Current Estrogen Users Research Articles

Exogenous Hormone Use and Endometrial Cancer in U.S. Black Women.

Background: Although endometrial cancer risk differs among white and black women, few data on its associations with exogenous hormone use in the latter group are available. Studies have reported lower endometrial cancer risk among users of oral contraceptives (OCs), but higher risk among users of estrogen-only female menopausal hormones (FMHs). Evidence for the risk among estrogen plus progestin FMHs users is equivocal.Methods: We followed 47,555 Black Women's Health Study participants with an intact uterus from 1995 through 2013. Data on exogenous hormone use, covariates, and endometrial cancer were obtained biennially. Self-reported incident cases of endometrial cancer were confirmed by medical records or cancer registries whenever possible. We estimated incidence rate ratios (IRRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression.Results: We observed 300 endometrial cancer cases during 689,546 person-years of follow-up. Compared with never use, ≥10 years' duration of OC use was associated with lower risk (multivariable IRR = 0.45, 95% CI, 0.27-0.74), but risk was higher among current users of estrogen-only (IRR = 3.78, 95% CI, 1.69-8.43) and estrogen plus progestin FMH (IRR = 1.55, 95% CI, 0.78-3.11). Risk was not increased among former users of estrogen-only (IRR = 0.87, 95% CI, 0.44-1.72) or estrogen plus progestin FMH (IRR = 0.63, 95% CI, 0.36-1.09).Conclusions: Current use of estrogen-only and estrogen plus progestin FMH was associated with increased risk of endometrial cancer. Risk appeared lower among former users of estrogen plus progestin FMH. Long-term OC use was associated with reduced risk.Impact: Our results are generally consistent with those among white women. Cancer Epidemiol Biomarkers Prev; 27(5); 558-65. ©2018 AACR.

Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies.

We synthesize the current literatures and use the power of meta-analysis to examine trends on association between hormone replacement therapy (HRT) and the risk of breast cancer (BC). We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science from their inception until Jan 2017. Prospective studies that provided adjusted risk estimates of HRT and BC risk were eligible. Categorical and dose-response meta-analyses followed the PRISMA were conducted using random effects model and restricted cubic spline model, respectively. Forty-seven publications from thirty-five unique studies were included, involving 3,898,376 of participants and 87,845 of BC cases. Compared with non-users, RR for current estrogen-only therapy (ET) users was 1.14 (95% confidence interval (CI) = 1.05–1.22), and for per year increases was 1.02 (95% CI = 1.02–1.02). Moreover, RR for current estrogen plus progestin therapy (EPT) users was 1.76, (95% CI = 1.56–1.96), and for per year increases was 1.08 (95% CI = 1.08–1.08). Dose-response analyses revealed 8–10 years’ onset peaks, and indicated residual increased BC risk remained after stopping use of ET regimen rather than for EPT. Effect-modifiers like BMI, duration of use, race/ethnicity, routes of administration were recognized. In Conclusions, current use of EP or EPT and ever use of tibolone are associated with an elevated risk of BC. Compared with slim HRT users and non-users, lower BC risks were found among overweight/obese HRT users and former EPT users, respectively. Both ET and EPT users are associated with higher risk of lobular BC than ductal BC, and more ER-positive than negative BC cases were detected among EPT users.

Bioavailable Insulin-like Growth Factor-I Inversely Related to Weight Gain in Postmenopausal Women Regardless of Exogenous Estrogen

Weight gain, insulin-like growth factor-I (IGF-I) levels, and excess exogenous steroid hormone use are putative cancer risk factors, yet their interconnected pathways have not been fully characterized. This cross-sectional study investigated the relationship between plasma IGF-I levels and weight gain according to body mass index (BMI), leptin levels, and exogenous estrogen use among postmenopausal women. This study included 794 postmenopausal women who enrolled in an ancillary study of the Women's Health Initiative Observational Study between February 1995 and July 1998. The relationship between IGF-I levels and weight gain was analyzed using ordinal logistic regression. We used the molar ratio of IGF-I to IGF binding protein-3 (IGF-I/IGFBP-3) or circulating IGF-I levels adjusting for IGFBP-3 as a proxy of bioavailable IGF-I. The plasma concentrations were expressed as quartiles. Among the obese group, women in the third quartile (Q3) of IGF-I and highest quartile of IGF-I/IGFBP-3 were less likely to gain weight (>3% from baseline) than were women in the first quartiles (Q1). Among the normal-weight group, women in Q2 and Q3 of IGF-I/IGFBP-3 were 70% less likely than those in Q1 to gain weight. Among current estrogen users, Q3 of IGF-I/IGFBP-3 had 0.5 times the odds of gaining weight than Q1. Bioavailable IGF-I levels were inversely related to weight gain overall. Although weight gain was not consistent with increases in IGF-I levels among postmenopausal women in this report, avoidance of weight gain as a strategy to reduce cancer risk may be recommended.

Postmenopausal Estrogen Therapy and Risk of Gallstone Disease: A Population-Based Case–Control Study

Female gender and increasing age are key risk factors for gallstone disease; therefore, postmenopausal women are at high risk. Estrogen increases cholesterol saturation of bile and may further increase gallstone risk, but population-based evidence is sparse. Our objective was to examine the association between postmenopausal estrogen therapy and risk of gallstone disease and the impact of duration of treatment and use of opposing progestin. We conducted a population-based case-control study. Cases were postmenopausal women (defined as aged ≥45years) with gallstone disease identified in the period 1996-2010. For each case, we selected ten population controls matched to cases by age and sex. We defined exposure as any use of estrogen (opposed and unopposed by progestin). Cases/controls were categorized as current estrogen users if their last prescription was redeemed <90days before gallstone diagnosis (or corresponding date for controls); all other users were categorized as former users. The reference group consisted of cases/controls with no/rare estrogen use. Medical databases covering the population of Northern Denmark (2.4 million inhabitants through the period 1996-2010). We used conditional logistic regression to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of gallstone disease in women treated with estrogen. The ORs were adjusted for relevant comorbidity, other drugs known to influence gallstone risk, and parity. We identified 16,386 cases with gallstone disease and 163,860 controls. A total of 1,425 cases (8.7%) and 8,930 controls (5.4%) were current estrogen users, yielding an adjusted OR for gallstone disease of 1.74 (95% CI 1.64-1.85) compared with non-users. The corresponding adjusted OR for former users was 1.35 (95% CI 1.28-1.42). The results suggested a duration response for current users. Use of unopposed estrogen was associated with higher adjusted ORs than estrogen opposed by progestin. Postmenopausal estrogen therapy was associated with increased risk of gallstone disease in current and former estrogen users. Use of unopposed estrogen was associated with higher risk than use of estrogen opposed by progestin; this finding needs to be confirmed and explored further in future studies.

Abstract B71: Does hormone replacement therapy or mammography screening affect breast cancer incidence rates in Taiwan? A nationwide cohort study

Abstract Background: Breast cancer incidence in Taiwan is continuous rising to the leading cancer incidence rate in women according to cancer registry. We hypothesize hormone replacement therapy (HRT) or mammography screening affect the breast cancer incidence. Objectives: 1) To determine whether a similar decline of HRT use and breast incidence occurred in Taiwan. 2) To compare frequency and dose of use HRT with breast cancer incidence. 3) To compare change of mammography rates in different age groups and period of time with breast cancer incidence and mortality. Methods: Breast cancer incidence in most industry countries declines as HRT use drops. This study analyzed national health insurance data from 2000-2008. Women aged above 40 years who was diagnosis postmenopausal or osteopenic were extracted from database for analysis. This research looked at information from prescriptions for HRT, mammography rates and breast cancer incidence and mortality rates. Approximately 82,478 postmenopausal or osteopenic women were included in this analysis. Odd ratios were derived from nested case control estimation to compare with HRT use, total dose and total duration of HRT. Mammography rates in different age groups and different period of year were compared by using national health insurance data. Results: We found that a reduced frequency of use of HRT was reflected in the decrease in dispensed HRT prescriptions after 2002 announced be the Women Health Initiative (WHI) in Taiwan. The largest drop in use of HRT occurred between 2002 and 2003 and continuous drop is noted during our study period. Compared with never users, estrogen and progestin users were with higher risk of breast cancer (OR: 1.58, 95% CI 1.16-2.14, p&amp;lt;0.003) and higher among current users of estrogen only (OR: 1.48, 95% CI 1.13-1.93, p&amp;lt;0.004). The HRT use, total dose of HRT and duration of HRT all showed dose-response effects (OR: 2.42 for HRT use more than 30 times; OR: 3.59 for total use of HRT for more than 3 years; OR: 3.18 for duration of use HRT). They are all statistical significant (p&amp;lt;0.001). Compared with mammography rates with different period of time, the study found that nearly 40% rise in breast cancer rates coincided with the 50% increase in mammography rates between 2000 and 2008. The breast cancer incidence increased following by mammography rates inclined, particular in aged 40 to 59 years group during 2001 to 2005 and 2006 to 2010. Breast cancer incidence rates began to increase dramatically in 2006 to 2010 among women aged 40-49 years. Compared with total mortality to incidence ratio [1-(M/I)] (proxy site-specific cancer survival), the survival ratio increased from 74.7% (2000) to 81.3% (2008). Conclusion: The breast cancer risk was elevated with the use of combined HRT. In Taiwan, breast cancer incidence rates continuous increase among aged 40-59 years, which is likely explained by the promotion of mammography for government breast cancer screening programs from 2003. Mortality to incidence ratio in Taiwan did show some improvement, but still limit. Some argue that the plasticizers - DEHA, DBP, BBP, DEHP, DOP - as estrogen-like substances is the cause which was discovered widely used for food packaging and illegally add into food drink in Taiwan food industry may disturb the endocrine system. Further long-term surveillance studies of time trend and spatial patterns between breast cancer incidence rate and screening rates can help reconcile the potential population-level association of these two factors. Citation Format: Eng-Mei Tsai, Po-Huang Chiang, Yen-Chen Chang. Does hormone replacement therapy or mammography screening affect breast cancer incidence rates in Taiwan? A nationwide cohort study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B71.

Abstract 31: The association between GWAS SNPs and mammographic density in Norwegian postmenopausal women stratified by nongenetic factors.

Abstract Background: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Dense breast tissue is characterized by increased stromal tissue and possibly by increased numbers of breast epithelial cells. Twin studies have suggested that part of the variation in MD is determined by genetic factors, however, it is also clear that non-genetic factors such as hormone use, body weight and reproductive factors play a role. Exactly which genetic factors determine MD is not clear, although several genome-wide association studies (GWAS) conducted over the past few years have suggested a number of variants. We hypothesized that the effect of genetic variants on MD may be strongly modified by non-genetic factors. We therefore evaluated the association between percent MD and 17 single nucleotide polymorphisms (SNPs) identified from several published GWAS of MD/breast cancer by strata defined by non-genetic factors. Methods: We assessed MD on 2036 postmenopausal women aged 50-69 years who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 using a computer assisted method (Madena, University of Southern California). We used linear regression (additive model) to determine the association between each SNP and MD, adjusting for age and body mass index (BMI). The postmenopausal women were stratified on postmenopausal hormone therapy (HT) use, parity, BMI, and alcohol intake. Results: In all postmenopausal women a variant (rs29815829) in the FGFR2 gene and a variant (rs3734805) in the 6q25.1 gene associated significantly with MD (regression coefficient (beta)=-1.42, p=0.0306 and beta=0.74, p=0.0390). The same variants showed significant associations in never HT users with slightly stronger effect estimates, but not in current combined estrogen and progestin therapy users. We also observed some possible effect modification by parity. In all postmenopausal parous women as well as in parous never HT users, the 6q25.1 and the FGFR2 variants were the most important (lowest p-values). However, in nulliparous never HT users a variant (rs3803662) in the TOX3 gene and a variant (rs1045485) in the CASP8 gene associated significantly with MD (beta=1.41, p=0.0120 and beta= 1.42, p=0.0275). There were no apparent differences between alcohol drinkers or non-drinkers in never HT users, regardless of parity. When examining strata of BMI among never HT users, we found a significant association with MD in the CASP8 gene (rs1746827) in women with a BMI &amp;lt; 25 (beta=0.81, p=0.0507) and in the FGFR2 gene (rs2981582) in women with a BMI &amp;gt;25 &amp;lt;29 (beta=-2.34; p=0.0284). Conclusion: We found some evidence that the associations between variants in the 6q25.1 gene and in the FGFR2 gene and MD were modified by HT use. Further, our results suggest that the genetic determinants of MD may differ between parous and nulliparous women, and across BMI strata. Citation Format: Merete Ellingjord-Dale, Isabel dos Santos Silva, Eunjung Lee, Elisabeth Couto, David Van Den Berg, Solveig Hofvind, Tom Grotmol, Giske Ursin. The association between GWAS SNPs and mammographic density in Norwegian postmenopausal women stratified by nongenetic factors. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 31.

Abstract LB-60: Long-term use of hormone therapy and breast cancer incidence and mortality

Abstract Background: The risk of breast cancer associated with longer-term use of both estrogen (ET) or estrogen + progesterone (E+P) hormone therapy (HT) cannot be determine from existing randomized controlled trials. Methods: The Nurses’ Health Study included 121,700 female registered nurses aged 30-55 in 1976 who have been followed with biennial questionnaires to medication use, risk factors and cancer incidence. Only postmenopausal women were included in this analysis. The main outcome was incidence of invasive breast cancer. We additionally evaluated the risk of fatal breast cancer (breast cancer diagnosis that resulted in breast cancer death). Results: During 1.57 million person-years of follow-up from 1980 through 2008, 5631 incident invasive breast cancers were diagnosed and 884 died of breast cancer. Breast cancer risk increased with duration of current E+P use without evidence for a plateau (e.g. RR 1.88 (95% CI 1.64-2.16) for 10-14.9 years and RR 2.35 (95% CI 1.90-2.92) for 15-19.9 years of use). More than 10 years of current ET use was also associated with increased breast cancer risk (RR 1.22 (95% CI 1.06-1.40) for 10-14.9 years and RR 1.43 (95% CI 1.22-1.68) for 15-19.9 years of use). Past E+P was also weakly associated with breast cancer risk. When the population was restricted to the same entry criteria as the Women's Health Initiative trial, we also observed a non-significant deceased risk of breast cancer HT with current ET use similar in magnitude to that seen in the trial (RR 0.61 (95% CI 0.63-1.05) for &amp;lt; 5 years and RR 0.93 (95% CI 0.76-1.14) for 5-9.9 years), but still observed an increased risk with current ET users of 15-19.9 years (RR 1.30 (95% CI 1.07-1.59). Effects were stronger for ER positive tumors and among thinner women. Results were similar when limited to women who underwent regular screening. Although breast cancer incidence was increased in these groups, there was no increase in the risk of fatal breast cancer with either E+P or ET use (RR 1.05 (95% CI 0.67-1.68) and RR 1.08 (0.80-1.46) for 10-19.9 years of current use respectively). Conclusions: Both past and current E + P users and current long-term ET users were at increased breast cancer risk. We did not observe an increase in fatal breast cancer with HT use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-60. doi:1538-7445.AM2012-LB-60

Abstract 655: Menopausal hormone therapy and breast cancer risk: The CECILE Study

Abstract Breast cancer in post-menopausal women has been associated with the use of menopausal hormone therapy (MHT). Estrogen-only (EO) and combined estrogen-progestagen (EP) therapies have been evaluated as potentially carcinogenic to human by the IARC. However, the type of estrogen and progestagen in the MHT varies considerably by country. For example, besides synthetic progestagens, the use of natural progesterone in combined EP therapy is specific to France. We investigated whether the association between MHT and breast cancer in postmenopausal women differ by type of chemical compound. We conducted a population-based case-control study in France in 762 cases and 840 controls recruited among postmenopausal women in two French “départements”. Data were collected including name of medication, date of start and end of each medication used. Unconditional logistic regression models were used, with adjustment for age, study area, and known risk factors for breast cancer. We observed a significant increased risk of breast cancer for current users of estrogen plus synthetic progestagen while no association was found for any use of estrogen-only therapy or combined therapy of estrogen plus natural progesterone. Among current users of estrogen plus synthetic progestagen, the association with breast cancer increased with duration of use and was higher in women who started their treatment before or shortly after menopause. Our study suggests that the use of natural progesterone as the progestagen component in a combined EP therapy is not associated with an increased risk of breast cancer. This result reinforces the findings reported in another cohort study of French women (E3N). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 655. doi:1538-7445.AM2012-655

Hormonal Factors and Risks of Esophageal Squamous Cell Carcinoma and Adenocarcinoma in Postmenopausal Women

The incidences of esophageal adenocarcinoma and squamous cell carcinoma (SCC) are higher in males than in females. We investigated whether female-related hormonal factors are associated with risks of these two types of esophageal cancer. We examined the association between use of hormone therapy (HT) and the risks of esophageal adenocarcinoma and SCC in postmenopausal women enrolled in the Women's Health Initiative (WHI) clinical trials and observational studies. Twenty-three esophageal adenocarcinoma and 34 esophageal SCC cases were confirmed among the 161,080 participants, after a median of 11.82 years of follow-up. Risk of esophageal SCC was lower among HT users (past users: HR = 0.25, 95% CI: 0.06-1.10 in 2 cases; current users: HR = 0.41, 95% CI: 0.18-0.94 in 9 cases). A decreased esophageal SCC risk was observed for current users of estrogen plus progestin (E+P) therapy (HR = 0.25, 95% CI: 0.07-0.86 in 3 cases) but not for current users of estrogen-only therapy (HR = 0.96, 95% CI: 0.28-3.29 in 6 cases). No association was observed between the use of HT and the risk of esophageal adenocarcinoma. No other reproductive or hormonal factors were significantly associated with the risk of either SCC or adenocarcinoma. Current use of E+P therapy was found to be associated with a decreased risk of esophageal SCC, but no association was observed with esophageal adenocarcinoma. To provide more definitive evidence, a pooled analysis of all available studies or a much larger study would be needed.

A cross-sectional and 10-year prospective study of postmenopausal estrogen therapy and blood pressure, renal function, and albuminuria

Blood pressure, urine albumin-to-creatinine ratio, and estimated glomerular filtration rate (GFR) are highly correlated conditions. The longitudinal effect of exposure to postmenopausal estrogen therapy on these traits studied together has not been reported. This was a cross-sectional study of 1,044 older postmenopausal community-dwelling women from the Rancho Bernardo Study (1992-1996); 443 women were reevaluated ∼ 10 years later (2002-2005). We determined the cross-sectional and prospective association of baseline postmenopausal estrogen therapy and blood pressure, urine albumin-to-creatinine ratio, GFR, and the odds of categorical hypertension (physician diagnosis, medication, or blood pressure ≥ 140/≥ 90 mm Hg), chronic kidney disease (GFR ≤ 60 mL/min per 1.73 m2), and albuminuria (urine albumin-to-creatinine ratio ≥ 25 mg/g). At baseline, the mean age was 68.3 years for current estrogen users, 75.4 years for past users, and 74.3 years for never users. In the cross-sectional analyses, current users had lower diastolic blood pressure and lower odds of having chronic kidney disease, independent of covariates. In the ∼ 10-year follow-up, comparisons between never, past, and current estrogen use (91% continuous use since baseline), the mean diastolic blood pressure declined over time in current users, whereas systolic blood pressure increased among never users. Urine albumin-to-creatinine ratio also increased in never users and decreased in current users; GFR did not differ by estrogen use. In cross-sectional analyses, estrogen users had better GFR and blood pressure than nonusers did, but the 10-year follow-up showed improved blood pressure and decreased urine albumin-to-creatinine ratio among mostly long-term current users, without differences in GFR by estrogen use. This study suggests no association of GFR with 10 years of continuous estrogen use and an inverse association with albuminuria.

Breast cancer risk in relation to the interval between menopause and starting hormone therapy.

BackgroundAlthough breast cancer risk is greater in users of estrogen–progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence.MethodsA total of 1 129 025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided.ResultsDuring 4.05 million woman-years of follow-up, 15 759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (Pheterogeneity < .001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen–progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50–59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen–progestin formulations who began use less than 5 years after menopause.ConclusionsThere was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen–progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later.

Discovery and Validation of Breast Cancer Early Detection Biomarkers in Preclinical Samples

Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of blood-based biomarkers useful for the early detection of breast cancer could have a major impact on reducing breast cancer disease burden by identifying cancers early when they are most treatable. We conducted a series of large-scale proteomic discovery and validation studies using preclinical samples from the Women's Health Initiative Observational Study prospective cohort. Of the 503 proteins quantified in experiments conducted on samples from ER(+) breast cancer patients and matched controls, 57 differentiated cases from controls. The seven candidates were assessed in an independent validation set with a commercially available ELISA assay. We confirmed that one of these candidates, epidermal growth factor receptor (EGFR), was elevated in cases versus controls. Compared to women in the lowest EGFR quartile, those in the highest quartile has a 2.90-fold (p = 0.0005) increased risk of developing breast cancer. An interaction with use of menopausal hormone therapy was observed such that among current estrogen plus progestin users, those in the highest EGFR quartile had a 9.04-fold (p = 0.0004) increased risk of developing breast cancer. While the performance of EGFR in terms of sensitivity and specificity is insufficient for it to be used on its own clinically, the formal validation of EGFR suggests that there may indeed be changes in the plasma proteome prior to the clinical diagnosis of breast cancer that are detectable and of potential clinical utility.

Detection of Elevated Plasma Levels of Epidermal Growth Factor Receptor Before Breast Cancer Diagnosis among Hormone Therapy Users

Applying advanced proteomic technologies to prospectively collected specimens from large studies is one means of identifying preclinical changes in plasma proteins that are potentially relevant to the early detection of diseases such as breast cancer. We conducted 14 independent quantitative proteomics experiments comparing pooled plasma samples collected from 420 estrogen receptor-positive (ER(+)) breast cancer patients ≤17 months before their diagnosis and matched controls. Based on the more than 3.4 million tandem mass spectra collected in the discovery set, 503 proteins were quantified, of which 57 differentiated cases from controls with a P value of <0.1. Seven of these proteins, for which quantitative ELISA assays were available, were assessed in an independent validation set. Of these candidates, epidermal growth factor receptor (EGFR) was validated as a predictor of breast cancer risk in an independent set of preclinical plasma samples for women overall [odds ratio (OR), 1.44; P = 0.0008] and particularly for current users of estrogen plus progestin (E + P) menopausal hormone therapy (OR, 2.49; P = 0.0001). Among current E + P users, the EGFR sensitivity for breast cancer risk was 31% with 90% specificity. Whereas the sensitivity and specificity of EGFR are insufficient for a clinically useful early detection biomarker, this study suggests that proteins that are elevated preclinically in women who go on to develop breast cancer can be discovered and validated using current proteomic technologies. Further studies are warranted to examine the role of EGFR and to discover and validate other proteins that could potentially be used for early detection of breast cancer.

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.

Abstract 4815: Elevated plasma levels of epidermal growth factor receptor prior to diagnosis of breast cancer in preclinical specimens from the Women's Health Initiative Observational Study

Abstract Background: Applying advanced proteomic technologies to prospectively collected specimens from large studies is one means of identifying preclinical changes in plasma proteins that are potentially relevant to the early detection of diseases such as breast cancer. Methods: We conducted biomarker discovery and validation experiments using pre-clinical samples from a case-control study nested in the Women's Health Initiative (WHI) Observational Study (OS). In the discovery phase of this study we conducted fourteen independent quantitative proteomics experiments comparing pooled plasma samples collected from 420 estrogen receptor positive (ER+) breast cancer patients ≤17 months prior to their diagnosis and matched controls that involved immunodepletion, isotopic labeling with acrylamide, extensive fractionation, and high resolution tandem mass spectrometry. Eight proteins that differentiated between cases and controls, for which quantitative assays were available, were assessed in an independent validation set consisting of 198 ER+ breast cancer case/control sets. Results: Based on the over 3.4 million tandem mass spectra collected in the discovery set, 545 proteins were quantified of which 79 differentiated cases from controls with a p-value&amp;lt;0.05. Eight of these 79 candidates had an available ELISA assay and were assessed in our validation set. Of these eight candidates, epidermal growth factor receptor (EGFR) was validated as a predictor of breast cancer risk in our independent set of preclinical plasma samples among women overall [odds ratio (OR)=1.44, p-value=0.0008], and particularly among current users of estrogen plus progestin (E+P) menopausal hormone therapy (OR=2.41, p-value=0.0001). Among current E+P users EGFR's sensitivity for ER+ breast cancer risk was 31% with 90% specificity, and compared to those in the lowest EGFR quartile those in the highest EGFR quartile had a 9.04-fold (95% CI: 2.78-33.21) increased risk of developing ER+ breast cancer. Conclusions: While EGFR's sensitivity and specificity are insufficient for a clinically useful early detection biomarker, this study is important in two respects. First, no prior studies have validated even a single breast cancer early detection biomarker in preclinical specimens to the degree we have here. This suggests that detectable changes in the plasma proteome may indeed be present preclinically for relatively small tumors such as ER+ breast cancer. Second, consideration of other exposures in biomarker discovery studies is likely critical given that while overall EGFR modestly distinguished cases from controls, among E+P users this relationship was considerably stronger. Further studies are warranted to both examine the role of EGFR and to discover and validate other proteins that could potentially be used for breast cancer early detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4815.

Postmenopausal Hormone Use and Symptoms of Gastroesophageal Reflux

The association of elevated levels of estrogen and progesterone with increased gastroesophageal reflux (GERD) has been reported in a number of studies. Observations supporting this association include decreases found in lower esophageal sphincter (LES) pressures during pregnancy and with the use of sequential oral contraceptives, and data showing that postmenopausal hormone (PMH) therapy may increase the risk of GERD symptoms in overweight and obese women. This prospective cohort study evaluated the risk of GERD among postmenopausal women using PMH therapy, selective estrogen receptor modulators (SERMs), or over-the-counter (OTC) hormone preparations. The study subjects were female nurses with GERD symptoms among a cohort of 51,637 postmenopausal women enrolled in the Nurse’s Health Study who provided information biennially on use of PMH therapy since 1976 and on GERD symptoms, current use of SERMS or OTC hormone preparations since 2002. Of the 51,637 women in the total cohort, 12,018 women (23%) reported GERD symptoms. Multivariate logistic regression analysis showed that compared with women who never used PMH, the odds ratio (OR) for the risk of GERD symptoms was 1.46 (95% confidence interval [CI], 1.36–1.56) for past users of PMH, 1.66 (95% CI, 1.54–1.79) for current users of estrogens only, and 1.41 (95% CI, 1.29–1.54) for current users of combined estrogen and progesterone. The associations persisted after controlling for potential confounders: age-adjusted, age- and body mass index adjusted, and multivariate models. The risk of GERD symptoms associated with PMH use was significantly greater with both increasing dosage and duration of estrogen use (P value for trends <.001). Compared with women who never used PMH or SERMs, women currently using a SERM had an OR for GERD symptoms of 1.39 with a 95% CI of 1.22–1.59. Women currently using OTC hormone preparations had an OR for GERD symptoms of 1.37 with a 95% CI of 1.16–1.62) compared with nonusers. These findings show that postmenopausal use of estrogens, SERMs, or OTC hormone preparations is associated with increased risk of GERD symptoms.

Postmenopausal hormone therapy and incident urinary incontinence in middle-aged women

The objective of the study was to examine the association of hormone therapy with incident urinary incontinence (UI) in postmenopausal women aged 37-54 years in the Nurses' Health Study II. Participants reported use of hormone therapy, including hormone type, on biennial questionnaires from 1989 to 2001. Among 7341 postmenopausal women reporting no UI in 2001, we identified 1026 women who developed UI at least monthly between 2001 and 2003. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Women currently using hormone therapy had 1.39-fold (95% CI, 1.16-1.67) increased odds of incident UI, compared with women who never used hormone therapy. ORs were similar in current users of oral estrogen alone (OR, 1.35, 95% CI, 1.03-1.78) and oral estrogen with progestin (OR, 1.37, 95% CI, 1.13-1.67). These findings suggest an increased risk of UI associated with use of postmenopausal hormone therapy in younger postmenopausal women.

Postmenopausal Hormone Use and Symptoms of Gastroesophageal Reflux

Previous studies suggest that elevated levels of estrogen and progesterone, either through endogenous or exogenous sources, increase gastroesophageal reflux. To evaluate the relationship between symptoms of gastroesophageal reflux disease (GERD) and postmenopausal hormone (PMH) therapy, including the use of selective estrogen receptor modulators and over-the-counter (OTC) hormone preparations, we performed a prospective cohort study of 51,637 postmenopausal women enrolled in the Nurses' Health Study who provided data on the use of PMH therapy biennially since 1976, and information about symptoms of GERD in 2002. Among eligible participants, 12 018 women (23%) reported GERD symptoms. Compared with women who never used PMHs, the multivariate odds ratio (OR) for the risk of GERD symptoms was 1.46 (95% confidence interval [CI], 1.36-1.56) for past hormone users, 1.66 (95% CI, 1.54-1.79) for current users of estrogen only, and 1.41 (95% CI, 1.29-1.54) for current users of combined estrogen and progesterone. The risk of GERD symptoms increased significantly with increasing estrogen dosage (P < .001) and increasing duration of estrogen use (P < .001). Moreover, current selective estrogen receptor modulator users experienced an OR of 1.39 (95% CI, 1.22-1.59) for GERD symptoms, and women currently using OTC hormone preparations had an OR of 1.37 (95% CI, 1.16-1.62). Postmenopausal use of estrogens, selective estrogen receptor modulators, or OTC hormone preparations is associated with a greater likelihood of symptoms of GERD. This suggests a hormonal component to the pathophysiologic characteristics of GERD in women.

Response to Letter Regarding Article, “Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study”

We thank Drs Micheletti and Chevallier for their interest in our report.1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value ( P <0.006) indicates that the probability of the result being due to chance is very small. Second, only the main effects …

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen. We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0). Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.