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© 2002 American Society for Clinical Oncology Does Menopausal Hormone Replacement Therapy Interact With Known Factors to Increase Risk of Breast Cancer?ByFrom the Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; Research and Evaluation Department, Kaiser Permanente Medical Care Program, Southern California, Pasadena, CA; and Department of Radiation Oncology, New York University, New York, NY. Address correspondence to Giske Ursin, MD, PhD, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Rm 4407, Los Angeles, CA 90089; email: gursin{at}hsc .usc.edu.
PURPOSE: We and other investigators have previously shown that postmenopausal combined estrogen and progestin replacement therapy (EPRT) increases the risk of breast cancer and that the risk associated with EPRT is substantially higher than for estrogen replacement therapy (ERT) alone. The present study was conducted to determine whether any particular subgroup of women are at particularly high risk of breast cancer if they use EPRT and whether tumor characteristics in women who develop cancer while on ERT or EPRT are different from those in women not using ERT or EPRT. PATIENTS AND METHODS: We conducted a population-based case-control study in Los Angeles, CA, with patients diagnosed with breast cancer in the late 1980s and early 1990s. Control subjects were matched to patients on age, ethnicity, and neighborhood of residence. We present data on 1,897 postmenopausal patients and 1,637 controls aged 55 to 72 years who had not undergone a simple hysterectomy.
RESULTS: Relative risk of breast cancer associated with EPRT use did not vary with body mass index (body mass index at or below v above median [24.6 kg/m2]; P = .98), alcohol intake ( CONCLUSION: We found no evidence that the risk of breast cancer associated with EPRT is limited to subgroups of women with specific cofactors. Tumors in EPRT users are more often hormone receptor–positive, indicating that they may have a better prognosis than breast cancer overall.
THERE IS GROWING epidemiologic evidence that combined estrogen and progestin replacement therapy (EPRT) increases the risk of breast cancer substantially more than estrogen replacement therapy (ERT) alone.1-6 However, it is unclear whether specific subgroups of women are at particularly high risk of breast cancer if they use these different forms of hormone replacement therapy (HRT). Studies of mammographic density changes, a strong predictor of breast cancer risk, in women using combined therapy suggest this possibility, because only a minority of such women (approximately 20%) develop substantially increased mammographic density (increased Breast Imaging Reporting and Data System category).7 Identifying which women are at particularly high risk would obviously be important both for individual patients and in understanding the biologic basis for the increase in risk. Presently almost nothing is known about which subgroups may be at increased risk, although one study suggested that the effect of EPRT may be stronger in lean than in heavy women.8 We studied whether the risk of breast cancer associated with EPRT was modified by several of the characteristics of the women in our large case-control study of the effects of ERT and EPRT on breast cancer risk.4 We examined whether the EPRT effect varies with body weight, body mass index (BMI), history of benign breast disease, oral contraceptive use, alcohol intake, and family history of breast cancer. We also looked at tumor characteristics of women who develop breast cancer on EPRT, because one small study has suggested that EPRT differentially increases risk of lobular carcinoma.9 The results of our study, which is the largest breast cancer case-control study conducted in the United States to date in terms of EPRT use, are given below.
The methods of this study have been described in detail previously.4 Briefly, patients were women with a first diagnosis of breast cancer identified through the Los Angeles County Cancer Surveillance Program (LACCSP) (Los Angeles County National Cancer Institute Surveillance, Epidemiology, and End Results registry) who were English-speaking residents of Los Angeles County. Patients were aged 55 to 72 years at first diagnosis and were diagnosed with breast cancer during one of the following three periods: (1) from March 1, 1987, through December 31, 1989 (white and Latina patients); (2) from January 1, 1992, through December 31, 1992 (white, Latina, and African-American patients); or (3) September 1, 1995, through April 30, 1996 (white, Latina, and African-American patients). All subjects were born in the United States, Canada, or Western Europe. We identified 3,976 patients, of whom 2,653 (67%) were interviewed. Control women were individually matched to patients by age (± 3 years), ethnicity (white, Latina, or African-American), and neighborhood of residence. A match was identified for 2,429 cases. The median number of households contacted before identifying an eligible control was 33. The first identified control who was eligible was interviewed in 1,893 instances, the second eligible control was interviewed in 394 instances, and the third eligible control was interviewed in 142 instances. In general, the same female nurse-interviewer interviewed the case patient and her matched control. We obtained complete reproductive, contraceptive, and physical exercise histories on all subjects up to the date of the case patient’s diagnosis and imposed time restrictions on these variables during the statistical analysis. A reference date, defined as the month and year that was 12 months before the date of the case patient’s diagnosis, was assigned to each case-control pair. An album with color photographs of all hormone preparations used in the United States was used to facilitate recall of specific brands of hormone used. Each subject signed an informed consent form, and study procedures were approved by the University of Southern California institutional review board, in accordance with assurances for protecting human subjects approved by the United States Department of Health and Human Services. Women who had undergone a simple hysterectomy (599 case patients and 537 controls) were excluded in these as well as the previous analyses,4 because age at menopause, a strong negative confounder, cannot be accurately determined in these women. Including these women in the analyses could substantially bias the results.5,10 We also excluded premenopausal women. We defined HRT to be any hormone replacement therapy, ie, either ERT or EPRT or a combination of both. For women who started HRT before their last menstrual period, we set age at menopause equal to the age at which they started HRT use, because we assumed HRT was taken for menopausal symptoms. We estimated the Quetelet Index or BMI as weight (in kilograms) divided by height (in meters) squared. For the patients diagnosed on or before December 31, 1991, we abstracted hormone receptor information from pathology reports or LACCSP abstracts and, when necessary, from hospital records.11 Estrogen receptor (ER) and progesterone receptor (PR) status became mandatory reportable data items for all breast cancer patients in California in 1992. Therefore, for patients diagnosed in 1992 or later, we obtained hormone receptor information from electronic LACCSP files. We obtained ER and PR status on 1,231 case patients. We used the cutpoints for positive hormone receptors as determined by each laboratory. The data were analyzed using univariate and multivariate conditional logistic regression methods.12 Because many women were excluded (because of their simple hysterectomy, see above), the matching was not retained in the analyses. Instead, we conducted detailed stratified analyses, adjusting for age at reference date (2-year categories), year of birth (2-year categories), socioeconomic level (based on average education and income in the residence census tracts of cases and controls, four categories), and ethnicity (African-American, white, or Latina). In addition, we adjusted for type of menopause (natural or bilateral oophorectomy), age at natural menopause (continuous), age at bilateral oophorectomy (continuous), age at menarche (continuous), family history of breast cancer in mother or sister (yes or no), personal history of benign breast disease (yes or no), nulliparity (yes or no), age at first full-term pregnancy (continuous), duration of oral contraceptive use (continuous), body weight (continuous), and drinks of alcohol per week (continuous). We present data categorized by some of these variables as well as adjusted for them. Relative risks were estimated by odds ratios (ORs) with associated 95% confidence intervals (95% CIs). We estimated ORs per 5 years of use as well as ORs for categories of duration of use. Tests for trend were calculated across categories of duration of use (scored as 1, 2, and so on). All significance levels (P values) reported are two-sided. Because women could have used ERT, EPRT, or both, and because use of one would result in nonuse of the other, we adjusted for one when we examined the effect of the other. To determine whether variables such as family history were effect modifiers, we tested whether the fit of the multivariate logistic regression model with a single HRT duration variable was improved by fitting separate duration variables for each subgroup of the potential modifying variable and similarly for ERT and EPRT. The likelihood ratio test of these two models tests whether the slope of the trend associated with duration of hormone use in one category of the risk factor (eg, positive family history) differs statistically from the slope of the trend in the other risk factor category (eg, negative family history). The P values for these likelihood ratio tests are provided in the tables; a P value less than .05 indicates significant effect modification on a multiplicative scale. In Table 1, we provide the ORs and P values for trend tests and effect modification tests for only one measure of effect (OR per 5 years of use) for HRT, ERT, and EPRT. In Tables 2 through 6, we provide statistics and tests for both this measure as well as those associated with specific categories of duration of use.
Table 1 shows the ORs of breast cancer associated with duration of ERT and EPRT by levels of other potential risk factors. In general, the results were constant across strata of these other variables and varied around the previously reported estimates from this study4 of little increased risk of ERT and a risk of EPRT of approximately 5% per year of use. Women with a first-degree family history of breast cancer were not at particularly high risk if they had used any type of HRT. Parous women were at slightly higher risk of breast cancer than nulliparous women if they had used EPRT, but the difference between nulliparous and parous women was not statistically significant. Type of menopause, history of benign breast disease, alcohol use, and oral contraceptive use did not modify the effect of ERT or EPRT on breast cancer risk. There was a suggestion that the effect of EPRT, but not ERT, was stronger in women with an early menarche. We did not have the power to address effect modification by ethnicity, but the estimates were similar when African-American patients were excluded (data not shown). There was little evidence of effect modification by BMI whether we used the median BMI as the cutpoint (Table 2) or BMI values of 24, 25, or 27 kg/m2, as used by others (data not shown). Using body weight instead of BMI did not alter this conclusion. Tables 3 through 6 present analyses stratified by tumor characteristics of the women. EPRT seemed to increase the risk of both ductal and lobular cancer by similar amounts (Table 3). However, there were substantially different effects of HRT, ERT, and EPRT by hormone receptor status. When we analyzed data by ER and PR status combined, the effect of HRT, ERT, and EPRT on breast cancer risk was largely limited to ER+ PR+ (Table 4) and ER- PR+ (data not shown) tumors. This difference was most striking when we analyzed data by PR status; the effects of ERT and EPRT on risk were stronger in women with PR+ than PR- tumors (Table 5). There were also differences in risk with ER status, but these were smaller effects than observed for PR status (Table 6).
The risk of breast cancer associated with EPRT was in general consistent across strata of other potential risk factors. In particular, we found little evidence that the effect of EPRT was stronger in leaner women, as previously suggested. In a Swedish case-control study,2 women with 5 or more years of EPRT use had more than two-fold increased risk of breast cancer than those who had never used EPRT among the leaner women (BMI < 27 kg/m2) but not among the heavier women. In data from the Breast Cancer Detection Demonstration Project,3 EPRT increased risk 12% per year of use among recent users with BMI of 24.4 kg/m2 or less but by only 4% per year in heavier women; these latter results were, however, based on only 35 breast cancer cases. Our results do not confirm these results and suggest that the risk of breast cancer associated with EPRT use is the same in heavy as in lean women. In the collaborative group reanalysis of all existing breast cancer and HRT data,8 HRT use (almost exclusively ERT use) was associated with greater breast cancer risk in women with BMI less than 25 kg/m2. We found little increase in breast cancer risk associated with ERT use whether women were lean or heavy. The most commonly used estrogen in this study was conjugated equine estrogen in doses of 0.625 mg or lower, whereas the most commonly used progesterone was medroxyprogesterone acetate. To what extent our findings are applicable to populations where other preparations are used is unclear. Results from Sweden,2 where other EPRT regimens are more common,1 have in general yielded similar results on breast cancer risk as studies in the United States.3,4 However, there is some evidence that EPRT regimens with testosterone-derived progestins (19-nor steroids) may increase breast cancer risk more than those based on progesterone-derived progestins such as medroxyprogesterone acetate.2 Although we find it unlikely, it is possible that the observed patterns in this study would be different for other EPRT regimens. We made many comparisons in this study; 24 tests for effect modification are listed in Table 1 alone. By chance, we would expect one to be significant. Our borderline statistically significant finding that the effect of EPRT is stronger in women with an early menarche is therefore likely a chance finding. Alternatively, women with early menarche may have different hormone metabolism or higher hormone levels in response to postmenopausal HRT than women with later menarche. Although we found slightly higher risk estimates in nulliparous women as well as in women with a late age at first birth, neither finding was statistically significant. However, if hormones have stronger detrimental effects on undifferentiated breasts,13 then this could explain an increased risk of EPRT in nulliparous women. We found no evidence that the effect of EPRT was restricted to lobular cancers. This is consistent with data from the Breast Cancer Detection Demonstration Project, where an increased risk with ductal cancer was found,3 but not with data from a smaller study in Washington, where risk seemed limited to lobular cancer.9 The latter result is possibly a chance finding. We found that women who use EPRT are at especially high risk of developing receptor-positive cancer. Previous studies have found that tumors in HRT users tend to be smaller and of lower stage8 compared with breast tumors overall. Although EPRT in our study increased breast cancer risk of all stages,4 our results suggest the possibility that breast cancer in EPRT users may have a better prognosis than breast cancer as a whole,14 because the association seems to be limited to ER+ PR+ tumors. Previous data have been mixed in terms of whether HRT users are more or less likely to have ER+ or PR+ tumors,15,16 possibly because of inadequate sample sizes to detect differential effects associated with EPRT. However, our results are consistent with a growing amount of data suggesting that hormonal risk factors preferentially increase the risk of ER+ PR+, as opposed to negative, tumors. Early age at menarche,17,18 nulliparity,18,19 late age at first birth,19 BMI,11,18-20 alcohol intake,21 and dietary fat22 have all been found to be stronger risk factors for ER+ PR+ compared with other breast cancers. Although we observed few ER- PR+ tumors (3%), our results suggest that the major subdivision of tumors associated with EPRT use is between PR- and PR+ (as opposed to ER- and ER+), because risk of ER- PR+ tumors was similar to ER+ PR+ tumors (data not shown). Horwitz23 has argued that because estrogen is necessary for PR expression, there should be few breast cancers that are ER- PR+, and among these, some may be falsely ER-, because for various reasons the ER may be unmeasurable. Although this misclassification of ER+ tumors as ER- would dilute any true difference between the ER- and ER+ groups, it may be that PR rather than ER is the key to whether EPRT will increase cell proliferation and ultimately cancer progression. An interesting question is whether the increasing EPRT use over time has altered the prevalence of ER+ PR+ tumors. Glass and Hoover24 reported a proportionally greater increase in the number of ER+ than ER- breast tumors in women older than 45 years of age from the mid-1970s to the mid-1980s. This increase was seen to the same degree for both localized and regional disease and parallels the increasing use of EPRT during this time period. We could find no useful data on PR+ prevalence over time. Can our finding that EPRT differentially increases the risk of ER+ PR+ tumors help explain how breast cancer occurs in EPRT users? In premenopausal women, ER expression levels have been reported to be higher in the follicular than in the luteal phase of the cycle.25-27 However, Khan et al28 found that in postmenopausal healthy women, HRT users have higher levels of ER than nonusers, and estrogen and progesterone may upregulate PR expression.29 If EPRT upregulates both ER and PR (or predominantly PR) in normal cells, then an interesting question is whether these cells now have a growth advantage and are at increased risk of transforming into malignant cells. An alternative could be that EPRT causes an already existing small receptor–positive tumor to grow more, or that EPRT upregulates ER and PR in the already malignantly transformed cells. Other interesting questions are whether ERT and EPRT differentially regulate hormone receptor expression and whether longer duration of use causes additional alterations in the regulatory mechanism. Additional data on how EPRT alters hormone receptor expression and what role this plays in the carcinogenic process are clearly needed.
Supported by grant nos. CA 17054, CA 14089, and ES 07048 and contract PC 67010 from the National Institutes of Health, by grant no. 1FB-0341 from the California Breast Cancer Research Program of the University of California, and by Subcontract 050-E8709 from the California Public Health Institute, which is supported by the California Department of Health Services as part of its statewide cancer reporting program mandated by Health and Safety Code Section 210 and 211.3.
The ideas and opinions expressed herein are those of the authors, and no endorsement by the State of California or the California Public Health Foundation is intended or should be inferred.
1. Persson I, Weiderpass E, Bergkvist L, et al: Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control 10: 253-260, 1999[CrossRef][Medline] 2. Magnusson C, Baron JA, Correia N, et al: Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer 81: 339-344, 1999[CrossRef][Medline]
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Schairer C, Lubin J, Troisi R, et al: Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283: 485-491, 2000
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Ross RK, Paganini-Hill A, Wan PC, et al: Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst 92: 328-332, 2000
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Rockhill B, Colditz GA, Rosner B: Bias in breast cancer analyses due to error in age at menopause. Am J Epidemiol 151: 404-408, 2000
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Colditz GA, Rosner B: Cumulative risk of breast cancer to age 70 years according to risk factor status: Data from the Nurses’ Health Study. Am J Epidemiol 152: 950-964, 2000 7. Greendale GA, Reboussin BA, Sie A, et al: Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Ann Intern Med 130: 262-269, 1999 8. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047-1059, 1997[CrossRef][Medline] 9. Li CI, Weiss NS, Stanford JL, et al: Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women. Cancer 88: 2570-2577, 2000[CrossRef][Medline]
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Pike MC, Ross RK, Spicer DV: Problems involved in including women with simple hysterectomy in epidemiologic studies measuring the effects of hormone replacement therapy on breast cancer risk. Am J Epidemiol 147: 718-721, 1998
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Enger SM, Ross RK, Paganini-Hill A, et al: Body size, physical activity, and breast cancer hormone receptor status: Results from two case-control studies. Cancer Epidemiol Biomarkers Prev 9: 681-687, 2000 12. Breslow NE, Day NE: Statistical Methods in Cancer Res, Volume 1, in : The Analysis of Case-Control Studies. Lyon, France, International Agency for Research on Cancer, 1980 13. Russo J, Russo IH: Cellular basis of breast cancer susceptibility. Oncol Res 11: 169-178, 1999[Medline] 14. Osborne CK, McGuire WL: The use of steroid hormone receptors in the treatment of human breast cancer: A review. Bull Cancer 66: 203-209, 1979[Medline]
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Yoo KY, Tajima K, Miura S, et al: Breast cancer risk factors according to combined estrogen and progesterone receptor status: A case-control analysis. Am J Epidemiol 146: 307-314, 1997 18. Potter JD, Cerhan JR, Sellers TA, et al: Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women’s Health Study: How many kinds of breast cancer are there? Cancer Epidemiol Biomarkers Prev 4: 319-326, 1995[Abstract]
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Huang WY, Newman B, Millikan RC, et al: Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am J Epidemiol 151: 703-714, 2000 20. Giuffrida D, Lupo L, La Porta GA, et al: Relation between steroid receptor status and body weight in breast cancer patients. Eur J Cancer 28: 112-115, 1992 21. Enger SM, Ross RK, Paganini-Hill A, et al: Alcohol consumption and breast cancer oestrogen and progesterone receptor status. Br J Cancer 79: 1308-1314, 1999[CrossRef][Medline] 22. Kushi LH, Potter JD, Bostick RM, et al: Dietary fat and risk of breast cancer according to hormone receptor status. Cancer Epidemiol Biomarkers Prev 4: 11-19, 1995[Abstract] 23. Horwitz KB: The central role of progesterone receptors and progestational agents in the management and treatment of breast cancer. Semin Oncol 15: 14-19, 1988
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Glass AG, Hoover RN: Rising incidence of breast cancer: Relationship to stage and receptor status. J Natl Cancer Inst 82: 693-696, 1990 25. Battersby S, Robertson BJ, Anderson TJ, et al: Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast. Br J Cancer 65: 601-607, 1992[Medline] 26. Markopoulos C, Berger U, Wilson P, et al: Oestrogen receptor content of normal breast cells and breast carcinomas throughout the menstrual cycle. Br Med J 296: 1349-1351, 1988 27. Soderqvist G, von Schoultz B, Tani E, et al: Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. Am J Obstet Gynecol 168: 874-879, 1993[Medline]
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Khan SA, Sachdeva A, Naim S, et al: The normal breast epithelium of women with breast cancer displays an aberrant response to estradiol. Cancer Epidemiol Biomarkers Prev 8: 867-872, 1999 Submitted June 1, 2001; accepted September 21, 2001. This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
one v < one drink per week; P = .16), parity (nulliparous v parous; P = .45), history of benign breast disease (yes v no; P = .99), or family history of breast cancer (first degree v none; P = .57). All of these results were compatible with our previously reported estimate of an increased risk of breast cancer of 5% per year of use of EPRT. Hormone users, principally EPRT users, were more likely to have hormone receptor–positive, especially progesterone-positive, tumors. 
