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Physical inactivity, high postmenopausal body mass index, alcohol consumption and use of menopausal hormone therapy are established risk factors for breast cancer. Less is known about whether these factors influence the risk of progression of benign and premalignant breast lesions to invasive breast cancer. This registry-based cohort study was based on women with a precancerous lesion who were followed for breast cancer. The cohort consisted of 11 270 women with a benign lesion, 972 women with hyperplasia with atypia and 2379 women with carcinoma in situ diagnosed and treated after participation in BreastScreen Norway, 2006-2016. Information on breast cancer risk factors was collected by a questionnaire administered with the invitation letter. Cox regression analysis was used to estimate the association between breast cancer and physical activity, body mass index, alcohol consumption, tobacco smoking and menopausal hormone therapy, adjusted for age. During follow-up, 274 women with a benign lesion, 34 women with hyperplasia with atypia and 118 women with carcinoma in situ were diagnosed with invasive breast cancer. We observed an increased risk of breast cancer associated with use of menopausal hormone therapy for women with a benign or premalignant lesion. Alcohol consumption and tobacco smoking showed suggestive increased risk of breast cancer among women with a benign lesion. We were only to a limited degree able to identify associations between modifiable risk factors of breast cancer and the disease among women with a precancerous lesion, and a larger study is needed to confirm or refute associations., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objectives: With the present study, we aimed to investigate the association between menopausal hormone therapy (HT) and risk of colorectal cancer (CRC)., Setting: Cohort study based on the linkage of Norwegian population-based registries., Participants: We selected 466822 Norwegian women, aged 55-79, alive and residing in Norway as of 1 January 2004, and we followed them from 2004 to 2008. Each woman contributed person-years at risk as non-user, current user and/or past HT user., Outcome Measures: The outcome of interest was adenocarcinoma of the colorectal tract, overall, by anatomic site and stage at diagnosis. Incidence rate ratios (RRs) with 95% CIs were estimated by Poisson regression and were used to evaluate the association between HT and CRC incidence., Results: During the median follow-up of 4.8 years, 138 655 (30%) women received HT and 3799 (0.8%) incident CRCs occurred. Current, but not past, use of HT was associated with a lower risk of CRC (RR 0.88; 95% CI 0.80 to 0.98). RRs for localised, regionally advanced and metastatic CRC were 1.13 (95% CI 0.91 to 1.41), 0.81 (95% CI 0.70 to 0.94) and 0.79 (95% CI 0.62 to 1.00), respectively. RRs for current use of oestrogen therapy (ET) were 0.91 (95% CI 0.80 to 1.04) while RR for current use of combined oestrogen-progestin therapy (EPT) was 0.85 (95% CI 0.70 to 1.03), as compared with no use of HT. The same figures for ET and EPT in oral formulations were 0.83 (95% CI 0.68 to 1.03) and 0.86 (95% CI 0.71 to 1.05), respectively., Conclusions: In our nationwide cohort study, HT use lowered the risk of CRC, specifically the most advanced CRC., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The association between use of menopausal hormone therapy (HT) and occurrence of skin malignant melanoma (SMM) is controversial. We investigated the issue in a nationwide cohort of 684,696 Norwegian women, aged 45-79 years, followed from 2004 to 2008. The study was based on linkage between Norwegian population registries. Multivariable Poisson regression models were used to estimate the effect of HT use, different HT types, routes of administration and doses of estrogen and progestin on the risk of SMM. During the median follow-up of 4.8 years, 178,307 (26%) women used HT, and 1,476 incident SMM cases were identified. Current use of HT was associated with increased risk of SMM (rate ratios (RR) = 1.19; 95% confidence interval (CI) 1.03-1.37). Plain estrogen therapy was associated with an increased risk of SMM (RR 1.45; 95% CI 1.21-1.73), both for oral (RR 1.45; 95% CI 1.09-1.93) and vaginal (RR 1.44; 95% CI 1.14-1.84) formulations, while combined estrogen and progestin therapy (EPT) was not (RR 0.91; 95% CI 0.70-1.19). We performed a dose-response analysis of estrogen and progestin in women using tablets, and found that use of estrogens was associated with increased risk (RR 1.24; 95% CI 1.00-1.53 per 1 mg/day) and use of progestins with decreased risk (RR 0.71; 95% CI 0.57-0.89 per 10 mg/month) of SMM. In conclusion, estrogens were associated with increased risk of SMM, while combinations of estrogens and progestins were not. Our results suggest that estrogens and progestins might affect the risk of SMM in opposite ways., (© 2017 UICC.)

Background: Estrogen plus progestin therapy increases both mammographic density and breast cancer incidence. Whether mammographic density change associated with estrogen plus progestin initiation predicts breast cancer risk is unknown., Methods: We conducted an ancillary nested case-control study within the Women's Health Initiative trial that randomly assigned postmenopausal women to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. Mammographic density was assessed from mammograms taken prior to and one year after random assignment for 174 women who later developed breast cancer (cases) and 733 healthy women (controls). Logistic regression analyses included adjustment for confounders and baseline mammographic density when appropriate., Results: Among women in the estrogen plus progestin arm (97 cases/378 controls), each 1% positive change in percent mammographic density increased breast cancer risk 3% (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01 to 1.06). For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased 3.6-fold (95% CI = 1.52 to 8.56). The effect of estrogen plus progestin use on breast cancer risk (OR = 1.28, 95% CI = 0.90 to 1.82) was eliminated in this study, after adjusting for change in mammographic density (OR = 1.00, 95% CI = 0.66 to 1.51)., Conclusions: We found the one-year change in mammographic density after estrogen plus progestin initiation predicted subsequent increase in breast cancer risk. All of the increased risk from estrogen plus progestin use was mediated through mammographic density change. Doctors should evaluate changes in mammographic density with women who initiate estrogen plus progestin therapy and discuss the breast cancer risk implications., (Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.)

Purpose: Breast cancer associated with estrogen-progestin (EP) therapy may have more favorable characteristics than cancer in never users, but results are conflicting. It is not well known either whether Body Mass Index (BMI) modifies this association. We investigated breast cancer characteristics in EP users for lean (BMI < 25 kg/m 2 ) and overweight women (BMI ≥ 25 kg/m 2 )., Methods: The Icelandic Cancer Detection Clinic cohort, with information on breast cancer risk factors for 90% of Icelandic women, was linked with the population-based Icelandic Cancer Registry. A total of 781 women with invasive breast cancer diagnosed 51 years or older were matched with 7761 controls from the cohort. Conditional logistic regression was used for estimating adjusted odds ratios (OR) and 95% confidence intervals (CI) according to tumor characteristics, stratified by BMI. Polytomous logistic regression was applied in a case-only analysis for testing whether the risk associated with EP use differed according to tumor characteristics., Results: Ever EP users had a twofold higher risk of breast cancer compared with never users (OR 2.05, 95% CI 1.71-2.45). In lean women, EP use was significantly less likely to be associated with grade 2 or 3 tumors than grade 1 tumors, contrary to overweight women for whom risk was increased irrespective of grade. EP use in overweight women was associated with a higher risk of lobular than ductal cancer (OR 2.75, 95% CI 1.29-5.87)., Conclusion: Among lean EP users, tumor characteristics were more favorable than among never users. This effect was not observed for overweight women.

There is convincing evidence that combined estrogen-progestin therapy (EPT) increases the risk of breast cancer. However, the effect of different formulations, preparations and routes of administration is largely unknown. Estrogen only-therapy (ET) is, in general, not associated or weakly associated with breast cancer risk. We investigated the effect of hormone therapy (HT) with ET, EPT, and tibolone on risk of invasive breast cancer. Information on HT use was obtained from the Norwegian Prescription Database, and breast cancer incidence from the Cancer Registry of Norway. Poisson regression was used to estimate the incidence rate ratios (RR). We analyzed data from 686,614 Norwegian women, aged 45-79 years in January 2004, followed until December 2008, of whom 178,383 (26%) were prescribed HT. During the average 4.8 years of follow-up, 7,910 invasive breast cancers were registered. Compared with nonusers, current users of estradiol-norethisterone acetate (NETA)(EPT) had a RR of 2.74 (95% CI: 2.55-2.95). Users of the high dose estradiol-NETA formulation Kliogest(®) had a RR of 3.26 (95% CI: 2.84-3.73), while users of the low dose Activelle(®) had a RR of 2.76 (95% CI: 2.51-3.04). Current users of tibolone had a RR of 1.91 (95% CI: 1.61-2.28). Current users of ET with oral or transdermal estradiol had a RR of 1.40 (95% CI: 1.16-1.68), and 1.40 (95% CI: 1.00-1.95), respectively. The increased incidence rates approximates one extra invasive breast cancer case diagnosed for every 259 women using estradiol-NETA for one year, and one extra case for every 475 women using tibolone. In conclusion, use of estradiol-NETA and tibolone preparations is associated with an increased breast cancer risk., (© 2015 UICC.)

Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995-1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995-1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.

Introduction: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Estrogen and progestin therapy (EPT) has been associated with increases in MD. Dense breast tissue is characterized by increased stromal tissue and (to a lesser degree) increased numbers of breast epithelial cells. It is possible that genetic factors modify the association between EPT and MD, and that certain genetic variants are particularly important in determining MD in hormone users. We evaluated the association between MD and 340 tagging single nucleotide polymorphisms (SNPs) from about 30 candidate genes in hormone metabolism/growth factor pathways among women who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004., Methods: We assessed MD on 2,036 postmenopausal women aged 50 to 69 years using a computer-assisted method (Madena, University of Southern California) in a cross-sectional study. We used linear regression to determine the association between each SNP and MD, adjusting for potential confounders. The postmenopausal women were stratified into HT users (EPT and estrogen-only) and non-users (never HT)., Results: For current EPT users, there was an association between a variant in the prolactin gene (PRL; rs10946545) and MD (dominant model, Bonferroni-adjusted P (Pb) = 0.0144). This association remained statistically significant among current users of norethisterone acetate (NETA)-based EPT, a regimen common in Nordic countries. Among current estrogen-only users (ET), there was an association between rs4670813 in the cytochrome P450 gene (CYP1B1) and MD (dominant model, Pb = 0.0396). In never HT users, rs769177 in the tumor necrosis factor (TNF) gene and rs1968752 in the region of the sulfotransferase gene (SULT1A1/SULT1A2), were significantly associated with MD (Pb = 0.0202; Pb = 0.0349)., Conclusions: We found some evidence that variants in the PRL gene were associated with MD in current EPT and NETA users. In never HT users, variants in the TNF and SULT1A1/SULT1A2 genes were significantly associated with MD. These findings may suggest that several genes in the hormone metabolism and growth factor pathways are implicated in determining MD.

A decline in breast cancer incidence has been observed in several countries after 2002. Reduced use of menopausal hormonal therapy (HT), as a consequence of the publication of results from the Women's Health Initiative, has been argued to be the main reason. In Norway, the governmentally funded Norwegian Breast Cancer Screening Program (NBCSP) was implemented during the same time period as the increased use of HT. This study investigated trends in breast cancer incidence by use of HT and introduction of the screening program. We obtained rates of breast cancer from the Cancer Registry of Norway and sales data of HT preparations from the Norwegian Institute of Public Health. Mammography rates were estimated from published reports. Breast cancer incidence rates increased steadily from 1956 to the end of the 20th century, particularly in women aged 55-69 during 1996-2002 residing in the counties where the NBCSP was first introduced. The rates declined after 2002-2003. HT use increased in 1987-2001, peaking around year 2000. In particular, sales of combined estrogen and progestogen preparations declined after 2002. Among women aged 55-59, rates of hormone receptor positive breast cancers peaked in 2000-2003. No such trend was seen in other age groups. In conclusion, the interpretation of breast cancer incidence trends in Norway from 1987 to 2009 is complicated because the NBCSP was introduced during a period with increasing HT use. Both factors likely contributed to the observed trends, and the role of each may vary across age groups., (Copyright © 2011 UICC.)

While studies have shown that use of postmenopausal hormone therapy with estrogen and progestogen (EPT) increases mammographic density, aspects of this association remain unclear. We examined whether mammographic density differed by type of hormone therapy (HT) used, dose, duration of use, time since last use, and whether the effects are modified by age and body mass index (BMI). Using a cross-sectional design, we recruited 2,424 postmenopausal women aged 50-69 years participating in the Norwegian Breast Cancer Screening Program. Mammographic density was assessed with a computer-assisted method, and we estimated mean absolute and percent mammographic density through multiple linear regression, and adjusting for possible confounders. Mammographic density was higher among current HT users (percent density: 22.6%; 95% CI: 22.1-23.2%) than among former (17.7%; 17.2-18.2%) or never users (16.3%; 15.7-16.8%). The highest density was seen in current EPT users of high-dose norethisterone acetate (NETA) regimens who had a percent density of 26.2% (24.3-28.1%). Results differed when considering the combined effect of age and BMI. The effect of EPT on mammographic density was modified by age and BMI, with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ≥ 26). A higher mammographic density was found in EPT users compared to never HT users, particularly in women using high-dose NETA regimens. Age and BMI modified the association between EPT use and mammographic density.

Introduction: The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy., Methods: We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT)., Results: The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT = 0.002; overall PACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women., Conclusions: We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT.

Objective: Although the Women's Health Initiative trial suggested that menopausal hormone therapy (HT) does not reduce coronary heart disease mortality overall, subsequent results have suggested that there may be a benefit in younger women. The California Teachers Study questionnaire and mortality data were used to examine whether age modified the association between HT and the relative risk of overall mortality and ischemic heart disease deaths., Methods: Participants from the California Teachers Study were 71,237 postmenopausal women (mean age, 63 y; range, 36-94 y) followed prospectively for mortality and other outcomes from 1995-1996 through 2004., Results: Age at baseline was a much more important modifier of HT effects than was age at start of therapy. Risks for all-cause mortality (n = 8,399) were lower for younger current HT users at baseline than for never users (for women ≤ 0 y: hazard ratio, 0.54; 95% CI, 0.46-0.62). These risk reductions greatly diminished, in a roughly linear fashion, with increasing baseline age (for women 85-94 y: hazard ratio, 0.94; 95% CI, 0.81-1.10 for all-cause mortality). Similar results were seen for ischemic heart disease deaths (n = 1,464). No additional significant modifying effects of age at first use, duration of use, or formulation were apparent., Conclusions: These results provide evidence that reduced risks of mortality associated with HT use are observed among younger users but not for older postmenopausal women, even those starting therapy close to their time of menopause.

Objective: To investigate whether obesity and hormone therapy (HT) are associated with ovarian cancer risk among women in the California Teachers Study cohort., Methods: Of 56,091 women age ≥ 45 years, 277 developed epithelial ovarian cancer between 1995 and 2007. Multivariate Cox regression was performed., Results: Among women who never used HT, greater adult weight gain, waist circumference and waist-to-height ratio, but not adult BMI, increased risk of ovarian cancer. Compared to women who never used HT and had a stable adult weight, risk of ovarian cancer was increased in women who gained ≥ 40 lb (relative risk (RR) 1.8, 95% confidence interval (CI): 1.0-3.0) or used HT for >5 years (RR 2.3 95% CI: 1.3-4.1). Having both exposures (RR 1.9, 95% CI: 0.99-3.5), however, did not increase risk more than having either alone. Results were similar for waist circumference and weight-to-height ratio; however, differences across HT groups were not statistically significant., Conclusions: This study suggests that abdominal adiposity and weight gain, but not overall obesity, increase ovarian cancer risk and that there may be a threshold level beyond which additional hormones, whether exogenous or endogenous, do not result in additional elevation in risk. However, large pooled analyses are needed to confirm these findings.

Background: Although it is well established that combined estrogen-progestin therapy (EPT) increases breast cancer risk, questions remain regarding the effect of different formulations of hormones, whether certain women are at particularly high risk, and whether risk varies by tumor subtype., Methods: We investigated hormone therapy (HT) use in relation to breast cancer risk in the California Teachers Study cohort; after a mean follow-up of 9.8 years, 2,857 invasive breast cancers were diagnosed., Results: Compared with women who had never used HT, women who reported 15 or more years of estrogen therapy (ET) use had a 19% greater risk of breast cancer (95% confidence interval, 1.03-1.37), whereas women using EPT for 15 or more years had an 83% greater risk (95% confidence interval, 1.48-2.26). Breast cancer risk was highest among women using continuous combined EPT regimens. Risks associated with EPT and ET use were increased with duration of HT use for women with a body mass index (BMI) of <29.9 kg/m(2) but not for women with BMI of >or=30 kg/m(2). Elevated risks associated with EPT and ET use were confined to tumors that were positive for both estrogen and progesterone receptors and those that were HER2+ but were slightly diminished for HER2- tumors., Conclusions: Breast cancer risks increased with longer duration of ET and EPT use, and risks were highest for continuous-combined EPT use. Furthermore, risks varied by BMI and tumor subtype., Impact: These findings underscore the need for personalized risk-benefit discussions with women contemplating HT use., ((c)2010 AACR.)

Objective: To investigate whether hormone therapy (HT) and obesity are associated with endometrial cancer risk among postmenopausal women in the California Teachers Study cohort., Methods: Of 28,418 postmenopausal women, 395 developed type 1 endometrial cancer between 1995 and 2006. Multivariate Cox regression was performed to estimate relative risks (RR), stratified by HT use (never used, ever estrogen alone (ET) or exclusively estrogen-plus-progestin (EPT))., Results: Among women who never used HT, overall and abdominal adiposity were associated with increased risk; when evaluated simultaneously, abdominal adiposity was more strongly associated (RR 2.2, 95% confidence interval (CI): 1.1-4.5 for waist >or=35 vs. <35 inches). Among women who ever used ET, risk was increased in women with BMI >or= 25 kg/m(2) (RR 1.6, 95% CI: 1.1-2.3 vs. <25 kg/m(2)). Neither overall nor abdominal obesity was associated with risk in women who exclusively used EPT (p-interaction <0.001 for BMI by HT use)., Conclusions: Among women who never used HT, risk was strongly positively related to obesity and may have been influenced more by abdominal than by overall adiposity; however, due to small numbers, this latter finding requires replication. Among women who ever used ET, being overweight at baseline predicted higher risk, whereas use of EPT mitigated any effects of obesity.

Purpose: Among unanswered questions is whether menopausal use of estrogen therapy (ET) or estrogen-plus-progestin therapy (CHT) increases risk of developing fatal breast cancer i.e., developing and dying of breast cancer. Using a population-based case-control design, we estimated incidence rate ratios of fatal breast cancer in postmenopausal hormone therapy (HT) users compared to non-users by type, duration, and recency of HT use., Methods: HT use prior to breast cancer diagnosis in 278 women who died of breast cancer within 6 years of diagnosis (cases) was compared with use in 2224 controls never diagnosed with breast cancer using conditional logistic regression. Measures taken to address potential bias and confounding inherent in case-control studies included collecting and adjusting for detailed data on demographic and other factors potentially associated both with HT use and breast cancer., Results: Fifty-six per cent of cases and 68% of controls reported HT use. Among current 3+ year HT users, odds ratios and 95% confidence intervals for death were 0.83 (0.50, 1.38) and 0.69 (0.44, 1.09), respectively, for exclusive use of CHT or of ET, and were 0.94 (0.59, 1.48) and 0.70 (0.45, 1.07) for any use of CHT or of ET regardless of other hormone use., Conclusion: Point estimates suggest no increased risk of fatal breast cancer with HT use, although 50% increases in risk in longer-term current CHT users cannot be ruled out., ((c) 2010 John Wiley & Sons, Ltd.)

Estrogen-alone therapy (ET) or estrogen and progestin (EPT) as menopausal hormone therapy (HT) has been commonly used to alleviate menopausal symptoms. Treatments containing > or = 10 days per month of progestin are considered relatively safe with respect to endometrial cancer risk. However, the endometrial safety of long-term EPT regimens is uncertain. We conducted a case-control study of 311 invasive endometrial cancer cases and 570 controls nested within the California Teachers Study cohort. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (95% CI) for the association between long-term HT use and endometrial cancer risk, and to assess the modifying effect of body mass index (BMI). Long-term (> or = 10 years) use of ET, sequential EPT with <10 days per month progestin, and continuous-combined EPT (> or = 25 days/month progestin) were all associated with an elevated risk of endometrial cancer (OR, 4.5; 95% CI, 2.5-8.1; OR, 4.4; 95% CI, 1.7-11.2; and OR, 2.1; 95% CI, 1.3-3.3, respectively; all P(trend) < 0.001). The risk associated with short-term use was elevated only for ET preparations. The association for continuous-combined EPT was confined to thinner women (BMI, <25 kg/m2; P(interaction) = 0.03). Among heavier women (BMI, > or = 25 kg/m2), use of continuous-combined EPT was associated with a statistically nonsignificant reduction in risk. These findings confirm that long-term use of ET, sequential EPT, or, among normal weight women, continuous-combined EPT is associated with increased risk of endometrial cancer.

Introduction: Recent, international declines in breast cancer incidence are unprecedented, and the causes remain controversial. Few data sources can address breast cancer incidence trends according to pertinent characteristics like hormone therapy use history., Methods: We used the prospective California Teachers Study to evaluate changes in self-reported use of menopausal hormone therapy (HT) between 1995 to 1996 and 2005 to 2006 and age-adjusted breast cancer incidence among 74,647 participants aged 50 years or older. Breast cancer occurrence was determined by linkage with the California Cancer Registry., Results: During 517,286 woman years of follow up, 565 in situ and 2,668 invasive breast cancers were diagnosed. In situ breast cancer incidence rates in this population did not change significantly from 2000 to 2002 to 2003 to 2005, whereas rates of invasive breast cancer declined significantly by 26.0% from 528.0 (95% confidence intervals (CI) = 491.1, 564.9) per 100,000 women in 2000 to 2002 to 390.6 (95% CI = 355.6, 425.7) in 2003 to 2005. The decline in invasive breast cancer incidence rates was restricted to estrogen receptor-positive tumors. In 1996 to 1999 and 2000 to 2002 invasive breast cancer incidence was higher for women who reported current HT use especially estrogen-progestin (EP) use at baseline than for never or past users; but by 2003 to 2005 rates were comparable between these groups. For women who were taking EP in 2001 to 2002,75% of whom had stopped use by 2005 to 2006, incidence had declined 30.6% by 2003 to 2005 (P = 0.001); whereas incidence did not change significantly for those who never took HT (P = 0.33)., Conclusions: Few data resources can examine prospectively individual HT use and breast cancer diagnosis. Stable in situ breast cancer rates imply consistent levels of screening and suggest recent declines in invasive breast cancer to be explained predominantly by changes in HT use.

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer. The HTs used in Scandinavia is associated with higher risk estimates than those used in most other countries. Mammographic density is one of the strongest risk factors for breast cancer, and possibly an intermediate marker for breast cancer. We decided to examine the relationship between use of different types of HT and mammographic density in Norwegian women. Altogether, 1,007 postmenopausal participants in the governmental mammographic screening program were asked about current and previous HT use. Mammograms were classified according to percent and absolute mammographic density. Overall, current users of HT had on average 3.6% higher mean percent mammographic density when compared with never users (p < 0.001). After adjustment for age at screening, number of children and BMI in a multivariate model, women using the continuous estradiol (E(2)) plus norethisterone acetate (NETA) combination had a mean percent mammographic density significantly higher than never users (6.1% absolute difference). Those using the continuous E(2) plus NETA combination had an 4.8% (absolute difference) higher mean percent mammographic density after <5 years of use when compared with never users, while the corresponding number for >or=5 years of use was 7% (p-trend < 0.001). We found similar associations when absolute mammographic density was used as the outcome variable. In summary, our study shows a statistical significant positive dose-response association between current use of the continuous E(2) plus NETA combination and both measures of mammographic density.

Background: Postmenopausal use of estrogen and progestin therapy increases breast density and breast discomfort. Whether this increase in breast density is heralded by new-onset breast discomfort is unknown., Methods: We used data from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study, which retrieved and examined baseline and 12-month mammograms for 594 (67.9%) of 875 women aged 45 to 64 years enrolled in the randomized controlled trial. Treatments included placebo, 0.625 mg/d of conjugated equine estrogens, 0.625 mg/d of conjugated equine estrogens and medroxyprogesterone acetate (10 mg/d for 12 d/mo or 2.5 mg/d continuously), or 0.625 mg/d of conjugated equine estrogens and 200 mg/d of micronized progestin for 12 d/mo. Breast density (the percent of the breast composed of dense tissue) was calculated from digitized mammograms obtained at baseline and at 12-month follow-up. Breast discomfort was ascertained at baseline and at follow-up using standardized self-report questionnaires. In bivariate analysis, and then in multivariable linear regression models, we assessed the association between change in percent breast density from baseline to 12-month follow-up and new-onset breast discomfort in participants who had no breast discomfort at baseline (N = 533)., Results: After adjustment for age, treatment assignment (placebo, conjugated equine estrogens, or progestin-containing regimen), and other potential confounders, women with new-onset breast discomfort had a 3.9% increase in percent breast density compared with a 0.6% increase in percent breast density among women without new-onset breast discomfort (beta = .033, P<.001). The association between incident breast discomfort and increased percent breast density was similar in all active treatment arms., Conclusion: In postmenopausal women randomly assigned to menopausal hormone therapy vs placebo, new-onset breast discomfort is associated with increased mammographic density.

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., (Copyright 2006 Wiley-Liss, Inc.)

Introduction: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast., Methods: We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17beta-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17beta-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/>or= 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD., Results: The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%)., Conclusion: Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.

Purpose: Postmenopausal estrogen and progestin therapy (EPT) increases mammographic percent density and breast cancer risk substantially more than does estrogen therapy alone. We determined whether increases in serum estrone as a function of treatment predict increases in mammographic percent density., Methods: We measured mammographic percent density and serum estrone levels in participants in the Postmenopausal Estrogen/Progestin Interventions Trial who were randomly assigned to receive conjugated equine estrogens (CEE) 0.625 mg/d; CEE and medroxyprogesterone acetate (MPA) 10 mg on days 1 to 12 per 28-day cycle; CEE and MPA 2.5 mg/d; or CEE and micronized progesterone (MP) 200 mg on days 1 to 12 per 28-day cycle. We used linear regression to determine whether serum estrone changes predicted mammographic percent density changes from baseline to 1 year., Results: Mammographic percent density increased with increasing change in estrone level in the EPT groups, but not in the CEE group. Combined, the mammographic percent density in the three EPT groups demonstrated an absolute increase of 2.95% per 100 pg/mL increase in serum estrone level (P =.0003). The absolute increases were 4.09% (P =.0018) in the CEE + MPA continuous group, 2.79% (P =.0292) in the CEE + MPA cyclical group, and 1.40% (P =.36) in the CEE + MP group, but the differences among the EPT groups were not statistically significant., Conclusion: Greater increase in serum estrone level as a function of treatment is a significant predictor of increase in mammographic percent density in women randomly assigned to the combination of estrogen and progestin.

Objective: We examined breast cancer risk related to lifetime exposure to oral contraceptives (OCs) and hormone replacement therapy (HRT) in postmenopausal women., Methods: The Women's Contraceptive and Reproductive Experiences (CARE) Study was a population-based case-control study that included 1847 postmenopausal women with incident invasive breast cancer, and 1932 control subjects, identified using random digit dialing., Results: 45% of cases and 49% of controls used both OCs and HRT. OC users were not at increased risk regardless of subsequent HRT exposure. HRT users who had used OCs previously did not have a higher risk of breast cancer than women with no exposure to OCs. We observed a negative interaction (p-value: 0.032) of combined hormone replacement therapy (CHRT) and past OC use. The increase in risk with CHRT was stronger in women who had never used OCs in the past (odds ratio: 1.05; 95% confidence interval: 1.01-1.10 per year of exclusive CHRT use) than in women who had used OCs (odds ratio: 1.00; 95% confidence interval: 0.97-1.03)., Conclusions: We found no indication that adverse effects of exposure to OCs or HRT appeared only in the presence of the other hormone or were exacerbated by exposure to the other hormone.

Background: Mammographic density is an independent risk factor for breast cancer. Postmenopausal hormone use is associated with an increase in mammographic density, but the magnitude of the density increase is unknown., Methods: Baseline and 12-month mammograms were obtained for 571 (65%) of the 875 women, aged 45-64 years, who were enrolled in the Postmenopausal Estrogen/Progestin Interventions Trial and randomly assigned to receive placebo, daily conjugated equine estrogens at 0.625 mg/day (CEE), daily CEE and medroxyprogesterone acetate (MPA) at 10 mg/day on days 1-12 (CEE+MPA-cyclic), daily CEE and MPA at 2.5 mg/day (CEE+MPA-continuous), or daily CEE and micronized progesterone (MP) at 200 mg/day on days 1-12 (CEE+MP). We analyzed digitized mammograms to determine the percentage of the left breast that was composed of dense tissue (i.e., mammographic percent density). Linear regression analysis was used to examine the effects of treatments on the change in mammographic percent density between baseline and 12 months, before and after adjustment for possible confounders. All statistical tests were two-sided., Results: The adjusted absolute mean changes in mammographic percent density over 12 months were 4.76% (95% confidence interval [CI] = 3.29% to 6.23%), 4.58% (95% CI = 3.19% to 5.97%), and 3.08% (95% CI = 1.65% to 4.51%) for women in the CEE+MPA-cyclic, CEE+MPA-continuous, and CEE-MP groups, respectively. Each of those absolute mean changes was statistically significantly different from the adjusted absolute mean change in mammographic percent density for women in the placebo group, which was -0.07% (95% CI = -1.50% to 1.38%)., Conclusion: Greater mammographic density was associated with the use of estrogen/progestin combination therapy, regardless of how the progestin was given, but not with the use of estrogen only.

Previously, we described the reduction in mammographic densities that occurred in premenopausal women after 12 months on a hormonal regimen designed to be chemopreventive for breast (and ovarian) cancer consisting of a gonadotropin-releasing hormone agonist (GnRHA) plus low-dose add-back estrogen-progestin. We sought to determine whether the density reduction persisted with continuation of the regimen for 24 months, and, if so, whether the densities would return to baseline after the regimen was discontinued. Twenty-one women, 27-40 years of age, with a 5-fold greater than normal risk of breast cancer, were randomly assigned in a 2:1 ratio to the treatment group (14 women) and to a control group (7 women). The percentage of mammographic densities, calculated as the proportion of the breast area on the mammogram containing densities, were assessed blindly using a computer-based threshold method at baseline, after 12 and 24 months of treatment, and at between 6 and 12 months after treatment was stopped. The previously described percentage of mammographic density reductions of 9.7% (P = 0.012) after 12 months of treatment were increased slightly to 11.4% (P = 0.010) after 24 months of treatment, but the additional change was not statistically significant. Ten of 11 treated women assessed at 24 months had reduced percentages of mammographic densities compared with baseline. Six to 12 months after completion of treatment, the mean percentage of mammographic density in the treated group was no different from that at baseline (mean decline of 2.0%; P = 0.73). The women in the control group had no statistically significant changes in densities over the period of the study. Reductions in mammographic densities engendered by the GnRHA plus a low-dose add-back estrogen-progestin regimen persist as long as the women receive treatment. The densities return to baseline when the women resume normal menstrual cycles. These results confirm that mammographic densities are influenced by ovarian function. Improved efficacy of mammographic screening is to be expected as long as a woman continues on such a regimen. Whether such a regimen is chemopreventive for breast cancer remains to be established, but the recent report on a randomized trial of use of GnRHA alone in premenopausal breast cancer cases showing a marked reduction in incidence of contralateral disease provides strong support for the hypothesis.