Hormone replacement therapy and breast cancer in former users of oral contraceptives--The Norwegian Women and Cancer study

Combined estrogen-progestin menopausal therapy (HRT) and combined estrogen-progestin contraceptives (OC) both increase breast cancer risk during current use and a few years after. We investigated risk of breast cancer in women who were users of HRT dependant on former history of OC use in a large, national population-based cohort study, the Norwegian Women and Cancer study (NOWAC). Exposure information was collected through postal questionnaires. Based on follow-up of 30,118 postmenopausal women by linkage to national registers of cancer, deaths, and emigration we revealed 540 incident breast cancer cases between 1996 and 2004. Compared to never users of either drugs current use of HRT gave a significant (p = 0.002) higher risk of breast cancer in former OC users, RR = 2.45 (95% CI 1.92-3.12), than among never users of OCs, RR = 1.67 (1.32-2.12). Relative risk of current use of HRT was similar for estrogen only and combinations with progestin added in ever users of OCs. The increased risk of breast cancer in current HRT users with a history of former OC use could have potential great impact on postmenopausal breast cancer risk as the proportion of postmenopausal women with former OC use will continue to increase.     

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

The overall tumour incidence and breast cancer incidence related to hormone replacement therapy (HRT) were followed in a population-based cohort of 29 508 women, aged 25-65 when interviewed in 1990-92. By the end of the follow up in December 1999, there were 226 611 person-years of observation. A total of 1145 malignant tumours were recorded (expected 1166.6; SIR = 0.98, 95% CI 0.93-1.04). There was a small excess of breast cancer with 434 observed and 387.69 expected (SIR = 1.12, 95% CI 1.02-1.23). Among about 3 663 ever users of HRT, there was no increase in overall tumour incidence (SIR = 0.98, 95% CI 0.86-1.12) but a significant excess of breast cancer (SIR = 1.35, 95% CI 1.09-1.64) compared with never users (SIR = 1.07, 95% CI 0.96-1.19). Breast cancer increased with increasing duration of use and for 48-120 months use the SIR was 1.92 (95% CI 1.32-2.70). There was no significant interaction with family history of breast cancer although an independent additive effect was suggested between HRT use and family history. In a Cox regression model time to breast cancer in relation to duration of HRT use was analysed adjusting for age at menarche, age at menopause, age at first full term pregnancy, parity and age at diagnosis. A significantly higher risk was seen for longer duration of HRT use compared with never users. No increased risk is seen in women beyond 5 years after stopping HRT. There was no interaction between previous use of oral contraceptives and later HRT use.     

Increased incidence of small and well-differentiated breast tumours in post-menopausal women following hormone-replacement therapy

Exposure to hormone-replacement therapy (HRT) has consistently been associated with an increased incidence of breast cancer, particularly of small tumours. Other tumour characteristics in relation to HRT have received less scientific attention. Our aim in this population-based prospective cohort study was to assess whether HRT is associated with an increased incidence of breast-cancer subgroups defined in terms of stage, type (according to the WHO system), Nottingham grade and the Nottingham Prognostic Index (NPI). Evaluation was based on a cohort of 5,865 post-menopausal women followed for an average of 9.8 years. Twenty percent of women reported current use of HRT at the time of the baseline interview. Record linkage with the Swedish Cancer Registry and local clinical registries identified 141 incident invasive breast-cancer cases. All tumours were reclassified by 1 pathologist. The incidence of breast cancer in HRT users was 377/10(5) and in non-users 221/10(5) person-years [relative risk (RR) = 1.72, 95% confidence interval (CI) 1.17-2.52]. This risk remained statistically significant after adjustment for established risk factors in a Cox proportional hazards analysis (RR = 1.66, 95% CI 1.12-2.45). Among HRT users, there was over-representation of cases with stage I tumours (adjusted RR = 2.33, 95% CI 1.44-3.76), of lobular carcinomas (RR = 4.38, 95% CI 1.60-12.0) and of tubular tumours (RR = 4.81, 95% CI 1.37-16.8). Nottingham grade I/II carcinomas (RR = 2.02, 95% CI 1.29-3.16) and cases with NPI < or = 3.4 (RR = 2.29, 95% CI 1.41-3.72) were similarly over-represented among HRT users. Incidence of breast cancer was increased in post-menopausal women who used HRT at baseline. Among HRT users, there was over-representation of tumours that, with regard to stage, type and grade, are associated with a favourable prognosis.     

Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study

BACKGROUND: The goal of the current study was to investigate the relation between hormone replacement therapy (HRT) and breast carcinoma in a prospective study cohort. Particular attention was paid to the type of HRT used and to the association of HRT type with estrogen receptor status and tumor histology. METHODS: Between 1993 and 1997, a total of 29,875 women were enrolled in the Danish Cancer Society's prospective "Diet, Cancer and Health" study. Among 23,618 women who were assumed to be postmenopausal and for whom information on HRT use was available, we identified 423 cases of breast carcinoma over a median follow-up period of 4.8 years. Statistical analyses were based on the Cox proportional hazards model, with age serving as the time parameter. RESULTS: The breast carcinoma incidence rate ratio (IRR) was 2.22 (95% confidence interval [CI], 1.80-2.75) for users of HRT at baseline compared with women who never received HRT. Among HRT users (relative to nonusers), the IRR for estrogen receptor-positive tumors (2.38; 95% CI, 1.84-3.06) was greater than the IRR for estrogen receptor-negative tumors (1.56; 95% CI, 1.00-2.43). HRT use at baseline also was analyzed in relation to the incidence of lobular carcinoma and the incidence of ductal carcinoma; the adjusted IRR associated with HRT use was 3.53 (95% CI, 1.94-6.41) for lobular carcinoma and 2.10 (95% CI, 1.64-2.70) for ductal carcinoma. The likelihood of developing estrogen receptor-positive breast carcinoma was found to depend significantly on the type of HRT regimen used (P = 0.03), with women receiving continuous therapy having the greatest probability of developing estrogen receptor-positive disease. CONCLUSIONS: An increased breast carcinoma IRR was found to be associated with current HRT use. In addition, relative to other types of HRT regimens, continuous estrogen + progestin regimens were found to be associated with an increased risk of breast carcinoma, and particularly estrogen receptor-positive breast carcinoma.     

Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden

BACKGROUND: The authors previously reported an increased risk of breast carcinoma with longer duration of hormone replacement therapy (HRT) use. It is unclear if different types of HRT confer different risks. METHODS: In this study, a population-based cohort of 29,508 women were interviewed during 1990-1992 to determine whether there are any differences in breast carcinoma risk according to different types and duration of HRT use. RESULTS: At the end of the follow-up period in December 2001, the cohort constituted 298,649 person-years. Slightly more breast carcinoma cases were seen (n = 556) than expected (n = 508.37; standardized morbidity ratio =1.09, 95% confidence interval [CI] = 1.00-1.19). Approximately 3663 women had ever used HRT. In Cox regression models, time to breast carcinoma in relation to duration and type of HRT use was analyzed, adjusting for age at menarche, age at first full-term pregnancy, parity, age at menopause, family history of breast carcinoma, and age at interview. In women with a natural menopause, a significantly higher risk was observed for longer duration of combined continuous HRT use compared with never users (hazard ratio [HR] = 4.60, 95% CI = 2.39-8.84). Nonsignificant elevated risks also were observed for longer combined sequential (HR = 2.23, 95% CI = 0.90-5.56), gestagen only (HR = 3.74,9 5% CI = 0.94-14.97), and estriol use (HR = 1.89, 95% CI = 0.81-4.39). No increased risk was seen in women after 5 years of nonuse. When studying women who ever used only one type of HRT, even more elevated HRs for gestagen-containing preparations were seen. The highest risks were associated with the combined continuous and gestagen-only therapy in women with >/= 48 months of use. Use of estradiol without progestins did not increase breast carcinoma risk significantly. The authors estimated the cumulative risk of breast carcinoma in a 50-year-old woman with gestagen-containing therapies for >/= 48 months, with a follow-up of 10 years, to be 7% (95% CI = 5.4-11.4%) compared with 2% (95% CI = 1.6%-2.9%) for never-users of HRT. CONCLUSIONS: Longer use of HRT containing progestins significantly elevates breast carcinoma risk whereas estradiol use does not. Continued use of progestins rendered the highest risks. The yearly risk of breast carcinoma for long-term users of progestins is of the magnitude of 50% the risk of a BRCA1 mutation carrier.     

Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: a prospective study.

BACKGROUND: It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16alpha-hydroxyestrone (16alpha-OHE1) are associated with an enhanced risk of breast cancer. We examined the association between the metabolite levels and breast cancer in a nested case-control study, which also addressed hormone replacement therapy (HRT) and estrogen receptor status of the tumors. METHODS: 24,697 postmenopausal Danish women were enrolled in the "Diet, Cancer and Health" cohort. During follow-up, 426 breast cancer cases were identified and controls were matched by age at diagnosis, baseline age, and HRT use. The concentrations of 2-OHE and 16alpha-OHE1 in spot urine were measured by an enzyme immunoassay. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated for total and estrogen receptor-specific breast cancer and were stratified according to HRT use. RESULTS: A higher incidence of estrogen receptor-positive breast cancer with an enhanced 2-OHE level was observed among current HRT users, IRR per doubling = 1.30 (95% CI, 1.02-1.66), whereas no association was seen among nonusers of HRT, IRR per doubling = 1.00 (95% CI, 0.69-1.45). The association between estrogen receptor-positive breast cancer and the 16alpha-OHE1 metabolite level was in the opposite direction but slightly weaker and statistically insignificant. For estrogen receptor-negative breast cancer, no significant associations were seen. CONCLUSIONS: The risk of breast cancer, in particular the estrogen receptor-positive type, was enhanced among postmenopausal women using estradiol-based HRT and among those who had a high 2-OHE concentration.     

Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe

Epidemiologic studies have shown an increased risk of breast cancer following hormone replacement therapy (HRT). The aim of this study was to investigate whether different treatment regimens or the androgenecity of progestins influence the risk of breast cancer differently. The Danish Nurse Cohort was established in 1993, where all female nurses aged 45 years and above received a mailed questionnaire (n = 23,178). A total of 19,898 women returned the questionnaire (86%). The questionnaire included information on HRT types and regimens, reproductive history and lifestyle-related factors. Breast cancer cases were ascertained using nationwide registries. The follow-up ended on 31 December 1999. Women with former cancer diagnoses, women with missing information on HRT, surgical menopause, premenopausal, as well as hysterectomized women were excluded, leaving 10,874 for analyses. Statistical analyses were performed using Cox proportional hazards model. A total of 244 women developed breast cancer during follow-up. After adjustment for confounding factors, an increased risk of breast cancer was found for the current use of estrogen only (RR = 1.96; 95% CI = 1.16-3.35), for the combined use of estrogen and progestin (RR = 2.70; 95% CI = 1.96-3.73) and for current users of tibolone (RR = 4.27; 95% CI = 1.74-10.51) compared to the never use of HRT. In current users of combined HRT with testosterone-like progestins, the continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cyclical combined regimens (RR = 4.16, 95% CI = 2.56-6.75, and RR = 1.94, 95% CI = 1.26-3.00, respectively). An increased risk of breast cancer was noted with longer durations of use for the continuous combined regimens (p for trend = 0.048). The European traditional HRT regimens were associated with an increased risk of breast cancer. The highest risk was found for the use of continuous combined estrogen and progestin.     

Does hormone replacement therapy increase the frequency of breast atypical hyperplasia in postmenopausal women? Results from the Bouches du Rhone district screening campaign

It is thought that the risk of atypical hyperplasia (AH) increases with age, particularly among postmenopausal women. Three hypotheses were investigated to try to explain this phenomena: use of hormone replacement therapy (HRT), increased breast cancer screening and improvements in radiological quality. Data were collected from the Bouches du Rh?ne breast cancer screening programme database and from the pathological registry of all women operated on for breast diseases in the district. The AH incidence rate was studied using a Poisson regression analysis. The change in the profile of breast diseases was explored through studying changes in the proportion of AH among benign lesions and malignant diseases. The AH incidence rate significantly increased over time (13.6% per year). The proportion of AH among the benign diseases increased with time and was significantly higher for HRT users (Odds Ratio (OR)=2.05; 95% Confidence Interval (CI): 1.43-2.93). While AH decreased with age among HRT non-users, it increased among users as a proportion of both benign and malignant lesions. The AH incidence rate significantly increased among pre- and postmenopausal women. Our study suggests that this increase is partly explained by the incidental discovery of these lesions by mammography and partly by a real increase of the disease among HRT users.     

Estrogen-biosynthesis gene CYP17 and its interactions with reproductive, hormonal and lifestyle factors in breast cancer risk: results from the Long Island Breast Cancer Study Project

The genes that are involved in estrogen biosynthesis, cellular binding and metabolism may contribute to breast cancer susceptibility. We examined the effect of the CYP17 promoter T --> C polymorphism and its interactions with the reproductive history, exogenous hormone use and selected lifestyle risk factors on breast cancer risk among 1037 population-based incident cases and 1096 population-based controls in the Long Island Breast Cancer Study Project. Overall, there were no associations between the CYP17 genotype and breast cancer risk. Among postmenopausal women, the joint exposure to higher body mass index (BMI) and the variant C allele was associated with an increased risk of breast cancer [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.15-2.22]. The joint exposure to the variant C allele and long-term use of hormone replacement therapy (HRT) (>51 months) was related to an increased risk of breast cancer (OR, 1.51; 95% CI, 0.99-2.31) especially estrogen receptor-positive, progesterone receptor-positive breast cancer (OR, 1.87; 95% CI, 1.08-3.25). Among the control population, the CYP17 variant C allele was inversely associated with long-term use of postmenopausal HRT and a higher BMI in postmenopausal women. In conclusion, the findings suggest that the CYP17 variant C allele may increase breast cancer risk in conjunction with long-term HRT use and high BMI in postmenopausal women.     

Risk of endometrial cancer in relationship to cigarette smoking: results from the EPIC study

Current epidemiologic evidence indicates that cigarette smoking reduces the risk of endometrial cancer. We examined data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to analyze further aspects of the smoking-endometrial cancer relationship, such as possible modifying effects of menopausal status, HRT use, BMI and parity. In a total of 249,986 women with smoking exposure and menopausal status information, 619 incident endometrial cancer cases were identified during 1.56 million person-years of follow-up. Among postmenopausal women, the hazard ratio (HR) for current smokers versus never smokers was 0.70 (95% CI = 0.53-0.93), while it was 1.75 (95% CI = 1.13-2.70) among premenopausal women at recruitment. After adjustment for risk factors, the HR for postmenopausal women was slightly attenuated to 0.78 (95% CI = 0.59-1.03). No heterogeneity of effect was observed with HRT use or BMI. Among premenopausal women, current smokers of more than 15 cigarettes per day or who smoked for 30 years or more at the time of recruitment had a more than 2-fold increased risk of endometrial cancer compared to never smokers (HR = 2.54; 95% CI = 1.47-4.38 and HR = 2.23; 95% CI = 1.04-4.77, respectively). Past smoking was not associated with endometrial cancer risk, either among pre- or postmenopausal women. In this prospective study, we observed an increased risk of endometrial cancer with cigarette smoking in premenopausal women. The reduction of endometrial cancer risk observed among postmenopausal women does not have direct public health relevance since cigarette smoking is the main known risk factor for cancer.     

Breast cancer with different prognostic characteristics developing in Danish women using hormone replacement therapy

The aim of this study is to investigate the risk of developing prognostic different types of breast cancer in women using hormone replacement therapy (HRT). A total of 10 874 postmenopausal Danish Nurses were followed since 1993. Incident breast cancer cases and histopathological information were retrieved through the National Danish registries. The follow-up ended on 31 December 1999. Breast cancer developed in 244 women, of whom 172 were invasive ductal carcinomas. Compared to never users, current users of HRT had an increased risk of a hormone receptor-positive breast cancer, but a neutral risk of receptor-negative breast cancer, relative risk (RR) 3.29 (95% confidence interval (CI): 2.27-4.77) and RR 0.99 (95% CI: 0.42-2.36), respectively (P for difference=0.013). The risk of being diagnosed with low histological malignancy grade was higher than high malignancy grade with RR 4.13 (95% CI: 2.43-7.01) and RR 2.17 (95% CI: 1.42-3.30), respectively (P=0.063). For breast cancers with other prognostic characteristics, the risk was increased equally for the favourable and non favourable types. Current users of HRT experience a two- to four-fold increased risk of breast cancer with various prognostic characteristics, both the favourable and non favourable types. For receptor status, the risk with HRT was statistically significantly higher for hormone receptor-positive breast cancer compared to receptor-negative breast cancer.     

Use of hormone therapy and risk of breast cancer detected at screening and between mammographic screens

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer, but in women undergoing breast cancer screening it is not clear whether use of HT is associated with increased risk of breast cancer detected at screening or between screens (interval cancer). Further, it is unclear whether the use of the HTs that have been common in Scandinavia is associated with higher risk of breast cancer than the HTs used in other countries. Our study was based on data from 296,651 women aged 50-69 years, who participated in the Norwegian Breast Cancer Screening Program during 1995-2004. After a mean enrollment time of 3.8 years, 1,512 women were diagnosed with invasive screen detected breast cancer, and 814 with invasive interval breast cancer. Cox regression models were used to estimate hazard ratios (HRs) of breast cancer associated with HT use, after adjusting for confounders. Ever users of HT had a 58% increased risk of breast cancer, compared to never users. The HRs associated with HT use were 1.45 (95% confidence interval (CI) = 1.29-1.63) for screen detected and 1.89 (95% CI = 1.61-2.23) for interval cancer. The difference between screen detected and interval cancer was statistically significant (p = 0.011). The HR of breast cancer increased with duration of HT use, but significantly more so for interval than for screen detected cancer (use of HT for 5 or more years compared to never use; HR = 2.91, 95% CI = 2.10-4.04 and HR = 1.94, 95% CI = 1.51-2.50, respectively; p = 0.002). The population attributable fraction of breast cancer due to HT use was 19.8% overall. Ever users of HT tended to develop a cancer of lower grade. No other differences in histological tumor characteristics were observed between ever and never users of HT among screen detected or interval cancers. The estimated risks of either breast cancer overall with HT use are higher in Norway than reported in similar studies from the U.S. HT-use is a stronger risk factor for interval cancer than for screen detected cancer. The increased risk of interval cancer, which may partly be due to decreased sensitivity of mammograms in HT users, remains a challenge in breast cancer screening programs.     

Patterns of alcohol consumption and breast cancer risk in the California Teachers Study cohort.

Alcohol consumption of approximately two drinks or more per day has been associated with elevated breast cancer risk in the California Teachers Study cohort as well as in many other populations. The objective of this analysis is to examine effects of age at drinking and drinking patterns and to identify effect modifiers. Of the 103,460 at-risk cohort members, age <85, who resided in California and completed the baseline alcohol assessment, 1,742 were diagnosed with invasive breast cancer after joining the cohort and before January 2001. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence used various sources. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RRs). Elevated breast cancer risk was most evident for recent drinking [RR = 1.28, 95% confidence interval (CI): 1.06-1.54 for >/=20 g/day versus nondrinkers], with no clear pattern for consumption during earlier periods of life. This elevation in risk was 32% among postmenopausal women (95% CI: 1.06-1.63) and 21% among pre/perimenopausal women (95% CI: 0.76-1.92). Highest risks associated with heavy alcohol consumption were observed among postmenopausal women with a history of biopsy-diagnosed benign breast disease (RR = 1.97, 95% CI: 1.39-2.79 compared to nondrinkers without benign breast disease) or who had used combination hormone replacement therapy (HRT) (RR = 2.24, 95% CI: 1.59-3.14 compared to nondrinkers who never used HRT). Recent alcohol consumption equivalent to two or more drinks per day increases the risk of invasive breast cancer, with the greatest RRs observed among heavy drinkers who are also postmenopausal and have a history of benign breast disease or who use HRT.     

Dietary carbohydrates and breast cancer risk: a prospective study of the roles of overall glycemic index and glycemic load

We examined breast cancer risk in association with overall glycemic index (GI), glycemic load (GL), and dietary carbohydrate and sugar intake in a prospective cohort of 49,613 Canadian women enrolled in the National Breast Screening Study who completed a self-administered food frequency questionnaire between 1980 and 1985. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow-up ending between 1998 and 2000. During a mean follow-up of 16.6 years, we observed 1,461 incident breast cancer cases. GI, GL, total carbohydrate and total sugar intake were not associated with breast cancer risk in the total cohort. However, there was evidence of effect modification of the association between GI and breast cancer risk by menopausal status (p = 0.01), the hazard ratio for the highest versus the lowest quintile level of GI being 0.78 (95% CI = 0.52-1.16; ptrend = 0.12) in premenopausal women and 1.87 (95% CI = 1.18-2.97; ptrend = 0.01) in postmenopausal women. The associations between GI and GL were not modified by body mass index (BMI) or by vigorous physical activity among pre- or postmenopausal women. Similarly, the associations between GI/GL and risk in postmenopausal women were not modified by BMI, vigorous physical activity, or ever use of hormone replacement therapy (HRT), although the associations were slightly stronger among those who reported no vigorous physical activity (ptrend = 0.02), among those who reported ever using HRT (ptrend = 0.02) and among normal-weight women (BMI < 25 kg/m2; ptrend = 0.03). Our data suggest that consumption of diets with high GI values may be associated with increased risk of breast cancer among postmenopausal women, possibly more so among subgroups defined by participation in vigorous physical activity, ever use of HRT and those who are not overweight.     

Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort

Most epidemiological studies have shown an increase in breast cancer risk related to hormone replacement therapy (HRT) use. A recent large cohort study showed effects of similar magnitude for different types of progestogens and for different routes of administration of estrogens evaluated. Further investigation of these issues is of importance. We assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women who had never taken any HRT 1 year before entering the E3N-EPIC cohort study (mean age at inclusion: 52.8 years); 948 primary invasive breast cancers were diagnosed during follow-up (mean duration: 5.8 years). Data were analyzed using multivariate Cox proportional hazards models. In this cohort where the mean duration of HRT use was 2.8 years, an increased risk in HRT users compared to nonusers was found (relative risk (RR) 1.2 [95% confidence interval 1.1-1.4]). The RR was 1.1 [0.8-1.6] for estrogens used alone and 1.3 [1.1-1.5] when used in combination with oral progestogens. The risk was significantly greater (p <0.001) with HRT containing synthetic progestins than with HRT containing micronized progesterone, the RRs being 1.4 [1.2-1.7] and 0.9 [0.7-1.2], respectively. When combined with synthetic progestins, both oral and transdermal/percutaneous estrogens use were associated with a significantly increased risk; for transdermal/percutaneous estrogens, this was the case even when exposure was less than 2 years. Our results suggest that, when combined with synthetic progestins, even short-term use of estrogens may increase breast cancer risk. Micronized progesterone may be preferred to synthetic progestins in short-term HRT. This finding needs further investigation.     

Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma

BACKGROUND: Observational studies and randomized trials have demonstrated that hormone replacement therapy (HRT) increases the recipient's risk of developing breast carcinoma. Because it is known that some breast malignancies are hormonally responsive and that others are not, it has been hypothesized that HRT may be associated with the development of estrogen receptor (ER)-positive/progesterone receptor (PR)-positive breast carcinoma more so than with the development of ER-negative/PR-negative breast carcinoma. METHODS: The Nurses' Health Study is a prospective cohort study that enrolled 121,700 female registered nurses ages 30-55 years in 1976. In the current study, the authors analyzed 2548 malignancies that developed among eligible postmenopausal women in that cohort between 1980 and 2000 and for which data on ER and PR status were available. RESULTS: Compared with women who had never used HRT, current long-term users of HRT were more likely to develop ER-positive/PR-positive breast carcinoma (multivariate risk ratio [RR], 1.80; 95% confidence interval [CI], 1.52-2.12) but were not any more likely to develop ER-negative/PR-negative disease (multivariate RR, 1.00; 95% CI, 0.72-1.39). This effect grew stronger with increasing duration of current HRT use and was also more pronounced among women with body mass index < 25 kg/m2. Furthermore, the association between HRT use and ER-positive/PR-positive disease was stronger among patients receiving combined HRT (CHRT) regimens, which included estrogen and progesterone, than among users of estrogen alone (ERT). In addition, tumors tended to develop more quickly in current users of CHRT than in ERT users. CONCLUSIONS: The finding that current users of HRT were more likely to develop ER-positive/PR-positive tumors than they were to develop ER-negative/PR-negative ones suggests that both endogenous and exogenous hormonal factors may influence breast tumor characteristics. In analyses of the effects of hormonal factors on breast tumor development, ER-positive/PR-positive tumors and ER-negative/PR-negative tumors should be considered separately from each other.     

Tibolone and risk of gynecological hormone sensitive cancer

Risk of ovarian cancer with hormone therapy is associated with use of both unopposed estrogen therapy and combined estrogen–progestin therapy, whereas for endometrial cancer addition of continuous progestin decreases the estrogen induced increased risk. Less is known about risk with use of tibolone; a synthetic steroid with estrogenic, progestagenic and androgenic properties. We assessed these associations in a prospective cohort study, including all Danish women 50–79 years of age and followed 1995–2009. National Danish Registers captured individually updated exposure information, cancer cases including histology and confounding factors. Poisson regression analyses provided multiple adjusted incidence rate ratios (IRRs). More than 900,000 women were followed for 9.8 years on average; 4,513 were diagnosed with ovarian cancer and 6,202 with endometrial cancer. Compared to women never on postmenopausal hormone therapy, current users of tibolone had an increased IRR for ovarian cancer (1.42(95% confidence interval [CI], 1.01–2.00) and serous ovarian tumors (2.21(95%CI 1.48–3.32)). The risk increased with duration of use, particularly for serous ovarian tumors. Compared to never users, the IRR of endometrial cancer was 3.56(95%CI 2.94–4.32) among current users of tibolone and 3.80(95%CI 3.08–4.69) of Type I endometrial cancer. The steepest risk increase with duration of use was for Type I tumors. In conclusion, tibolone is associated with increased risk for ovarian and endometrial cancer overall; and particular the risk of serous ovarian tumors and Type I endometrial cancer. Because the associations are stronger with increasing durations of use – and for hormone sensitive tumors – the results seem indicative of causality.     

Weight gain, body mass index, hormone replacement therapy, and postmenopausal breast cancer in a large prospective study.

Excess adiposity and hormone replacement therapy (HRT) are important contributors to postmenopausal breast cancer risk. HRT has been shown to modify the association between body weight and breast cancer risk, although few studies are sufficiently large to examine the risk of breast cancer associated with body mass index (BMI) and weight gain separately among current HRT users and nonusers. This study includes 1,934 incident breast cancer cases occurring among 62,756 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort. Age-adjusted incidence rates were calculated, and Cox proportional hazards models were used to examine the association of BMI and adult weight gain (since age 18 years) with breast cancer risk stratified by HRT use. Total adult weight gain strongly predicted breast cancer risk among former and never HRT users (P for trend < 0.0001). Weight gain of 21-30 pounds was associated with a rate ratio of 1.4 (95% confidence interval 1.1-1.8); rates doubled among women gaining >70 pounds compared with women who maintained their weight within 5 pounds of their weight at age 18. After accounting for weight gain, neither recent BMI nor BMI at age 18 were independent predictors of risk. Among current HRT users, no association was seen between breast cancer and either BMI or weight gain. Adult weight gain is strongly associated with postmenopausal breast cancer only among non-HRT users in this study. These data illustrate the importance of examining breast cancer risk factors separately by HRT use; the effects of other risk factors may be attenuated or obscured among women taking HRT.     

Postmenopausal breast cancer risk and interactions between body mass index,menopausal hormone therapy use,and vitamin D supplementation: Evidence from the E3N cohort

Experimental studies suggest protective effects of vitamin D on breast carcinogenesis, but epidemiological evidence is not conclusive. Body mass index (BMI) has been shown to modulate the effect of supplementation on the vitamin D status, but its potential influence on the relationship with breast cancer risk has been little studied. We investigated a potential interaction between BMI and vitamin D supplementation on breast cancer risk while considering an already reported interaction between vitamin D supplementation and menopausal hormone therapy (MHT) use. Vitamin D supplementation was prospectively investigated in 57,403 postmenopausal women from the French E3N cohort including 2,482 incident breast cancer cases diagnosed between 1995 and 2008. Multivariable hazard ratios (HR) for primary invasive breast cancer and 95% confidence intervals (CI) were estimated using Cox models. Among MHT ever users, vitamin D supplementation was associated with decreased breast cancer risk, similarly across BMI strata (P_homogeneity = 0.83). Among MHT never users, ever vitamin D supplementation was associated with increased postmenopausal breast cancer risk in women with baseline BMI <25 kg/m² (HR = 1.51, 95% CI: 1.13, 2.02), but not in women with higher BMI (0.98, 95% CI: 0.62, 1.56), P_homogeneity = 0.12. In conclusion, our findings suggest that vitamin D supplementation may reduce the excess breast cancer risk in MHT users, but draw attention on a potential risk in postmenopausal women not exposed to high exogenous or endogenous hormones, i.e. non‐overweight MHT‐non users, especially in the present context of increasing vitamin D supplement use and decreasing MHT use.