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ORIGINAL RESEARCH |
From the Population Studies and Prevention Program, Karmanos Cancer Institute at Wayne State University, Detroit, Michigan; Department of Obstetrics and Gynecology, Henry Ford Health Systems, Detroit, Michigan; Fred Hutchinson Cancer Research Center, Seattle, Washington; Karmanos Cancer Institute at Wayne State University, Department of Internal Medicine, Detroit, Michigan; Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Preventive Medicine, University of Southern California, Los Angeles, California; Divisions of Reproductive Health and Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia; and Contraception and Reproductive Health Branch, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, Maryland.
Address reprint requests to: Linda K. Weiss, PhD, Cancer Centers Branch, Office of Centers, Training and Resources, National Cancer Institute, 6116 Executive Boulevard, Suite 700, Bethesda, MD 20892-8345; E-mail: lw187q{at}nih.gov.
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ABSTRACT |
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TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: A multicenter, population-based, case-control study was conducted in five United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823 postmenopausal white and black women (1870 cases and 1953 controls) aged 35–64 years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using standard, unconditional, multivariable logistic regression analysis. Potential confounders were included in the final model if they altered ORs by 10% or more. Two-sided P values for trend were computed from the likelihood ratio statistic.
RESULTS: Continuous combined HRT was associated with increased breast cancer risk among current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17). Additionally, a statistically significant trend indicating increasing breast cancer risk with longer duration of continuous combined HRT was observed among current users (P = .01). There were no positive associations between breast cancer risk and other HRT regimens.
CONCLUSION: Our data suggest a positive association between continuous combined HRT and breast cancer risk among current, longer term users. Progestin administered in an uninterrupted regimen may be a contributing factor. Risk dissipates once use is discontinued.
Approximately six million US women reported using hormone replacement therapy (HRT) in 1992.1 Although use varies by geographical region, socioeconomic status, and race,2–5 it has undoubtedly risen over the past 2 decades due to the aging of the US population, the concomitantly increasing proportion of menopausal women, and prior reports of the beneficial effects of HRT on health. Although current usage figures are difficult to establish, popular brands of estrogen and combined estrogen-progestin products ranked tenth and 50th by dollar volume, respectively, in the US prescription market for the year 2000.6
A possible relationship between HRT and breast cancer has been explored in numerous epidemiological studies over the past several decades, with inconsistent results due to variations in study design; sample sizes insufficient for statistically accurate subgroup analyses; failure to control for confounders; and alterations over time in formulation, dose, regimen, and other parameters of use.7–22 Additionally, few studies to date have included sample sizes sufficient for differential assessment of risk related to sequential estrogen-progestin replacement therapy (sequential HRT), involving progestin taken with estrogen for a limited number of days each month, versus continuous combined HRT, in which progestin is taken with estrogen for all or most days each month.
Investigators of the Women’s Health Initiative Randomized Controlled Trial, the first randomized trial to assess risks and benefits associated with use of continuous combined HRT, recently reported an increased risk of breast cancer (1.26; 95% confidence interval [CI] 1.00, 1.59) after 5 years of follow-up among women receiving continuous combined HRT, as compared with those receiving placebos.23 Risks associated with use of other forms of combined HRT were not investigated in the Women’s Health Initiative Randomized Controlled Trial. The arm of the study focusing on estrogen replacement therapy (ERT) continues, with completion expected in 2005. Women and their physicians are understandably concerned about the implications of current and future findings for treatment decisions.
Here we report results of a large, multicenter, population-based, case-control study designed to examine the relationship between HRT and breast cancer risk based on regimen and duration and recency of use.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Overall study methods and random digit dialing outcomes have been previously described in greater detail elsewhere.24 In brief, qualifying cases were United States–born, English-speaking, white and black women (including Hispanics), 35–64 years of age at diagnosis. An active home telephone number was required as of the reference date, established for cases as date of first microscopic breast cancer diagnosis. Cases of younger or black patients were oversampled to approximate a uniform distribution across strata. Controls were selected to approximate the distribution of cases by study site, race, and 5-year age group. Of the 5982 eligible cases selected, 4575 (76.5%) were interviewed.
Controls consisted of women who had never been diagnosed with either invasive or in situ breast cancer, but met the remainder of the above criteria. Potential controls were identified via centralized random digit dialing, using an unclustered, equal probability sampling method; nonworking numbers were eliminated through automated technology.24,25 Date of initial household contact was used as the reference date. Controls were frequency matched to cases on the basis of race, 5-year age group, and geographical location, using stratified sampling.26,27 Approximately 82% of residential households contacted by random digit dialing were successfully screened. Of the 5956 eligible women selected as controls, 4682 (78.6%) were interviewed.
The protocol required that in-person interviews be conducted with all participants within 18 months of the reference date. Approximately 77% of participating cases and 88% of participating controls were actually interviewed within 6 months of that date. Reproductive and medical history, family history of cancer, and information on demographic, lifestyle, and other relevant variables were ascertained for all respondents. Exposure histories for all HRT use (including start and stop date, brand, regimen, and reasons for starting and discontinuing each episode) were obtained for the period preceding the reference date. Calendars were used to provide a frame of reference for all periods of HRT use, and color photographs assisted respondents in identifying specific brands. Institutional review board approval was obtained at each study site. A signed informed consent form was obtained from each participant before the interview.
Women were considered postmenopausal if they fell into any of the following categories (Table 1
): 1) known natural menopause, defined by last menstrual period (LMP) more than 12 months before the reference date, a 12-month gap between LMP and first use of HRT, or LMP at least 12 months before hysterectomy or bilateral oophorectomy; 2) known induced menopause, via bilateral oophorectomy, chemotherapy, or radiation before natural menopause; 3) known menopausal but type unclear, defined by bilateral oophorectomy before the reference date, with either a hysterectomy 1 year or more before oophorectomy or use of HRT in the 12-month period before oophorectomy; and 4) assumed natural menopause, defined as age 55 or older and either on HRT and still menstruating, with hysterectomy (without bilateral oophorectomy) before natural menopause, or with LMP 12 months or more before the reference date due to miscellaneous reasons unrelated to menopause. The last category also included women with LMP at least 12 months before the reference date, but with exact date of ovarian failure obscured by HRT. A total of 2651 cases and 2653 controls were excluded, including premenopausal women (2116 cases and 2061 controls), women with unknown menopausal status (53 cases and 66 controls), and women younger than 55 with unclear menopausal status at reference date (482 cases and 526 controls). The age threshold of 55 or older was based on analyses of women known to be either premenopausal or naturally menopausal with known age at menopause. Using this cutoff point, 97% of women 55 or older and 90% of women overall were correctly classified in regard to menopausal status.
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In our primary model, the referent group included women who indicated they had never used any form of HRT for reasons related to menopause. This model has been used in a number of other studies and has the advantage of providing a consistently defined "never user" group. We also estimated odds ratios (ORs) based on a second model employing never-users of a specific regimen as the referent group and adjusting simultaneously for duration of use of other HRT regimens, however, so that the results of this study could be compared to data analyzed similarly in the recent literature.21
The relationship between use of HRT and risk of breast cancer was assessed through calculation of ORs as estimates of relative risk, using standard, unconditional, multivariable logistic regression analysis. Tests for trends in duration of use were performed by adding the confounding variables and a dichotomous term for ever having used HRT (never, ever) and an ordinal term for five levels of duration (never or less than 6 months, 6 months to less than 2 years, 2 to less than 5 years, 5 to less than 10 years, and 10 or more years) to the logistic models. This strategy accounts for the potential threshold effect of ever/never use and allows the trend test to reflect the dose-response trend among HRT users.28 The P value was computed from the likelihood ratio statistic, comparing models with and without the ordinal term. Global tests of departure from linearity were performed using nested models as described by Breslow and Day.29 All P values reported are two sided.
We retained potential confounding variables (Table 1
) in the final model if they altered the ORs for HRT exposure by 10% or more. A change in ORs was evaluated by adding potential confounders singly to the model. We also fit models for each exposure that included all potential confounders improving model fit (using the criteria of P < .1) and found little difference between the resulting "best fit" models and our final model. Inclusion of quadratic terms to models that fit linear terms for HRT duration also did not improve model fit. Our final model therefore is that most parsimonious for describing the data, as recommended by Hosmer and Lemeshow.30
We also conducted parallel analyses adjusting for known or imputed age at menopause. In these analyses, age at menopause was imputed as follows: For women with a bilateral oophorectomy, but unclear type of menopause, age at menopause was imputed as age at date of oophorectomy. For women with a hysterectomy, age at menopause was imputed as either age at date of hysterectomy or age at first HRT use if that occurred after the hysterectomy. For all other women with unclear or unknown age at menopause, imputed age at menopause was established as age at either LMP or first HRT use. We also performed two subanalyses, one restricted to women with known type of menopause (natural and induced) and known age at menopause, and one to women without a hysterectomy before natural menopause. As previously noted, age at menopause was not a confounder in our data.
Risk of local or regional stage disease31 was assessed using a polytomous logistic model.30 When assessing the impact of HRT use on stage of disease at diagnosis, we also adjusted for history of recent screening mammography, which has been shown to be a potential confounder in some studies.
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RESULTS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A total of 1924 cases and 2029 controls were defined as postmenopausal using the above criteria. Of these 3953 women, 1252 cases (65.1%) and 1374 controls (67.7%) had used HRT during their lifetime. Approximately 5% of all users had only taken HRT in a form other than estrogen or progestin pills or estrogen patches. Excluding this group, 3823 women (1870 cases and 1953 controls) were available for analysis. Black women comprised 34.1% and 35.3% of the case and control groups, respectively. A higher proportion of white women (74.7%, versus 47.6% black) reported using HRT. Results are reported here for all women combined because the overall ERT and combined HRT analyses by race were similar, the numbers of black women in analyses of continuous combined HRT and sequential HRT were too small to provide an accurate assessment of differences, and effect modification by race was not statistically significant.
Cases and controls differed in several important respects (Table 1). Patients were older than controls and were more likely to have a first-degree family history of breast cancer, a natural menopause, and a recent screening mammogram. They were less likely to use oral contraceptives or to have an induced or early menopause or a young age at first pregnancy. On other variables, the distributions were more similar.
In analyses focusing on risk of breast cancer by HRT regimen and duration of use (Table 2), we observed a trend for increasing risk among longer term users of continuous combined HRT; this trend was not evident for other HRT regimens. The first reported ORs in Table 2 are based on our primary model, in which never-users of HRT constitute the reference group. In this model, no statistically significant differences between cases and controls were observed for any regimen. Odds ratios for short-term use (less than 6 months) of both combined HRT and continuous combined HRT indicated decreased risk. No major differences in analytic outcomes were noted when data for 5 or more years of use were restratified as 5 to less than 10 years and 10 or more years of use. A statistically significant trend for increasing risk with duration of use was found for combined HRT (P = .003) overall, but risk appeared confined to continuous combined HRT (P = .01). Table 2 also provides risk estimates based upon a second model in which the never-users of a particular regimen constitute the reference group, and there is simultaneous adjustment for use of other HRT regimens included in our analysis. Using this model, ORs for combined HRT lasting 2 to less than 5 years (1.34; 95% CI 1.05, 1.70) and 5 or more years (1.27; 95% CI 1.03, 1.56) and continuous combined HRT lasting 5 or more years (1.45; 95% CI 1.09, 1.91) were statistically significant. As in the primary model, a decreased risk was seen for short-term users of less than 6 months in both of these groups.
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When analyses were restricted to women having known natural or induced menopause and known menopausal age (Table 3), ORs for 5 or more years of combined HRT (1.49; 95% CI 1.05, 2.12) and continuous combined HRT (1.77; 95% CI 1.04, 3.01) were statistically significant. Odds ratios for short-term users again indicated decreased risk. Trends for increasing risk with longer duration of use were again found for combined HRT (P = .003) and continuous combined HRT (P = .01). When data were restratified to reflect 5 to less than 10 and 10 or more years of use (data not shown), ORs for 5 to less than 10 years of continuous combined HRT use were statistically significant (1.83; 95% CI 1.02, 3.27). Results of ERT analyses were similar to those presented in Table 2.
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), and found that current use of combined HRT of 5 or more years’ duration conferred a significant increase in risk (1.37; 95% CI 1.06, 1.77); this increase was confined to continuous combined HRT (1.54; 95% CI 1.10, 2.17), however. Among some past short-term users of combined HRT and continuous combined HRT, risk was slightly decreased. Associations between sequential HRT and breast cancer risk were not significant for either current or past users. P values for trend among current combined HRT and continuous combined HRT users were .03 and .04, respectively, indicating a positive duration-response relationship. There were no positive associations between ERT and breast cancer risk.
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Finally, in our data there were no statistically significant interactions between BMI and any HRT regimen.
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our study is one of relatively few to examine breast cancer risk in relation to specific HRT regimens. We collected detailed information on lifetime use of HRT from a large number of women residing in five different geographical areas of the United States. Additional strengths include population-based case identification, use of rapid case ascertainment methods to permit interview of cases within a short time frame after diagnosis, population-based control selection, collection of detailed data on a large number of potential confounders, standardized data collection across study locations, strict quality assurance monitoring, and over-sampling of black women and younger women.
Clearly, these analyses have limitations as well. Although memory aids were used to assist participants in recall, data were not verified against medical records, leaving open the possibility of recall bias. Sample sizes for some subgroup analyses were relatively modest, and results for those analyses must be interpreted cautiously. Too few black women were available in some HRT subcategories to assess differences in risk by race. Relatively few rural residents were included in the geographical areas covered by our study, and our results would not be generalizable to women in these areas if they differ in ways that modify or confound the effect of HRT on breast cancer risk. Our study included postmenopausal women with simple hysterectomies, and we adjusted only for type of menopause and matching variables.
We confined our analyses to pill and patch use and included women who used both ERT and combined HRT in the analyses of each regimen. For comparison, however, we also conducted several parallel and sub-analyses. Odds ratios for women using ERT were consistent over all of these analyses. In analyses of combined HRT, sequential HRT, and continuous combined HRT, trends were similar, but differences in estimates for some strata of combined HRT and continuous combined HRT were observed when the analysis group was restricted to women of known menopausal type and age (Table 3). Although numbers in these strata often were small, this finding suggests that ORs from our primary analyses may slightly underestimate the true relative risk.32,33
Finally, our trend analyses included short-term users as well as users of longer duration. In our data there was a fairly consistent negative association between short-term use of less than 6 months and breast cancer risk. Although the reasons for this pattern cannot be known with certainty from our own data, one possible operating factor could be "healthy screenee" bias: If some women are screened out of HRT use based on family or medical history, those initiating HRT may be at a lower baseline risk.34 Our decision to include short-term users in trend analyses was based on the premise that this effect would diminish over time and that risk would continue to increase in a linear fashion with age and longer duration of use. When short-term users were excluded from trend analyses, however, no significant duration-response relationship was observed.
A number of epidemiological studies have explored the relationship between HRT and breast cancer risk, with varying results.7–22 The recent pooled analysis of 51 epidemiological studies, focusing primarily on ERT users, demonstrated a modest increase in risk of breast cancer with increasing duration of use.35 Few studies have had the capability to assess the association between breast cancer risk and combined HRT according to regimen. Two recent investigations focusing on HRT regimens have reached somewhat differing conclusions. Ross et al21 determined that there was no relationship between ERT and breast cancer risk, regardless of duration of use, but that sequential combined HRT of 5 or more years was associated with increased risk (1.38; 95% CI 1.13, 1.68). The relative risk per 5 years of continuous combined HRT was 1.09 (95% CI 0.88, 1.35), with no differences between current and former users observed. A nested case-control study by Chen et al,22 on the other hand, found that the incidence of breast cancer was increased by 60–85% among recent, long-term users, regardless of regimen. A relatively small number of women in both studies had used continuous combined HRT.
In contrast to Ross et al21 and Chen et al,22 our findings included a significant increase in breast cancer risk among current, long-term users of continuous combined HRT, but no increased risk among users of sequential HRT. Using our data, we specifically compared results from our analytic model (with never-users as the referent group) with the analytic model used by Ross et al21 (with never-users of a particular regimen as the referent group and data adjusted for duration of use of other regimens) and found no significant associations between sequential HRT and breast cancer risk with either. Overall, our results were similar regardless of the model used, though continuous combined HRT use of 5 or more years was statistically significant using the approach by Ross et al.21 Other study design differences, including variation in the age of the study participants and criteria related to the inclusion of women with hysterectomies, may account for the disparities across these three studies.
Although the mechanism through which combined HRT and, more specifically, continuous combined HRT may increase breast cancer risk remains unclear, evidence from recent animal,36,37 clinical,38–40 and population studies19–21 points to a proliferative function of progestin in human breast tissue.41 Raafat et al36,37 recently reported an association between estrogen-progesterone therapy and epithelial cell proliferation in a murine model of early versus late menopause. In a study of breast tissue taken from excisional biopsies after mammography, Hofseth et al38 demonstrated that the addition of progestin to estrogen enhanced the rate of cell proliferation, number of cells present in terminal ductal lobular units, and glandular mass. These findings are supported by studies of mammographic density that also show quantitative increases in glandular density among women using combined HRT.39,40 A recent study by Foidart et al42 suggests that progestin exposure has an impact on apoptosis and that discontinuation of progestin is the trigger for the apoptotic mechanism. This latter finding may be particularly pertinent to our data indicating an association between continuous combined HRT and breast cancer risk.
In sum, our findings on continuous combined use among current long-term users are consistent with the findings from the Women’s Health Initiative Randomized Controlled Trial.23 Although absolute risk for any individual woman remains relatively low, findings indicate that restricting continuous combined HRT to short-term use for menopausal symptoms should be considered. Exercise, healthy diet, or other types of bone-building drugs may be better options for long-term prevention of osteoporosis. Unlike the randomized trial, however, our study also included former users, and our data indicate that the increased risk associated with use of continuous combined HRT dissipates quickly once use is discontinued. This information should be reassuring for women who have used it in the past. Our study also included current and former users of ERT and sequential HRT, and we observed no increase in breast cancer risk among these women.
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Footnotes |
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This study was funded by the National Institute of Child Health and Human Development, with additional support from the National Cancer Institute, through contracts with Emory University (N01-HD-3-3168), Fred Hutchinson Cancer Research Center (N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (N01-HD-3-3174), University of Pennsylvania (NO1-HD-3-3176), and University of Southern California (N01-HD-3-3175) and through an interagency agreement with the Centers for Disease Control and Prevention (Y01-HD-7022). The Centers for Disease Control and Prevention contributed additional staff and computer support. General support through SEER contract numbers N01-PC-67006 (Atlanta), N01-CN-65064 (Detroit), N01-PC-67010 (Los Angeles), and N01-CN-0532 (Seattle) is also acknowledged.
Received August 14, 2002. Received in revised form September 17, 2002. Accepted September 19, 2002.
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REFERENCES |
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S. Shantakumar, M. B. Terry, A. Paykin, S. L. Teitelbaum, J. A. Britton, P. G. Moorman, S. B. Kritchevsky, A. I. Neugut, and M. D. Gammon Age and Menopausal Effects of Hormonal Birth Control and Hormone Replacement Therapy in Relation to Breast Cancer Risk Am. J. Epidemiol., May 15, 2007; 165(10): 1187 - 1198. [Abstract] [Full Text] [PDF]
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 L. Rosenberg, J. R. Palmer, L. A. Wise, and L. L. Adams-Campbell A prospective study of female hormone use and breast cancer among black women. Arch Intern Med, April 10, 2006; 166(7): 760 - 765. [Abstract] [Full Text] [PDF]
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 C. M. Greiser, E. M. Greiser, and M. Doren Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials Hum. Reprod. Update, November 1, 2005; 11(6): 561 - 573. [Abstract] [Full Text] [PDF]
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J. A. Collins, J. M. Blake, and P. G. Crosignani Breast cancer risk with postmenopausal hormonal treatment Hum. Reprod. Update, November 1, 2005; 11(6): 545 - 560. [Abstract] [Full Text] [PDF]
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 M. Saitoh, M. Ohmichi, K. Takahashi, J. Kawagoe, T. Ohta, M. Doshida, T. Takahashi, H. Igarashi, A. Mori-Abe, B. Du, et al. Medroxyprogesterone Acetate Induces Cell Proliferation through Up-Regulation of Cyclin D1 Expression via Phosphatidylinositol 3-Kinase/Akt/Nuclear Factor-{kappa}B Cascade in Human Breast Cancer Cells Endocrinology, November 1, 2005; 146(11): 4917 - 4925. [Abstract] [Full Text] [PDF]
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 E. von Schoultz, L. E. Rutqvist, and on Behalf of the Stockholm Breast Cancer Study Gro Menopausal Hormone Therapy After Breast Cancer: The Stockholm Randomized Trial J Natl Cancer Inst, April 6, 2005; 97(7): 533 - 535. [Abstract] [Full Text] [PDF]
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H. B. Peterson, S. B. Thacker, P. S. Corso, P. A. Marchbanks, and J. P. Koplan Hormone Therapy: Making Decisions in the Face of Uncertainty Arch Intern Med, November 22, 2004; 164(21): 2308 - 2312. [Full Text] [PDF]
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 Breast Cancer Obstet. Gynecol., October 1, 2004; 104(4_suppl): 11S - 16S. [Full Text] [PDF]
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ESHRE Capri Workshop Group Hormones and breast cancer Hum. Reprod. Update, July 1, 2004; 10(4): 281 - 293. [Abstract] [Full Text] [PDF]
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 C. Antoine, F. Liebens, B. Carly, A. Pastijn, and S. Rozenberg Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women's Health Initiative trial Hum. Reprod., March 1, 2004; 19(3): 741 - 756. [Abstract] [Full Text] [PDF]
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 R M Fleming Do Women taking Hormone Replacement Therapy (HRT) have a Higher Incidence of Breast Cancer than Women who do not? Integr Cancer Ther, September 1, 2003; 2(3): 235 - 237. [Abstract] [PDF]
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T. Luukkainen Issues to debate on the Women's Health Initiative study: Failure of estrogen plus progestin therapy for prevention of breast cancer risk Hum. Reprod., August 1, 2003; 18(8): 1559 - 1561. [Abstract] [Full Text] [PDF]
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 HT and Breast Cancer: Do Different Regimens Confer Different Risks? Journal Watch Women's Health, January 22, 2003; 2003(122): 2 - 2. [Full Text]
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 Does HRT Regimen or Duration of Use Alter Breast-Cancer Risk? Journal Watch (General), January 14, 2003; 2003(114): 6 - 6. [Full Text]
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J. R. Scott Reflection Obstet. Gynecol., December 1, 2002; 100(6): 1145 - 1145. [Full Text] [PDF]
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