the hazard ratio for women using estrogen with progestin was 1.26 (95% CI, 1.00-1.59) at the end of 5 years of follow-up; the risk was greater for those who had taken female hormone supplements previously (eg, 1.81 for those with ≥10 years of previous use).15 Findings concerning estrogen alone have been less consistent. Many observational studies have reported an adverse effect of use of estrogen alone on breast cancer risk. In the combined analysis of more than 50 000 cases2 and in the Million Women Study,4 the relative risks for use of estrogen alone for 5 or more years were both 1.34 and statistically significant. In the follow-up study by Kerlikowske et al29 of women who underwent mammography examinations from 1996 to 2000, although the relative risk was significantly increased for women who used estrogen with progestin for 5 years or more, the corresponding estimate for those using estrogen alone for 5 years or more was decreased (0.92 [95% CI, 0.84-1.00]). However, this study is likely to have underestimated an adverse effect of estrogen alone, as well as of estrogen with progestin, because age at menopause was not controlled2,27; younger age at menopause is strongly inversely associated with breast cancer risk and positively associated with female hormone use, and allowance for it increases the risk estimates for those taking female hormone supplements. In contrast to the observational results, there was no increase in the risk of breast cancer among women using estrogen in the WHI; indeed, the hazard ratio was 0.77 and close to statistical significance (95% CI, 0.59-1.01).16 Convincing reasons for the discrepancy between the WHI results and the observational results, other than chance, are lacking.
The present finding that associations were strongest among the leaner women agrees with previous observational results.2- 6 The WHI did not find a significant modifying effect of BMI on the association between use of estrogen with progestin and increased breast cancer risk. However, the P value for interaction was .12, and the point estimates of risk were greater among women with a BMI of less than 30 than among heavier women.30 For estrogen use alone, the WHI found no modifying effect of BMI.16 Previous observational studies and the WHI2- 16,30 have not found evidence of a modifying effect of other risk factors on the associations of female hormone use with breast cancer risk, nor did the present study.
Associations of exogenous female hormone use with increased risk of breast cancer are biologically plausible. Endogenous estrogens are associated with increased risk of breast cancer.31,32 Progestin can act as a breast mitogen,33,34 which could explain a greater increase for combination therapy. The production of estrogen from adipose tissue is greater among heavier postmenopausal women compared with leaner women31; therefore, exogenous estrogens may have less of an effect on estrogen levels in heavier women, perhaps explaining the stronger association with female hormone supplement use in leaner women.
Selective losses are not a major concern in the present study because follow-up rates were satisfactory: more than 80% of the original cohort members who were still alive after 8 years of follow-up were still participating. Moreover, female hormone use and other important characteristics at baseline, such as menopausal status, of women who completed the final follow-up questionnaire in the period analyzed in the present report and women who did not were similar; this suggests the absence of selective losses.
The women reported their mammography use on each of the biennial follow-up questionnaires, and high proportions had undergone mammography. Thus, greater detection of breast cancer among those taking female hormone supplements due to greater medical surveillance is unlikely to explain the findings, particularly because results changed little when women who did not have a recent mammogram were excluded from the analysis.
The exposure data were collected prospectively, thereby eliminating reporting bias. Because the exposure data were collected before the release of the results of the WHI,15 changes in female hormone use in response to those findings cannot explain our results. Misclassification of use of estrogen taken with progestin as use of estrogen alone, and vice versa, would have resulted in overestimation of an effect of estrogen alone and underestimation of an effect of estrogen with progestin.
Misclassification of breast cancer cases was unlikely to have affected the results because self-report was accurate among the cases confirmed by medical records; in addition, the cases confirmed with medical records were similar to those for whom records were not obtained. However, the obtainment of medical records for only half of the cases in the present analyses made it infeasible to assess the effect of female hormone use according to factors such as the stage of the cancer or estrogen receptor status. Some observational data suggest that female hormone use is associated with early-stage breast cancer,4 but the use of estrogen with progestin was associated with more advanced stages of breast cancer in the WHI.15,30 A few studies have suggested that female hormone use is associated with estrogen receptor–positive tumors.13,35,36
The present results were consistent across strata of education. Virtually all participants in the BWHS have completed high school and, nationally, about 83% of black women of the same ages as BWHS participants have completed high school.37 In addition, BWHS participants resemble black women in other studies in terms of the distributions of risk factors for breast cancer such as age at menarche,18,21 age at first birth,18,20,21 and long-term oral contraceptive use.18,21 Thus, the present results are likely to be applicable to most US black women.
In summary, the present findings based on data from US black women strengthen the evidence that use of female hormone supplements increases the risk of breast cancer.
Correspondence: Lynn Rosenberg, ScD, Slone Epidemiology Center, Boston University, 1010 Commonwealth Ave, Boston, MA 02215 (email@example.com).
Accepted for Publication: October 20, 2005.
Author Contributions: The authors had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None.
Funding/Support: This study was supported by grant CA58420 from the National Cancer Institute, Bethesda, Md.
Acknowledgment: We acknowledge the dedication of the Black Women's Health Study participants and staff.