Non-contraceptive exogenous estrogens and risk of breast cancer: A review

Summary Results from epidemiologic and related studies of non-contraceptive estrogens and breast cancer are reviewed. Exogenous estrogens in high doses can enhance the risk of breast cancer. Moderate use of estrogens for menopausal symptoms probably has little effect on risk, but long-term users, and women who take high-strength preparations, appear to be at slightly increased risk. Exogenous estrogens probably reduce the protective effect of premenopausal oophorectomy, and may preferentially enhance the risk of breast cancer in women with some types of benign breast disease, although data from some studies do not support these conclusions. There is no evidence that the influence on risk of breast cancer is different for synthetic and conjugated estrogens. Needs for reanalyses of data from existing studies, and for additional investigations, are summarized. Address for Reprints: David B. Thomas, M.D., Dr.P.H., Program in Epidemiology and Biostatistics, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, USA.     

Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis of epidemiological studies

The association between alcohol consumption and an increased risk of breast cancer has been established. It is still unclear however, whether this relationship differs across the estrogen receptor (ER) and progesterone receptor (PR) tumors subtypes. To provide a quantitative assessment of the association between alcohol intake and the risk of ER-/PR-defined breast cancer, we conducted a meta-analysis of cohort and case-control studies. Studies were identified by a literature search of PubMed through April 20, 2007 and by searching the reference lists of relevant articles. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random-effects models. The summarized results of the meta-analysis comparing the highest versus the lowest consumption categories showed statistically significant higher risks of developing all ER+ (27%), all ER- (14%), ER+PR+ (22%) and ER+PR- (28%), but not ER-PR- tumors. The dose-response meta-analysis showed that an increase in alcohol consumption of 10 g of ethanol per day was associated with statistically significant increased risks for all ER+ (12%), all ER- (7%), ER+PR+ (11%) and ER+PR- (15%), but not ER-PR-. A statistically significant heterogeneity of the REs across all ER+ versus ER-PR- was observed (p(heterogeneity) = 0.02). The summarized results from studies with adjustment for postmenopausal hormone use, body mass index and family history of breast cancer were higher and statistically significantly different from those without. The observed positive associations with alcohol for ER+PR+ and ER+PR- tumors cannot be explained by estrogen-dependent pathway only. Further studies need to clarify the biological mechanisms.     

Birth order and breast cancer risk

It has been hypothesized that prenatal exposure to maternal estrogens may be a risk factor for breast cancer in the offspring. In two recent studies, maternal estradiol levels in the first pregnancy have been compared to those in the second, and in both studies levels were higher in the first pregnancy. If both the hypothesis and the reported findings were true, women born as their mother's second child would be expected to have lower risk for breast cancer than first-born women. Data from 1,468 cases of breast cancer and 4,175 hospital controls from three previously published studies were modelled through multiple logistic regression to evaluate this possibility. The size of the woman's sibship was not related to breast cancer risk. On the other hand, second-born women had, as predicted, lower breast cancer risk than first-born women, although the difference was nominally significant only among premenopausal women. The relative risk for breast cancer, contrasting second-born to first-born women, and the corresponding 95 per cent confidence intervals, were 0.71 (0.54–0.94) among premenopausal women, 0.94 (0.76–1.17) among postmenopausal women, and 0.86 (0.73–1.02) among all women, controlling for menopausal status.     

Alcohol consumption and risk of breast cancer: a cohort study

Objectives: To study the association between alcohol consumption and breast cancer risk. Methods: A case–cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40–59 at recruitment.) The cohort was recruited between 1980 and 1985, and during follow-up to the end of 1993 a total of 1469 women in the dietary cohort were diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons the analyses were based on 1336 cases and 5238 noncases. Results: When compared to nondrinkers the adjusted incidence rate ratios (95% confidence intervals) for those consuming>0 and 10g of alcohol/day, >10 and 20g/day, >20 and thinsp;30g/day, >30 and 40g/day, >40 and 50g/day, and >50g/day were 1.01 (0.84–1.22), 1.16 (0.91–1.47), 1.27 (0.91–1.78), 0.77 (0.51–1.16), 1.00 (0.57–1.75), and 1.70 (0.97–2.98), respectively; the associated p value for the test for trend was 0.351. Similar findings were obtained when analyses were conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, for screen-detected and interval-detected breast cancer, and by levels of other breast cancer risk factors. Conclusions: The results of this study suggest that alcohol consumption might be associated with increased risk of breast cancer at relatively high levels of intake.     

Alcohol and breast cancer risk: the alcoholism paradox

A population-based cohort study of 36 856 women diagnosed with alcoholism in Sweden between 1965 and 1995 found that alcoholic women had only a small 15% increase in breast-cancer incidence compared to the general female population. It is therefore apparent, contrary to expectation, that alcoholism does not increase breast-cancer risk in proportion to presumed ethanol intake.     

Menopausal estrogen use and the risk of breast cancer

Summary The relationship between the occurrence of female breast cancer and menopausal estrogen replacement was investigated in a population-based case-control study. One hundred and eighty-three white female residents of King County, Washington (ages 50–74) in whom breast cancer was diagnosed from July, 1977, through August, 1978, were interviewed with respect to reproductive and other factors, with emphasis on the use of estrogen-containing medication. For purposes of comparison, the same data were collected from 531 white female King County residents of the same ages without breast cancer. Use of menopausal estrogens was reported somewhat more commonly among controls than among cases (relative risk = 0.74, 95% confidence interval = 0.51–1.08) and some variation in proportions of users was present between different hysterectomy-oophorectomy subgroups. However, each of these differences could easily have been due to chance. No substantial trends in risk were apparent with increasing duration of use, time since first use, time since last use, or average dose. The findings suggest that in King County no important relationship exists between use of menopausal estrogens and the occurrence of breast cancer.     

Iron intake,oxidative stress-related genes and breast cancer risk

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case–control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER–/PR– breast cancer risk (all p_trend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR_{>18 vs. 0 mg/day} = 0.68, 95% CI: 0.51–0.91), and dietary heme iron was associated with an increased risk, particularly the ER–/PR– subtype (OR_{highest vs. lowest quintile} = 1.69, 95% CI: 1.16–2.47; p_trend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (p_interaction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.     

Endogenous sex steroids in premenopausal women and risk of breast cancer: the ORDET cohort

Introduction

Previous studies showed that higher testosterone levels are associated with greater risk of breast cancer in premenopausal women, but the literature is scant and inconsistent.

Methods

In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in blood samples collected on days 20 through 24 of their cycles.

Results

In logistic regression models, the multivariate odds ratios (ORs) of invasive breast cancer for women in the highest tertile of circulating FT compared with the lowest was 2.43 (95% confidence interval (95% CI), 1.15 to 5.10; P_trend = 0.03), whereas for total testosterone, the association had the same direction but was not statistically significant (OR, 1.27; 95% CI, 0.62 to 2.61; P_trend = 0.51). Endogenous progesterone was not statistically associated with breast cancer (OR, 1.16; 95% CI, 0.60 to 2.27; P_trend = 0.75), nor were the other considered hormones.

Conclusions

Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of FT are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetimes. No evidence of risk was found associated with the other endogenous sex steroids.     

The impact of alcohol consumption and physical activity on breast cancer: The role of breast cancer risk

High alcohol consumption and physical inactivity are known breast cancer risk factors. However, whether the association between these lifestyle factors and breast cancer is modified by a woman's additional breast cancer risk factors has never been studied. Therefore, a population-based prospective cohort study of 57,654 Swedish women aged 40–74 years, including 957 breast cancer cases, was performed. Alcohol consumption and physical activity were measured with validated web-based self-report questionnaires. The Tyrer–Cuzick risk prediction model was used to determine a woman's 10-year risk of developing breast cancer. Logistic regression models were used to explore whether the effect of alcohol consumption and physical activity on breast cancer was modified by additional breast cancer risk factors. Findings showed that increased alcohol consumption was associated with a higher breast cancer risk (OR = 1.26, 95% CI 1.01, 1.59). However, the association between lifestyle factors (alcohol consumption and physical activity) and breast cancer was generally the same for women at below average, average and above average risk of developing breast cancer. Therefore, additional breast cancer risk factors do not appear to modify the association between lifestyle (alcohol consumption and physical activity) and breast cancer. Considering the general health benefits, preventative lifestyle recommendations can be formulated about alcohol consumption and physical activity for women at all levels of breast cancer risk.     

Meat,fish and egg intake and risk of breast cancer

Intakes of animal protein, meat, and eggs have been associated with breast cancer incidence and mortality in ecological studies, but data from long-term prospective studies are limited. We therefore examined these relationships in the Nurses' Health Study. We followed 88,647 women for 18 years, with 5 assessments of diet by food frequency questionnaire, cumulatively averaged and updated over time. We calculated the relative risks (RR) and 95% confidence intervals (95% CI) for risk of developing invasive breast cancer, over categories of nutrient and food intake. During follow-up, 4,107 women developed invasive breast cancer. Compared to the lowest quintile of intake, the RR and 95% CI for the highest quintile of intake were 1.02 (0.92-1.14) for animal protein, 0.93 (0.83-1.05) for red meat and 0.89 (0.79-1.00) for all meat. Results did not differ by menopausal status or family history of breast cancer. We found no evidence that intake of meat or fish during mid-life and later was associated with risk of breast cancer.     

Serum concentrations of estrogens, sex hormone-binding globulin, and androgens and risk of breast cancer in postmenopausal women

We assessed the relationship between serum concentrations of estrogens, androgens, and sex hormone-binding globulin and risk of breast cancer among postmenopausal women. Study participants provided serum prior to breast biopsy or mastectomy in 3 hospitals in Grand Rapids, Michigan between 1977 and 1987. A total of 179 subjects with localized breast cancer were compared to 152 subjects with nonproliferative breast changes that have not been associated with elevated breast cancer risk. Increasing serum concentrations of estrone and estrone sulfate were associated with increases in breast cancer risk; the odds ratios (ORs) in the fourth quartiles compared to the first were 2.3 (95% confidence interval (CI) 1.1-4.6) for both (p-trend = 0.02 and 0.03, respectively). Estradiol and bioavailable estradiol concentrations were associated with nonstatistically significant increases in risk. Androstenediol levels were associated with risk (p-trend = 0.01); the OR in the fourth compared to the first quartile was 2.2 (95% CI 1.0-4.6). Testosterone, dehydroepiandrosterone and androstenedione levels were not associated with increased risk. Sex hormone-binding globulin was associated with a nonsignificant decrease in risk. Associations with estrone and estrone sulfate persisted after adjustment for androstenediol (ORs for fourth compared to first quartiles were 2.0 (95% CI 0.9-4.5) and 2.2 (95% CI 1.0-4.6), respectively (p-trend = 0.16 for both). The association with androstenediol was attenuated after adjustment for estrone (OR for fourth compared to first quartile was 1.6 (95% CI 0.7-3.6); p-trend = 0.13). Higher serum concentrations of estrogens were associated with increased breast cancer risk in postmenopausal women. Androgen levels were not independently associated with substantially increased risk.     

Cigarette smoking and breast cancer risk: a population-based study in Sweden

In a Swedish population-based case-control study, smoking showed no convincing association with risk of postmenopausal breast cancer - regardless of timing or level of smoking exposure - either overall or among subgroups.     

Lung cancer mortality risk among breast cancer patients treated with anti-estrogens

BACKGROUND:

The Women's Health Initiative randomized clinical trial reported that menopausal hormone therapy increases lung cancer mortality risk. If this is true, use of anti‐estrogens should be associated with decreased lung cancer mortality risk. The authors compared lung cancer incidence and mortality among breast cancer patients with and without anti‐estrogen therapy.

METHODS:

Our study included all 6655 women diagnosed with breast cancer between 1980 and 2003 and registered at the Geneva Cancer Registry. Among these women, 46% (3066) received anti‐estrogens. All women were followed for occurrence and death from lung cancer until December 2007. The authors compared incidence and mortality rates among patients with and without anti‐estrogens with those expected in the general population by Standardized Incidence Ratios (SIRs) and Standardized Mortality Ratios (SMRs).

RESULTS:

After a total of 57,257 person‐years, 40 women developed lung cancer. SIRs for lung cancer were not significantly decreased among breast cancer patients with and without anti‐estrogens (0.63, 95% confidence intervals [CI], 0.33‐1.10; and 1.12, 95% CI, 0.74‐1.62, respectively) while SMR was decreased among women with anti‐estrogens (0.13, 95% CI, 0.02‐0.47, P<.001) but not for women without anti‐estrogens (0.76, 95% CI, 0.43‐1.23).

CONCLUSIONS:

Compared with expected outcomes in the general population, breast cancer patients receiving anti‐estrogen treatment for breast cancer had lower lung cancer mortality. This study further supports the hypothesis that estrogen therapy modifies lung cancer prognosis. Cancer 2011. © 2011 American Cancer Society.     

Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (± 6 months) and date of sampling (± 3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥ age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.     

Metabolic disorders and breast cancer risk (United States)

Objective: To clarify the hormonal context of breast cancer etiology we used data from a large, population-based case–control study to investigate the relationship between breast cancer risk and a history of diabetes mellitus, disorders associated with estrogen stimulation (uterine fibroids, endometriosis, gallstones), and disorders associated with androgen stimulation (acne, hirsutism, and polycystic ovaries). Methods: Breast cancer patients between 50 and 75 years old were identified from state-wide tumor registries in Wisconsin, Massachusetts, and New Hampshire; controls were randomly selected from drivers' license lists (age less than 65) or Medicare enrollment files (age 65–74). Information on reproductive history, medical history, and personal habits was obtained by telephone interview. A total of 5659 cases and 5928 controls were interviewed and provided suitable data. Results: There was no overall association between breast cancer risk and reported history of diabetes mellitus, endometriosis, uterine fibroids, gallstones, or cholecystectomy. However, the disorders with androgenic associations all conferred an increased risk: the overall odds ratio (OR) for a history of acne was 1.4 (95% CI 1.0–1.9), that for hirsutism was 1.2 (95% CI 0.81–1.8), and that for polycystic ovaries 1.6 (95% CI 0.8–3.2). Diabetes mellitus diagnosed before age 35 conferred an odds ratio of 0.52 (95% 0.25–1.1), while diabetes diagnosed at a later age was associated with an increased risk (OR = 1.2, 95% CI 1.0–1.4). Conclusions: Androgen-related phenomena are likely to be important in the etiology of breast cancer.     

Noncontraceptive hormone use and risk of breast cancer

All British Columbia (Canada) women under 75 years of age who were diagnosed with breast cancer during 1988–89 were asked to complete a postal questionnaire which included detailed information on menopausal estrogen use. Controls were drawn from the Provincial Voters List, matched by five-year age category to the cases. The present analysis consists of 699 cases and 685 controls who were postmenopausal due to natural causes or to a hysterectomy. There was no overall increase in risk of breast cancer associated with ever-use of unopposed estrogen (odds ratio [OR] = 1.0,95 percent confidence interval [CI] = 0.8–1.3). For estrogen use of 10 years or longer, the relative risk [RR] was 1.6 (CI = 1.1–2.5). The risk estimate for current users was somewhat elevated (OR = 1.4, CI = 1.0–2.0). Compared with women who never used hormone preparations, women who had used estrogen plus progestogen had an RR of 1.2 (CI = 0.6–2.2). Our results suggest that ever-use of estrogen, with or without progestogen, does not appreciably increase the risk of breast cancer. However, long-term and recent use of unopposed estrogen may be associated with a moderately increased risk.Drs Yang and Band, and Mr Gallagher are with the British Columbia Cancer Agency, Vancouver, Britsh Columbia, Canada. Authors are also affiliated with the School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA (Drs Yang, Daling, White, and Weiss), and the Fred Hutchinson Cancer Research Center, Seattle, WA, USA (Drs Daling, White, and Weiss). Address correspondence to Mr Gallagher, Division of Epidemiology, Biometry and Occupational Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada, V5Z 4E6. This project is funded partially by Health and Welfare Canada, Grant #6610-1834-55 and by Workers Compensation Board of BC.     

Prospective study of alcohol consumption and breast cancer risk in Japanese women

Epidemiologic evidence is lacking for the association between alcohol consumption and the risk of breast cancer in Japanese women. We addressed this association in a prospective cohort study with an average follow-up of 7.6 years. At baseline (1988-1990), cohort participants completed a self-administered questionnaire that included alcohol use, reproductive history and hormone use. The women were followed up for breast cancer incidence through December 31, 1997. Cox proportional hazards models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer incidence and any association with alcohol consumption. During a follow-up of 271,412 person-years, we identified 151 women with breast cancer, of whom 45 were current drinkers and 11 drank > or =15 g of alcohol/day. After adjustment for age and other potential risk factors for breast cancer, the RR for current drinkers was 1.27 (95% CI 0.87-1.84) compared to nondrinkers. Average alcohol intake of <15 g/day did not significantly increase the risk for breast cancer. However, risk was significantly increased for women who consumed > or =15 g/day of alcohol (RR = 2.93, 95% CI 1.55-5.54). Age at starting drinking and frequency of consumption per week were not significantly associated with breast cancer risk. Our cohort study demonstrated that Japanese women who consume at least a moderate amount of alcohol have an increased risk of breast cancer.     

Low-to-moderate alcohol intake and breast cancer risk in Chinese women

Background:

Despite extensive investigation of the association between alcohol consumption and breast cancer risk, effect of low-to-moderate alcohol intake on breast cancer incidence has been inconsistent.

Methods:

A case–control study was conducted in China, 2004–2005 to examine the association by menopausal status, oestrogen (ER) and progesterone receptor (PR) status of the tumour. There were 1009 incident cases with histologically confirmed breast cancer and 1009 age-matched controls recruited. We assessed alcohol consumption by face-to-face interview using a validated questionnaire and obtained tumour ER and PR status from pathology reports.

Results:

Low-to-moderate alcohol consumption was inversely associated with breast cancer risk. Compared with nondrinkers, the adjusted odds ratios (ORs) for alcohol <5 g per day were 0.41 (95% confidence interval 0.27–0.62) and 0.62 (0.48–0.79) in postmenopausal and premenopausal women, respectively. The inverse association was consistent for alcohol <15 g per day across hormone receptor status groups with ORs of 0.36–0.56 in postmenopausal women and 0.57–0.64 in premenopausal women. An exception was that alcohol ⩾15 g per day appeared to increase the risk of breast cancers with discordant receptor status in postmenopausal women, that is, ER+/PR− or ER−/PR+ (4.27, 1.57–11.65).

Conclusion:

We found that low-to-moderate alcohol intake was not associated with increased risk of breast cancer in pre- or postmenopausal Chinese women. Future studies are required to understand differences in effect of alcohol on breast cancers by tumour hormone receptor status.