Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Part 1. The Collaborative Reanalysis

BACKGROUND Concern that hormone replacement therapy (HRT) may cause breast cancer has existed since the time it was introduced, and based on evidence in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that causality is now established. OBJECTIVE To evaluate the evidence for causality in the three studies. Methods Using generally accepted causal criteria, in this paper the authors begin with an evaluation of the CR. Analogous evaluations of the WHI and MWS will follow. RESULTS The findings in the CR did not adequately satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, dose/duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION HRT may or may not increase the risk of breast cancer, but the CR did not establish that it does.     

孕激素与他莫西芬合用降低子宫内膜癌的风险

他莫西芬由于其本身的优势仍是激素依赖型转移性乳腺癌的一线治疗用药,也是雌激素受体阳性、原发性早期乳腺癌术后辅助内分泌治疗的首选药物。乳腺癌患者在长时间服用他莫西芬后,可增加发生子宫内膜癌的危险性。孕激素不仅可以治疗乳腺癌,而且在口服避孕药、雌孕激素替代疗法中,孕激素有保护子宫内膜的作用。该文意在探讨长期口服他莫西芬治疗的乳腺癌患者加服小剂量孕激素降低子宫内膜异常的风险。     

Invited commentary: Postmenopausal unopposed estrogen and breast cancer risk in the Women's Health Initiative--before and beyond

Three large clinical trials provoked major debate when hormone replacement therapy (HRT) did not reduce coronary heart disease in postmenopausal women as expected from observational epidemiologic studies. Less discussion has ensued about breast cancer or other adverse events. In this issue of the Journal, investigators from the Women's Health Initiative (WHI) compare breast cancer findings from the randomized trial of unopposed estrogen with those from the large WHI observational study. This commentary briefly summarizes historical highlights of menopausal hormone use; risk-versus-benefit evaluations; scientific, clinical, and policy influences immediately before and during the WHI trial; breast cancer incidence trends; and the post-trial response in US clinical practice. Factors complicating interpretation of the results include differences in breast cancer risk profiles between women in the trial and those in the observational study cohort as well as heterogeneity in the definitions of menopause and prior use of HRT as applied by the WHI investigators to the two populations. Because millions of women use HRT, it is important to consider how the WHI and other research investigations might contribute to reducing gaps in understanding the relation between HRT and breast cancer risk.     

Use of HRT and the subsequent risk of cancer

At least 20 million women in developed countries are estimated to be currently using hormone replacement therapy (HRT). Almost 100 epidemiological studies have reported on the relationship between the use of HRT and the risk of cancer of female reproductive organs, namely the breast, uterus or ovary. Cancer at these sites is common and there are a priori reasons why the use of hormonal therapy to 'replace' the endogenous production of ovarian hormones after the menopause might increase the risk of these cancers. The available evidence indicates that the risk of breast cancer or endometrial cancer is increased while women are using HRT, the risk increasing with increasing duration of use. Most of the evidence about these cancers relates to use of HRT preparations containing oestrogens alone. The limited evidence about combination therapy, with oestrogens and progestogens, suggests that, compared to oestrogens alone, the effect on the breast is similar, but the effect on the endometrium is diminished, the diminution in risk being greater the more days each month that progestogens are used. The effect of HRT on breast cancer wears off after use ceases and has disappeared largely, if not wholly, within 5 years, whereas the effects on endometrial cancer take longer to wear off, if at all. The breast and endometrial cancers that are diagnosed in HRT users are less aggressive clinically than cancers in never-users but, as yet, there is little reliable information about the relationship between use of HRT and mortality from these cancers. For other cancer sites, the existing data about the effects of HRT are inconclusive. The longer the period of use of HRT, the greater the excess incidence of cancer of the breast and endometrium is likely to be. Use of HRT for short periods of time should have little effect on the incidence of these cancers. The cumulative excess incidence in 1000 women who used HRT for 10 years, beginning at age 50, is estimated to be six for breast cancer, 42 for endometrial cancer in women with an intact uterus using oestrogen therapy alone and about 20 for endometrial cancer in women with an intact uterus using oestrogen-progestogen combinations. The estimate for combined therapy is based on small numbers and may well vary with the type of preparation used. The overall balance between the excess incidence of these cancers and other effects of HRT needs to be evaluated carefully and will require more reliable data than exist at present.     

Hormone replacement therapy is not safe for breast cancer survivors

QuestionIs hormone replacement therapy safe for women with previous breast cancer?Study designRandomised controlled trial (interim analysis).Main resultsIn 345 women surviving breast cancer, there were more new breast cancer events in women taking HRT for menopausal symptoms compared with women receiving symptomatic treatment without hormones at a median of 2 years follow-up (absolute risk for new breast cancer: 26/174 [14%] with HRT vs 8/171 [5%] with no HRT; relative hazard 3.5, 95% CI 1.5 to 8.1).Authors’ conclusionsIn women surving breast cancer, those who received HRT for menopausal symptoms were at a higher risk of developing new breast cancers compared with those who received symptomatic treatment without hormones. These findings led to the termination of the trial.     

A comparison of different methods for including 'age at menopause' in analyses of the association between hormone replacement therapy use and breast cancer

BACKGROUND AND METHODOLOGY: Late 'age at menopause' is a recognised risk factor for postmenopausal breast cancer and is also associated with decreased use of hormone replacement therapy (HRT). When investigating the association between HRT use and breast cancer risk it is therefore necessary to adjust for the potential confounder, 'age at menopause'. 'Age at menopause', however, cannot be determined for women with a hysterectomy and ovarian conservation. Using data on 13 357 postmenopausal women in whom 396 cases of invasive breast cancer were diagnosed during 9 years of follow-up from the Melbourne Collaborative Cohort Study, we compared the estimates of relative risk of HRT use for breast cancer for three different methods of dealing with missing data: complete-case analysis, single imputation and multiple imputation. RESULTS: 'Age at menopause' was missing for 17% of the data. Both HRT use and 'age at menopause' were significant risk factors for breast cancer, although 'age at menopause' only marginally confounded the estimates of risk for HRT. Women with 'age at menopause' missing did not represent a random sample of the population. Complete-case analyses resulted in higher estimates of the risk associated with HRT use compared with the different methods of imputation. DISCUSSION AND CONCLUSIONS: We recommend that analyses investigating the association between HRT and breast cancer should present the results in two ways: excluding women with 'age at menopause' missing and including the women using multiple imputation. For both methods, estimates of risk, with and without the adjustment of 'age at menopause', should be given.     

Alcohol: the link between hormone replacement and breast cancer risk

Many women avoid or discontinue hormone replacement therapy due to the fear of breast cancer. They have read studies linking hormone use with increased breast cancer incidence. The link between alcohol use and breast cancer risk, in contrast, is at least as strong as that of hormone replacement therapy (HRT), yet little publicity has reached practicing physicians or patients. A new study by Ginsburg, suggests that women who use hormone replacement therapy experience an elevation in estradiol levels exceeding the ovulatory range (>300 pg/ml) with prolonged elevation for four hours, after consumption of a moderate amount of alcohol (2 to 4 ounces or .07 grams/kg). This provides a plausible explanation for the observation of increased breast cancer among women who drink alcohol regularly and suggests that a synergism between the two products may be possible. All of the epidemiologic data to date would suggest than an exposure threshold exists for hormone therapy or alcohol use. Existing literature was evaluated to identify studies that simultaneously measure alcohol and HRT exposure in relation to breast cancer incidence.

Two epidemiologic studies analyzed both exposures together. The adjustment for alcohol intake in HRT users by Kaufman eliminated any breast cancer risk associated with HRT (Relative Risk: 0.9, 95% Confidence Interval: 0.7–1.1). By subdividing the Iowa Women’s Health Study Cohort, Gapstur found that breast cancer risk was confined to women who used HRT and reported drinking at least 5 grams of alcohol per day. While more study is appropriate, these data are reminiscent of the link that was ultimately identified between the combination of oral contraceptives and smoking on arterial thrombosis. Alcohol and hormone exposure together may act synergistically to create increased breast cancer risk.

Given the prolonged elevation of estradiol levels in women who use hormones and consume moderate amounts of alcohol, new guidelines should be established to counsel women who choose to use HRT. They should be informed about the effect of moderate alcohol intake. More importantly, the women who choose to avoid alcohol while they use hormones can be reassured that there is little evidence to suggest that their risk of breast cancer is increased in any way.     

Factors Modifying the Association Between Hormone-Replacement Therapy and Breast Cancer Risk

Objectives: Hormone-replacement therapy (HRT) is an established risk factor for breast cancer. HRT users are different from non-users with respect to socio-economic and other characteristics. There may be women where the HRT-related risk could be modulated by other factors.Methods: We conducted a population-based case–control study with 688 breast cancer cases and 724 controls to characterize HRT users and to estimate odds ratios (OR) and 95% confidence intervals (CI) for HRT use and potentially risk modifying factors. Results: In women aged 50 years and older, 58% of controls and 61% of cases ever used HRT. Among women in natural menopause, HRT use for 10 years and more years was associated with an increased breast cancer risk (OR 1.79, 95% CI, 1.12–2.87), but not among women in surgical menopause (OR 0.61, 95% CI, 0.09–4.17). In the subgroup of women with a positive family history of breast cancer, each year of HRT use increased the risk by 1.22 (95% CI, 1.02–1.47). Another subgroup comprised women with at least 10 diagnostic mammograms (OR 4.04, 95% CI, 1.10–14.81 for using HRT 10 or more years).Conclusions: Long-term HRT use was associated with a breast cancer risk in women with natural menopause. Our findings suggest that this risk may be increased in women with a positive family history of breast cancer and in women who received frequent diagnostic mammographic screens.     

Hormone replacement therapy and breast cancer risk in a nationally representative cohort

BACKGROUND: The relative risk of breast cancer associated with the use of postmenopausal hormone replacement therapy (HRT) continues to be debated. We used a nationally representative cohort to study the issue. METHODS: This analysis utilized data from the NHANES I Epidemiologic Follow-up Study. Subjects were interviewed in 1971 through 1974 and four waves of follow-up interviews were conducted through 1992. Survival analysis of 5,761 postmenopausal women provided estimates of the relative risk of breast cancer in users of HRT when compared with non-users, controlling for potential confounders. RESULTS: There were 219 incident cases of breast cancer in 73,253 person-years of follow-up. The incidence rate was 326 per 100,000 person-years in women who had never used HRT and 255 per 100,000 in women who had ever used HRT. There was no statistically significant association between the HRT use and subsequent development of breast cancer: relative risk (RR) = 0.8, 95% confidence interval 0.6, 1.1. There was no trend in RR by length of HRT use: less than 3 years HRT use, RR = 0.9; 3 to 9 years , RR = 0.5; 10 or more years, RR = 0.8. CONCLUSIONS: This study, based on a nationally representative cohort followed for up to 22 years, failed to find an increased risk of breast cancer associated with the use of HRT. It provides further evidence that if there is an increased risk of breast cancer associated with HRT use, this risk is small.     

Risk of breast cancer in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen contraceptives

Recent studies have suggested that progestogen-only contraceptives and combined estrogen/progestogen oral contraceptives (COCs) may increase the risk of breast cancer among women less than 35 years of age or among recent users. The authors conducted a case-control study, in which cases of breast cancer (n = 484) [corrected] and controls (n = 1,625) hospitalized for conditions unrelated to contraceptive use were interviewed from 1994 to 1997 in hospitals in greater Cape Town, South Africa. The women were aged 20-54 years, resided in a defined area around Cape Town, and were Black or of mixed racial descent. The relative risk for exposure to injectable progestogen contraceptives (IPCs), mostly depot medroxyprogesterone acetate, was 0.9 (95% confidence interval (CI) 0.7, 1.2). There were no consistent associations within categories of age or recency or duration of use. For exposure to COCs, the overall relative risk was 1.2 (95% CI 1.0, 1.5). Among women below age 35 years, the relative risk was 1.7 (95% CI 1.0, 3.0), and it was unrelated to the duration or recency of use. The findings suggest that IPCs do not increase the risk of breast cancer, and that COCs may increase the risk among women below age 35 years, although bias cannot be excluded.     

Do soy isoflavones cause endometrial hyperplasia?

For many years, hormone replacement therapy (HRT) was considered the gold standard for the symptomatic treatment of menopause. Clinical trials have found that HRT reduces the symptoms of hot flashes and sweating, while also decreasing vaginal dryness and urinary tract infections. HRT has also been shown to be protective against colon cancer (37%) and hip fractures (34%). However, recent findings from the Women's Health Initiative (WHI) have revealed that long-term HRT may actually lead to an increase in heart disease (29%), breast cancer (26%) and other adverse events, such as stroke (41%). Consequently, many women in the United States and abroad are actively looking for alternative treatments for menopause, including botanical dietary supplements.     

A simulation using data from a primary care practice database closely replicated the women's health initiative trial

OBJECTIVE: In contrast to prior observational studies, hormone replacement therapy (HRT) did not prevent coronary heart disease in the Women's Health Initiative Randomized Controlled Trial (WHI RCT). To assess the validity of a novel observational study design, we compared the WHI RCT with a simulation using data from the United Kingdom General Practice Research Database (GPRD). STUDY DESIGN AND SETTING: A cohort from GPRD was used to simulate the WHI RCT by replicating, to the extent possible, all aspects of the RCT except randomization. The study included 37,730 Unexposed and 13,658 Exposed women treated with estrogen and norgestrel. RESULTS: Myocardial infarction (adjusted hazard ratio 0.95 [0.78-1.16]) was not decreased significantly in the GPRD Exposed group. Similar to the WHI RCT, stroke, venous thromboembolic events, and breast cancer were increased; and colorectal cancer was decreased. Although death appeared to decrease in the total cohort, it was unaltered in a subset of subjects without missing data on baseline covariates. CONCLUSION: A structured comparison using data from GPRD was largely concordant with the WHI RCT and did not show a cardioprotective effect of HRT. These findings further generalize the results of WHI and reinforce the potential utility of this analytic approach.     

The pill and cancer--IPPF response

The response of the International Medical Advisory Panel (IMAP) of the International Planned Parenthood Federation to 2 recent papers suggesting a link between cancer and oral contraceptive (OC) use is reported. The 1st paper by Pike et al. suggested an increased risk of breast cancer in women who use OCs containing high potency progestogens before age 25 for at least 4 years. It is noted that several methodological problems with the study design could have introduced a degree of selection of ascertainment bias. These issues include the procedures used for age matching between cases and controls, the 1/3 loss to follow-up among cancer cases, and the use of telephone interviews to ascertain OC use history. Moreover, data from other studies suggest that ever-users of OCs who develop breast cancer may be more likely to survive than women with breast cancer who have never used OCs, leading to the overrepresentation of women in the former group among surviving cases. The ranking of OCs by progestogen potency does not take the estrogen content into consideration. In addition, assessment of progestogen potency by use of a delay of menses test may not correlate with the degree of effect on the breast and has produced conflicting results when used by different researchers. Finally, the numbers of women using some OC brands were too small and the possibility that women may have changed OC brand over the study period was not considered. Largescale studies such as the UK Oxford-Family Planning Association contraceptive study and the Centers for Disease Control Cancer and Steroidal Hormone Study are curently being reanalyzed, controlling for type and amount of progestogen in the OCs. Until new data become available, IMAP believes there is insufficient evidence to recommend modification of existing practice. The 2nd study by Vessey et al. suggested a higher incidence of cervical cancer in OC users as compared to IUD users. However, several key modifying factors on the risk of cervical cancer, including age at 1st sexual intercourse and number of partners, could not be controlled for. Moreover, a high proportion of OC use involved preparations containing 50 mcg or more of estrogen. Although regular cervical smears are recommended for OC users, the IMAP again does not recommend any change in current practice. The IMAP noted that the possible cancer-related risks of OCs must be weighed against the protective effects of OCs against cancers of the endometrium and ovary, pelvic inflammatory disease, and unwanted pregnancies.     

Case-control study of postmenopausal hormone replacement therapy and endometrial cancer

This study evaluated recent inconsistent findings that adding progestins to postmenopausal estrogen replacement therapy protects against endometrial cancer. Using a population-based case-control study, the authors compared 511 endometrial cancer cases aged 50-79 years in the Philadelphia, Pennsylvania, region during 1999-2002 with 1,412 random-digit-dialing controls regarding postmenopausal hormone replacement therapy (HRT) use. Telephone interviews were performed with memory aids mailed in advance. An increased risk of endometrial cancer was observed among postmenopausal women using only unopposed estrogen for 3 or more years, compared with women who never used HRT (adjusted odds ratio = 3.4, 95% confidence interval (CI): 1.4, 8.3). Using combination HRT (of any duration) was associated with a substantial reduction in risk (odds ratio = 0.8, 95% CI: 0.6, 1.1). Comparing women using only combined estrogen and progestin for 3 or more years with women using only unopposed estrogen for 3 or more years, the authors found that the adjusted odds ratio was 0.2 (95% CI: 0.1, 0.6). Long-term use of unopposed estrogen is associated with increased risk for endometrial cancer, whereas combined estrogen plus progestin hormone therapy is not. Thus, if HRT is to be used in women with an intact uterus, this study confirms the benefit of adding progestins to the regimen.     

Investigating the Association of Lactation History and Postmenopausal Breast Cancer Risk in the Women's Health Initiative

Prolonged lactation (≥24 mo) has been associated with reduced breast cancer risk. This research examined this association in postmenopausal women in the Women's Health Initiative (WHI) Hormone Trial (HT) and Observational Study (OS). This retrospective cohort analysis included 69,358 predominantly overweight (65.4%), white (83.2%) postmenopausal women without breast cancer. Women in the HT were randomized to 0.625 mg conjugated equine estrogen (CEE), 0.625 CEE + 2.5 mg medroxyprogesterone acetate (CEE/MPA), or placebo. OS participants had no restrictions on hormone use. Lactation history was assessed via WHI Reproductive History Questionnaire. Most women breastfed at least 1 mo (58.0%); 35.4% breastfed 1–2 children; and 6.5% stated having breastfed ≥24mo. Women in the HT–CEE who breastfed their first child between 20–24 yr of age demonstrated a nonsignificant decreased risk of breast cancer (HR: 0.62; 95% CI: 0.38, 1.01). OS participants who reported CEE/MPA hormone use and age of first breastfeeding ≥30 yr showed a significant increased risk of breast cancer (HR: 1.66; 95% CI: 1.14, 2.41). Risk was increased if age of last breastfeeding was ≥35yr (HR: 1.50; 95% CI: 1.05, 2.14). This research did not demonstrate a significantly decreased risk of postmenopausal breast cancer in women who breastfed for ≥24 mo during their lifetime.     

Maternal factors and breast cancer risk among young women

The results from previous studies have provided evidence to support the hypothesised association between intrauterine oestrogen exposure and subsequent risk of breast cancer. Information has not been available to study this relationship for several perinatal factors thought to be related to pregnancy oestrogen levels. Data collected from the mothers of women in two population-based case–control studies of breast cancer in women under the age of 45 years (510 case mothers, 436 control mothers) who were diagnosed between 1983 and 1992 in three western Washington counties were used to investigate further the relationship between intrauterine oestrogen exposure and risk of breast cancer. A pregnancy weight gain of 25–34 pounds was associated with breast cancer risk (odds ratio [OR] = 1.5; 95% confidence interval [CI] 1.1, 2.0); however, women whose mothers gained 35 pounds or more were not at increased risk. Use of antiemetic medication in women with any nausea and vomiting (OR = 2.9; 95% CI 1.1, 8.1) and use of diethylstilboestrol (DES) (OR = 2.3; 95% CI 0.8, 6.4) appeared to be positively associated with breast cancer risk. The results from this study provide limited support for the hypothesis that in utero oestrogen exposure may be related to subsequent breast cancer risk among young women.     

绝经后妇女性激素补充治疗的相关研究

近年来 ,激素替代疗法已逐渐得到人们的认可 ,全世界每年约有两千万妇女接受该疗法。但自 2 0 0 2年 7月 ,妇女健康启动项目的临床试验结果报道公布于众后 ,激素替代疗法受到前所未有的挑战 ,亦令人们深感困惑。如何科学全面地分析该疗法的利与弊 ,已成为人们关注的焦点。该文对近年来激素替代疗法进行了背景回顾 ,客观地分析了激素替代疗法与乳腺疾病、心血管疾病、生活质量相关研究的争议和探讨 ,旨在为临床保健工作能比较合理化、规范化和个体化应用激素替代疗法提供理论依据。     

Do perceptions of risk and quality of life affect use of hormone replacement therapy by postmenopausal women?

BACKGROUND: Although the understanding of the health impact of hormone replacement therapy (HRT) is incomplete, even less is known about the attitudes, perceptions, and motivations of women faced with the decision to use HRT. The purpose of this study was to evaluate the relation between HRT use and women's perceptions of the risk and benefits associated with HRT use. METHODS: A written questionnaire was administered to 387 women, aged 45 years and older, responding to a health plan invitation for free bone mineral density screening. Women were asked to estimate the lifetime probability of developing breast cancer, uterine cancer, osteoporosis, and myocardial infarction when taking HRT and when not taking HRT. Women rated their quality of life in their current state of health, with breast cancer, with uterine cancer, with osteoporosis, and after myocardial infarction. RESULTS: HRT users perceived a greater risk reduction using HRT compared with HRT nonusers for osteoporosis (-34.9% vs -17.8%, P <.001) and myocardial infarction (-20.7% vs -8.4%, P <.001). HRT nonusers perceived a greater risk increase using HRT compared with HRT nonusers for breast cancer (16.5% vs 3.3%, P <.001) and uterine cancer (9.2% vs 0.6%, P =.004). HRT users estimated a greater quality-of-life reduction compared with HRT nonusers for osteoporosis (-31.0 vs -24.5, P =.006). CONCLUSIONS: Regardless of whether they used HRT, women in this study overestimated their risk for all four diseases. HRT users perceived greater benefit and less risk using HRT than nonusers. The results of our study show that continuing efforts are needed to help women understand the risks and benefits of HRT.     

A population-based cohort study of HRT use and breast cancer in Korea

The incidence of breast cancer has recently been ranked first in Korea. This is a population-based cohort study that aims to evaluate the risk of breast cancer from the use of hormone replacement therapy (HRT). A total of 9579 participants were observed between January 1998 and June 2004; 6108 women who took HRT constituted the HRT group, and 3471 women who did not take HRT constituted the non-HRT group. Using the database from the Korea Central Cancer Registry, the authors examined the incidence of breast cancer from HRT. A total of 26 cases of breast cancer developed in the HRT group as compared with the 13 cases in the non-HRT group, during the follow-up period. The relative risk of developing breast cancer in the HRT group was 1.16 times higher than in the non-HRT group, with a population attributable risk of 29.9%. The risk of breast cancer in the HRT group increased when the risk factors were adjusted in the model.     

Association of the joint effect of menopause and hormone replacement therapy and cancer in African American women: the Jackson Heart Study

Cancer is the second leading cause of death in the US and in Mississippi. Breast cancer (BC) is the most common cancer among women, and the underlying pathophysiology remains unknown, especially among African American (AA) women. The study purpose was to examine the joint effect of menopause status (MS) and hormone replacement therapy (HRT) on the association with cancers, particularly BC using data from the Jackson Heart Study. The analytic sample consisted of 3202 women between 35 and 84 years of which 73.7% and 22.6% were postmenopausal and on HRT, respectively. There were a total of 190 prevalent cancer cases (5.9%) in the sample with 22.6% breast cancer cases. Menopause (p<0.0001), but not HRT (p=0.6402), was independently associated with cancer. Similar results were obtained for BC. BC, cancer, hypertension, type 2 diabetes, prevalent cardiovascular disease, physical activity and certain dietary practices were all significantly associated with the joint effect of menopause and HRT in the unadjusted analyses. The family history of cancer was the only covariate that was significantly associated with cancer in the age-adjusted models. In examining the association of cancer and the joint effect of menopause and HRT, AA women who were menopausal and were not on HRT had a 1.97 (95% CI: 1.15, 3.38) times odds of having cancer compared to pre-menopausal women after adjusting for age; which was attenuated after further adjusting for family history of cancer. Given that the cancer and BC cases were small and key significant associations were attenuated after adjusting for the above mentioned covariates, these findings warrant further investigation in studies with larger sample sizes of cancer (and BC) cases.