Marit Waaseth

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.

Hormone replacement therapy use and plasma levels of sex hormones in the Norwegian Women and Cancer Postgenome Cohort – a cross-sectional analysis

BackgroundHormone replacement therapy use (HRT) is associated with increased breast cancer risk. Our primary objective was to explore hormone levels in plasma according to HRT use, body mass index (BMI) and menopausal status. A secondary objective was to validate self-reported questionnaire information on menstruation and HRT use in the Norwegian Women and Cancer postgenome cohort (NOWAC).MethodsWe conducted a cross-sectional study of sex hormone levels among 445 women aged 48–62 who answered an eight-page questionnaire in 2004 and agreed to donate a blood sample. The samples were drawn at the womens local general physicians offices in the spring of 2005 and sent by mail to NOWAC, Tromsø, together with a two-page questionnaire. Plasma levels of sex hormones and Sex Hormone Binding Globulin (SHBG) were measured by immunometry. 20 samples were excluded, leaving 425 hormone measurements.Results20% of postmenopausal women were HRT users. The plasma levels of estradiol (E2) increased with an increased E2 dose, and use of systemic E2-containing HRT suppressed the level of Follicle Stimulating Hormone (FSH). SHBG levels increased mainly among users of oral E2 preparations. Vaginal E2 application did not influence hormone levels. There was no difference in BMI between HRT users and non-users. Increased BMI was associated with increased E2 and decreased FSH and SHBG levels among non-users. Menopausal status defined by the two-page questionnaire showed 92% sensitivity (95% CI 89–96%) and 73% specificity (95% CI 64–82%), while the eight-page questionnaire showed 88% sensitivity (95% CI 84–92%) and 87% specificity (95% CI 80–94%). Current HRT use showed 100% specificity and 88% of the HRT-users had plasma E2 levels above the 95% CI of non-users.ConclusionUsers of systemic E2-containing HRT preparations have plasma E2 and FSH levels comparable to premenopausal women. BMI has an influence on hormone levels among non-users. NOWAC questionnaires provide valid information on current HRT use and menopausal status among Norwegian women who are between 48 and 62 years old.

Dietary intakes of retinol, beta-carotene, vitamin D and vitamin E in the European Prospective Investigation into Cancer and Nutrition cohort

Objectives:To describe the intake of the fat-soluble nutrients retinol, β-carotene, vitamin E and vitamin D and their food sources among 27 redefined centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Methods:Between 1995 and 2000, 36 034 subjects (age range: 35–74 years) completed a single standardized 24-h dietary recall using a computerized interview software program (EPIC-SOFT). Intakes of the fat-soluble nutrients were estimated using the standardized EPIC Nutrient Database.Results:For all the nutrients, in most centres, men had a higher level of intake than did women, even after adjustments for total energy intake and anthropometric confounders. Distinct regional gradients from northern to southern European countries were observed for all nutrients. The level intake of β-carotene and vitamin E also showed some differences by level of education, smoking status and physical activity. No meaningful differences in the nutrient intake were observed by age range.Conclusions:These results show differences by study centre, gender, age and various lifestyle variables in the intake of retinol, β-carotene, vitamin E and vitamin D between 10 European countries.

Breast cancer mortality in Norway after the introduction of mammography screening

An organized mammography screening program was gradually implemented in Norway during the period 1996–2004. Norwegian authorities have initiated an evaluation of the program. Our study focused on breast cancer mortality. Using Poisson regression, we compared the change in breast cancer mortality from before to during screening in four counties starting the program early controlling for change in breast cancer mortality during the same time in counties starting the program late. A follow‐up model included death in all breast cancers diagnosed during the follow‐up period. An evaluation model included only breast cancers diagnosed in ages where screening was offered. The study group had been invited for screening one to three times and followed for on average of 5.9 years. In the follow‐up model, 314 breast cancer deaths were observed in the study group, and 523, 404 and 638, respectively, in the four control groups. The ratio between the changes in breast cancer mortality between early and late starting counties was 0.93 (95% confidence interval [CI] 0.77–1.12). In the evaluation model, this ratio was 0.89 (95% CI: 0.71–1.12). In Norway, where 40% of women used regular mammography prior to the program, the implementation of the organized mammography screening program was associated with a statistically nonsignificant decrease in breast cancer mortality of around 11%.

Mammography activity in Norway 1983 to 2008.

Abstract Background. In Norway, an organized screening mammography program, the Norwegian Breast Cancer Screening Program (NBCSP) started in four counties in 1996 and became nationwide in 2004. We collected data on pre-program screening activity, and in view of this activity we evaluated the potential impact of the program on breast cancer mortality in Norway. Methods. We searched data sources on mammography activity in Norway. Three data sources reported on examination activity, and two on self-reported examinations. We aimed at calculating annual number of women examined by mammography from 1983 to 2008, and coverage rate in program and non-program Norwegian counties. Results. The annual number of women examined increased from 5000 in 1983 to 110 000 in 1993 to reach its maximum of 131 000 in 2002, excluding program examinations. The annual number of women examined in the organized program increased from 1996 to a steady state about 190 000 in 2004. Prior to start of the organized program, 40% of women in target age groups reported to have had mammography examination. During the years 1996–2002, 64% of first participants in the organized program reported to have been examined previously. Assuming that the Norwegian program would in absence of prior screening have decreased breast cancer mortality by 25%, and that the activity in- and outside the organized program were equally effective, the measured effect of the organized program would under actual circumstances be a reduction of 11%. Conclusion. The example of Norway illustrates that although monitoring of screening outcome is highly warranted, this may be seriously jeopardized if use of mammography examinations was widespread prior to implementation of an organized program.

Dietary intake of the water-soluble vitamins B1, B2, B6, B12 and C in 10 countries in the European Prospective Investigation into Cancer and Nutrition

Objectives:To describe the intake of vitamins thiamine (B1), riboflavin (B2), B6 (pyridoxine), B12 (cobalamine) and C (ascorbic acid) and their food sources among 27 centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Methods:Between 1995 and 2000, 36 034 persons aged between 35 and 74 years were administered a standardized 24-h dietary recall using a computerized interview software programme (EPIC-SOFT). Intakes of the four B vitamins and vitamin C were estimated using the standardized EPIC Nutrient Database (ENDB). Mean intakes were adjusted for age and weighted by season and day of recall.Results:Intake of B vitamins did not vary considerably between centres, except in the UK health-conscious cohort, in which substantially higher intakes of thiamine and lower intakes of vitamin B12 were reported compared with other centres. Overall, meat was the most important contributor to the B vitamins in all centres except in the UK health-conscious group. Vitamin C showed a clear geographical gradient, with higher intakes in the southern centres as compared with the northern ones; this was more pronounced in men than in women. Vegetables and fruits were major contributors to vitamin C in all centres, but juices and potatoes were also important sources in the northern centres.Conclusions:This study showed no major differences across centres in the mean intakes of B vitamins (thiamine, riboflavin, B6, B12), whereas a tendency towards a north–south gradient was observed for vitamin C.

Patterns of hormone therapy use in the Norwegian Women and Cancer study (NOWAC) 1996–2005

OBJECTIVES To examine patterns of use of hormone therapy (HT), including duration of use, in North Norway in 1996, 2002 and 2005. METHODS Within the NOWAC cohort we conducted a cross-sectional comparison of questionnaire data among women aged 48-62 years in 1996 (N=8822), 2002 (N=6262) and 2005 (N=4830). Response rates for first time respondents: 58% in 1996 and 66% in 2005. The 2002 participants were second time respondents including 4814 of the 1996 participants. The partial dependence was managed statistically using generalized estimating equations (GEE) and linear mixed models. RESULTS Use of HT increased from 1996 (30.5% current, 43.3% ever) to 2002 (38.2% current, 59.3% ever), and decreased toward 2005 (14.7% current, 35.8% ever). High-dose combinations were still the most used HT products in 2005, although low-dose estrogen products and tibolone had gained market shares. Current use of HT among pre-/perimenopausal women was 9.4% in 1996, 13.2% in 2002 and 0.6% in 2005. Mean duration of current HT use was 3.7 years in 1996, 5.8 years in 2002 and 6.3 years in 2005 (p<0.05). In 2005 current HT use was not associated with formerly known predictors, except age and menopausal status. CONCLUSIONS Succeeding high levels of HT use in 2002, the prevalence in 2005 is below that in 1996, in accordance with national policies. In 2005 climacteric complaints seems to be the only predictor of HT use. Extensive long-term use in 2005 raises questions regarding compliance with treatment recommendations.

Sex hormones and gene expression signatures in peripheral blood from postmenopausal women - the NOWAC postgenome study

BackgroundPostmenopausal hormone therapy (HT) influences endogenous hormone concentrations and increases the risk of breast cancer. Gene expression profiling may reveal the mechanisms behind this relationship.Our objective was to explore potential associations between sex hormones and gene expression in whole blood from a population-based, random sample of postmenopausal womenMethodsGene expression, as measured by the Applied Biosystems microarray platform, was compared between hormone therapy (HT) users and non-users and between high and low hormone plasma concentrations using both gene-wise analysis and gene set analysis. Gene sets found to be associated with HT use were further analysed for enrichment in functional clusters and network predictions. The gene expression matrix included 285 samples and 16185 probes and was adjusted for significant technical variables.ResultsGene-wise analysis revealed several genes significantly associated with different types of HT use. The functional cluster analyses provided limited information on these genes. Gene set analysis revealed 22 gene sets that were enriched between high and low estradiol concentration (HT-users excluded). Among these were seven oestrogen related gene sets, including our gene list associated with systemic estradiol use, which thereby represents a novel oestrogen signature. Seven gene sets were related to immune response. Among the 15 gene sets enriched for progesterone, 11 overlapped with estradiol. No significant gene expression patterns were found for testosterone, follicle stimulating hormone (FSH) or sex hormone binding globulin (SHBG).ConclusionsDistinct gene expression patterns associated with sex hormones are detectable in a random group of postmenopausal women, as demonstrated by the finding of a novel oestrogen signature.

Plasma Fatty Acid Ratios Affect Blood Gene Expression Profiles - A Cross-Sectional Study of the Norwegian Women and Cancer Post-Genome Cohort

High blood concentrations of n-6 fatty acids (FAs) relative to n-3 FAs may lead to a “physiological switch” towards permanent low-grade inflammation, potentially influencing the onset of cardiovascular and inflammatory diseases, as well as cancer. To explore the potential effects of FA ratios prior to disease onset, we measured blood gene expression profiles and plasma FA ratios (linoleic acid/alpha-linolenic acid, LA/ALA; arachidonic acid/eicosapentaenoic acid, AA/EPA; and total n-6/n-3) in a cross-section of middle-aged Norwegian women (n = 227). After arranging samples from the highest values to the lowest for all three FA ratios (LA/ALA, AA/EPA and total n-6/n-3), the highest and lowest deciles of samples were compared. Differences in gene expression profiles were assessed by single-gene and pathway-level analyses. The LA/ALA ratio had the largest impact on gene expression profiles, with 135 differentially expressed genes, followed by the total n-6/n-3 ratio (125 genes) and the AA/EPA ratio (72 genes). All FA ratios were associated with genes related to immune processes, with a tendency for increased pro-inflammatory signaling in the highest FA ratio deciles. Lipid metabolism related to peroxisome proliferator-activated receptor γ (PPARγ) signaling was modified, with possible implications for foam cell formation and development of cardiovascular diseases. We identified higher expression levels of several autophagy marker genes, mainly in the lowest LA/ALA decile. This finding may point to the regulation of autophagy as a novel aspect of FA biology which warrants further study. Lastly, all FA ratios were associated with gene sets that included targets of specific microRNAs, and gene sets containing common promoter motifs that did not match any known transcription factors. We conclude that plasma FA ratios are associated with differences in blood gene expression profiles in this free-living population, and that affected genes and pathways may influence the onset and progression of disease.

Prolactin Determinants in Healthy Women: A Large Cross-Sectional Study within the EPIC Cohort

Background: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear. Methods: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case–control study within the EPIC cohort. Results: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = <0.0001). Furthermore, prolactin levels were significantly higher among users of combined estrogen–progestin hormone therapy compared with users of estrogen-alone hormone therapy (6.66 vs. 5.90 ng/mL; Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, ≥3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers. Conclusions: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women. Impact: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin. Cancer Epidemiol Biomarkers Prev; 23(11); 2532–42. ©2014 AACR.