Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk

The authors reevaluated 10,366 consecutive breast biopsy specimens of benign lesions performed between 1950 and 1968. Follow-up information was obtained on 3303 women with a median duration of follow-up of 17 years. This sample contained 84% of the patients originally selected for follow-up. The relative risk (RR) of developing breast cancer was 0.98 for women who took exogenous estrogens as compared to 1.8 for women who did not. Exogenous estrogens lowered the observed breast cancer risk in women with atypical hyperplasia (RR = 3.0 versus 4.5), proliferative disease without atypia (RR = 0.92 versus 1.9), and in women without proliferative disease (RR = 0.69 versus 0.91). Women who took estrogens before 1956 were at 2.3 times the risk of other estrogen users, presumably due to a dose effect. There was no significant association between breast cancer risk and birth control pills, cigarette smoking, or alcohol consumption. Exogenous estrogens are not associated with increased breast cancer risk in women with benign breast disease. A previous history of benign breast disease does not contraindicate replacement estrogen therapy.     

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.     

Maternal age,parity, and pregnancy estrogens

Total estrogens (TE), estradiol (E2), estriol (E3), and human placental lactogen (hPL) were determined by radioimmunoassay in the blood of 126 pregnant women during their 26th and 31st weeks of pregnancy and the results were studied in relation to maternal age and parity. Total estrogens and E2 were lowest among the youngest women (<20 years) and highest among women aged 20–24 years, whereas older women (25 + years) had, on the average, intermediate values. For E3 the pattern was qualitatively similar to that of TE and E2 but less striking, and no maternal age pattern was evident with respect to hPL. Within maternal age groups, TE and E2 were higher among women in the first, than among those in their second, full-term pregnancy; the difference was about seven percent for TE (P=0.14) and about 14 percent for E2 (P=0.05). No parity patterns were evident with respect to E3 and hPL. There were fairly strong correlations between the determinations of the same hormone in the same woman during the 26th and 31st weeks of pregnancy; Pearson correlation coefficients were 0.60 for TE, 0.78 for E2, 0.60 for E3, and 0.72 for hPL. Since the risk of breast cancer increases apparently monotonically with maternal age at birth, the present data are equivocal with respect to the hypothesis linking levels of pregnancy estrogens to risk of breast cancer in the offspring. However, the data are compatible with hypotheses linking excessive pregnancy-estrogen exposure to conditions more common among first-born individuals, including testicular cancer and cryptorchidism.Drs Panagiotopoulou, Katsouyanni, Petridou, Garas, and Tzonou are from the Department of Hygiene and Epidemiology, University of AThens Medical School, Greece, and Dr Trichopoulos, to whom correspondence should be addressed, is from the Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. This study was supported by a grant from the Greek Ministry of Youth.     

Risk of endometrial cancer following cessation of menopausal hormone use (Washington, United States)

While there are a number of benefits to the health of postmenopausal women from use of unopposed estrogens, the increased risk of endometrial cancer related to these hormones has led many women to use combined estrogen-progestogen therapy instead, or not to use hormones at all. Most women who take hormones do so only in the early portion of their postmenopausal years, so the risk of endometrial cancer following cessation of use might bear heavily on the overal risk/benefit evaluation. We analyzed data from a case-control study of women in western Washington (United States) to assess the magnitude of excess risk of endometrial cancer following discontinuation of estrogen use. Cases (n=661) consisted of women aged 45 to 74 diagnosed between 1985 and 1991 who resided in one of three counties in Washington State. Controls (n=865) were identified by random-digit dialing. Subjects were interviewed in-person to ascertain current and prior hormone use. The analysis was restricted to women who had not received combined estrogen-progestin therapy. Among women who had used unopposed estrogens at some time, risk of endometrial cancer declined as time since last use increased. Nonetheless, even among women who used these hormones for just a few years, the risk remained elevated by 30 to 70 percent almost a decade after cessation. These results, combined with those of most (but not all) other studies of this issue, suggest that a woman who has discontinued unopposed estrogen therapy may retain a small increased risk of endometrial cancer for a long period of time.Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, the Department of Epidemiology, University of Washington Department of Biostatistics University of Washington, Seattle, WA. Department of Epidemiology, University of Washington, Seattle, WA 98195, USA. This research was supported by US National Cancer Institute contracts R01 CA47749 and R35 CA39779.     

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.     

Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European Prospective Investigation into Cancer and Nutrition

Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country‐specific self‐administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow‐up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country‐specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person‐years of follow‐up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23–1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40–2.24; p = 0.02 for combined vs. estrogen‐only). Continuous combined regimens conferred a 43% (95% CI: 19–72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen‐only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component.     

Risks of breast and endometrial cancer after estrogen and estrogen–progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.     

Smoking is associated with postmenopausal breast cancer in women with high levels of estrogens

We investigated the association between smoking and risk of postmenopausal breast cancer in groups defined by high levels of estrogens, a factor known to enhance tumour progression. Two prospective cohorts of Swedish women provided 260 postmenopausal breast cancer cases and 514 controls. Blood samples were collected at baseline, and anthropometry, life-style factors and reproductive history had been assessed. Subjects were classified into quartiles with regard to the level of estrone, and into three categories with regard to estradiol. All analyses of the relation between smoking and breast cancer were repeated in different categories of these hormones. Logistic regression analysis, adjusted for matching factors, i.e., age at baseline, storage time and sub-cohort, yielded odds ratios (OR) with 95% confidence intervals (CI). Ever-smoking was associated with breast cancer in the top category of estrone, 2.02 (1.17-3.49). The highest risk was seen among ex-smokers, 2.96 (1.53-5.75). The pattern was similar for estradiol. Recent smoking cessation was associated with a high OR in top categories of estrone, 4.38 (1.27-15.2) and estradiol 10.0 (1.14-88.7). Smoking initiation before the age of 20 was associated with breast cancer in the top category of estrone, 2.73 (1.27-5.91). Several potential confounders were introduced into the statistical model, but none remained using backward selection. We conclude that ever-smoking was associated with the risk of breast cancer in women with high levels of estrone, and that ex-smoking was associated with breast cancer in women with high levels of estrone or estradiol.     

Estrogen-regulated non-reproductive behaviors and breast cancer risk: Animal models and human studies

The possible role of personality patterns and psychosocial factors in breast cancer has been studied extensively, through both human and animal experiments. The data are conflicting, and the conclusions controversial. This review will serve two purposes. First, we present evidence that behavioral patterns most commonly linked to breast cancer risk are at least partly regulated by estrogens. This section will suggest that some estrogen-regulated behaviors may be markers of increased breast cancer risk. Second, we will briefly review recent findings in animals connecting psychosocial factors to cancer. We also will address the plausible biological mechanisms. The literature suggests that estrogens, particularly when exposure occurs during the critical developmental periods, such as in utero, puberty, pregnancy, and menopause, influence affective behaviors and increase breast cancer risk. The affective behaviors include depression, aggression, and alcohol intake. Thus, psychosocial and personality factors do not necessarily have a direct impact on breast cancer risk; instead, estrogens have a dual effect on behavior and on the breast.     

Circulating Sex Steroids and Breast Cancer Risk in Premenopausal Women

Evidence from both laboratory and epidemiologic studies indicate a key role of hormones in the etiology of breast cancer. In epidemiologic studies, indirect data, including the consistent associations observed between reproductive factors and breast cancer risk, support an important contribution of hormones to risk. Recently, the associations between circulating hormones in premenopausal women and subsequent risk of breast cancer have been evaluated. To date, both positive and null associations have been observed for estrogens and inverse and null associations for progesterone with breast cancer risk. For estrogens, the relationships may vary by menstrual cycle phase (e.g., follicular versus luteal phase), although this requires confirmation. Few studies have evaluated estrogen metabolites in relation to breast cancer risk; hence, no conclusions can yet be drawn. Findings for the largely adrenal-derived dehydroepiandrosterone (DHEA) and DHEA sulfate also are inconsistent and may vary by age. However, relatively consistent positive associations have been observed between testosterone (or free testosterone) levels and breast cancer risk; these associations are of similar magnitude to those confirmed among postmenopausal women. In this review, we summarize current evidence and identify gaps and inconsistencies that need to be addressed in future studies of sex steroids and premenopausal breast cancer risk.     

Circulating levels of sex hormones and their relation to risk factors for breast cancer: a cross-sectional study in 1092 pre- and postmenopausal women (United Kingdom)

Objective: To investigate the relationships between plasma concentrations of sex hormones and risk factors for breast cancer. Methods: We investigated the relationship of plasma concentrations of estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) with breast cancer risk factors in 636 premenopausal and 456 postmenopausal women. Risk factor data were obtained from questionnaires and hormone concentrations measured by immunoassays; variations in geometric means were compared using analysis of covariance. Results: SHBG decreased with increasing body mass index and increasing waist–hip ratio both in pre- and postmenopausal women. In postmenopausal women only, estradiol increased with increasing body mass index. In premenopausal women, estradiol decreased with increasing physical activity, estradiol was higher in current than in ex- and non-smokers, and FSH decreased with increasing alcohol intake. No associations were observed between sex hormones and age at menarche, parity, age at menopause, and previous use of oral contraceptives in either pre- or postmenopausal women. Conclusions: Certain factors such as obesity and perhaps waist–hip ratio, physical activity and alcohol consumption, but probably not age at menarche and parity, may mediate their effects on breast cancer risk by changing circulating concentrations of sex hormones.     

Pregnancy estriol,estradiol, progesterone and prolactin in relation to birth weight and other birth size variables (United States)

Objective: Because birth weight has been positively associated with adult life breast cancer risk and pregnancy estrogens have been hypothesized to affect breast cancer risk in the offspring, we have evaluated the association of pregnancy estriol (E3), estradiol (E2), progesterone and prolactin in maternal serum samples collected during the 16th and 27th gestational week with birth size parameters. Methods: Prospective study of 230 Caucasian women who delivered a live singleton after 37–42 weeks of gestation. Results: E3 at the 27th gestational week was significantly positively associated with birth weight, birth length and placental weight. Progesterone at the 27th gestational week was also significantly positively associated with birth weight and placental weight but, after mutual adjustment among the studied pregnancy hormones, these associations weakened considerably. There was also inconsistent evidence that SHBG and prolactin at the 27th gestational week may be respectively positively and inversely related with birth size parameters. Measurements during the 16th gestational week were generally unrelated to birth size parameters. Conclusions: Because E3 is a dominant estrogen during pregnancy, the positive association of it with birth weight allows the use of the latter as a proxy of in utero exposure to estrogens in breast cancer investigations.     

Associations of maternal and umbilical cord hormone concentrations with maternal,gestational and neonatal factors (United States)

Objective: Risks of some cancers in adults have been associated with several pregnancy factors, including greater maternal age and birth weight. For hormone-related cancers, these effects are hypothesized to be mediated through higher in utero estrogen concentrations. In addition, racial differences in pregnancy hormone levels have been suggested as being responsible for differences in testicular and prostate cancer risk by race. However, data on hormonal levels related to these characteristics of pregnancy are sparse, particularly those from studies of the fetal circulation. Methods: Estrogen and androgen concentrations were measured in maternal and umbilical cord sera from 86 normal, singleton pregnancies. Results: Birth size measures (weight, length and head circumference) were positively correlated with maternal estriol (r = 0.25–0.36) and with cord DHEAS concentrations (r = 0.24–0.41), but not with estrogens in cord sera. Maternal age was inversely correlated with maternal DHEAS, androstenedione and testosterone concentrations (r = –0.30, –0.25 and –0.30, respectively), but uncorrelated with estrogens in either the maternal or cord circulation. Black mothers had higher androstenedione and testosterone concentrations than white mothers, however, there were no racial differences in any of the androgens in cord sera. Cord testosterone concentrations were higher in mothers of male fetuses, while both maternal and cord concentrations of estriol were lower in these pregnancies. Conclusions: These data demonstrate associations between hormone concentrations and pregnancy factors associated with offspring's cancer risk, however, the hormones involved and their patterns of association differ by whether the maternal or fetal circulation was sampled. Hormone concentrations in the fetal circulation in this study are not consistent with the hypothesis that greater estrogen concentrations in high birth weight babies mediate the positive association with breast cancer risk observed in epidemiologic studies, or with the hypothesis that higher testosterone exposure in the in utero environment of black males explains their higher subsequent prostate cancer risk.     

Organochlorine compounds and estrogen-related cancers in women

The organochlorines, a diverse group of some 15,000 compounds, have been implicated increasingly as being harmful to humans. Some congeners of DDT and PCB elicit very weak to weak estrogenic responses in animals, while the dioxin TCDD and related compounds have antiestrogenic properties. This review summarizes the evidence regarding whether certain organochlorine compounds, usually as persistent food-chain contaminants, increase the risk of breast and endometrial cancers through their estrogenic potential. In humans, neither ecologic data nor occupational studies provide clear support for an association between organochlorine exposure and the occurrence of these cancers. In our summary analysis of occupational exposure, the rate ratio of breast cancer for exposed cf unexposed women was 0.84 (95 percent confidence interval [CI]=0.50–1.33) for PCBs and 1.08 (CI=0.68–1.58) for TCDD. Similarly, effect estimates close to unity were found in summary analysis of breast cancer case-control studies regarding levels of DDE and PCB in adipose tissue or serum. In two recent nested case-control studies using stored specimens, the odds ratio per standard deviation increase in serum p,p'-DDE was 1.27 (CI=0.95–1.69). Although estrogenic effects of certain organochlorine compounds should be easier to detect on the endometrium, we know of no analytic epidemiologic studies of endometrial cancer published to date. We conclude that available data do not indicate that organochlorines will affect the risk of these two cancers in any but the most unusual situation.This work was supported through a grant to Harvard University from the Chemical Manufacturers Association; further support was received from the Swedish Cancer Society. The completeness, accuracy and interpretation of the data presented in this report as well as the conclusion reached therein is the responsibility solely of the authors.     

Benefits and Harms of Phytoestrogen Consumption in Breast Cancer Survivors

Worldwide, breast cancer is the most common malignant neoplasm and the second most common causeof cancer death in women. This malignancy is recognized to be estrogen-dependent and due to this feature,hormone replacement therapy is regarded as potentially dangerous in breast cancer survivors who seek reliefof their menopausal symptoms. Whereas hot flashes are detected in nearly half of postmenopausal women witha relatively high frequency and severity, botanic sources of estrogens have been proposed as an alternativetreatment. Nevertheless, estrogenic properties of these compounds suggest possibility of stimulating cancerrecurrence or worsening prognosis in survivors. As well, effects in improving vasomotor climacteric changes iscontroversial. Many studies have considered the subject, some focusing on efficacy of phytoestrogens for controlof menopausal symptoms, and others discussing effects of these compounds on breast cancer outcome in termsof survival or recurrence. The present article is a concise review of the effects of consumption of phytoestrogenson menopausal symptoms, namely hot flashes, and breast cancer recurrence and mortality in survivors of thedisease. Overall, the major part of the current existing literature is in favor of positive effects of phytoestrogenson breast cancer prognosis, but the efficacy on menopausal symptoms is probably minimal at the best.     

History of breast-feeding in relation to breast cancer risk: a review of the epidemiologic literature

The purpose of this review is to critically evaluate the collective epidemiologic evidence that a history of breast-feeding may decrease the risk of breast cancer. Original data for inclusion were identified through a MEDLINE(R) search of the English language literature from 1966 through 1998. To date, virtually all epidemiologic data regarding breast-feeding and breast cancer risk are derived from case-control studies, which vary according to classification of breast-feeding history. Overall, the evidence with respect to "ever" breast-feeding remains inconclusive, with results indicating either no association or a rather weak protective effect against breast cancer. An inverse association between increasing cumulative duration of breast-feeding and breast cancer risk among parous women has been reported in some, but not all, studies; the failure to detect an association in some Western populations may be due to the low prevalence of prolonged breast-feeding. It appears that the protective effect, if any, of long-term breast-feeding is stronger among, or confined to, premenopausal women. It has been hypothesized that an apparently protective effect of breast-feeding may be due to elevated breast cancer risk among women who discontinue breast-feeding or who take medication to suppress lactation; however, the evidence is limited and should be interpreted with caution. The biology underlying a protective effect of breast-feeding and why this should be restricted to premenopausal women remain unknown, although several mechanisms have been postulated (hormonal changes, such as reduced estrogen; removal of estrogens through breast fluid; excretion of carcinogens from breast tissue through breast-feeding; physical changes in the mammary epithelial cells, reflecting maximal differentiation; and delay of the re-establishment of ovulation). While breast-feeding is a potentially modifiable behavior, the practical implication of reduced breast cancer risk among premenopausal women with prolonged durations of breast-feeding may be of marginal importance, particularly in Western societies.     

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.     

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.     

Relationship of hormone use to cancer risk.

Exogenous hormones are widely prescribed in the United States, primarily as oral contraceptives and hormone-replacement therapy. Each of these frequently used categories of drugs has important potential for altering risk of several major human cancers. The efficacy of oral contraceptives in preventing ovarian cancer and endometrial cancer is well established. There remains controversy about the relationship between oral-contraceptive use and breast cancer risk, but most studies show that use in the postmenarcheal and perimenopausal periods is associated with an increased risk of breast cancer in a duration-dependent manner. As with oral contraceptives, the relationship between estrogen-replacement therapy and breast cancer risk is controversial, but several well-designed studies showed a moderate increased risk after long-term use. Estrogen-replacement therapy is a major cause of endometrial cancer. Combination hormone-replacement therapy will probably reduce some of the excess risk of endometrial cancer, but few epidemiological data exist on this relationship. The sparse data suggest that combination therapy may enhance breast cancer risk. As with endometrial and ovarian cancers, hormonal chemoprevention of breast cancer is also feasible. We review two such strategies, ie, gonadotropin-releasing hormone agonists and the antiestrogenic drug tamoxifen.     

Estrogens, BRCA1, and breast cancer

Findings obtained in in vitro assays and animal studies indicate that estrogens might influence the activity of the tumor suppressor gene BRCA1, and BRCA1 in turn may suppress the activity of the estrogen receptor. This review will discuss the possibility that interactions between estrogens and BRCA1 partly explain why elevated circulating estrogen levels appear to increase breast cancer risk among postmenopausal women but not among young women. A hypothesis is proposed that estrogens have a dual role in affecting breast cancer risk. In young women whose breasts have not yet accumulated critical mutations required for cancer initiation and promotion, activation of BRCA1 by estrogens helps to maintain genetic stability and induce differentiation, and therefore estrogens do not increase breast cancer risk. Breasts of older women, in contrast, are likely to contain transformed cells whose growth is stimulated by estrogens. Although BRCA1 is also probably activated by estrogens in older women, its function may have been impaired, for example, due to increased methylation associated with aging. Estrogen exposure in women who carry germ-line mutations in BRCA1 may always increase breast cancer risk because estrogens would be able to cause DNA damage and increase genetic instability without being opposed by BRCA1-induced repair activity. This might lead to an increase in the number of overall mutations, including those that initiate breast cancer. In addition to increasing genetic instability, reduced BRCA1 activity may also be linked to changes in the mammary gland morphology that predispose individuals to breast cancer. For example, a persistent presence of lobules type 1, which are the least differentiated lobular structures in the human breast, is seen in the BRCA1 mutation carriers. The aim of this review is to discuss the role of premenopausal estrogens in breast cancer and to initiate more research that would lead to novel means of reducing breast cancer risk, particularly among BRCA1 mutation carriers.