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      Risk of dementia among postmenopausal breast cancer survivors treated with aromatase inhibitors versus tamoxifen: a cohort study using primary care data from the UK

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          Abstract

          Purpose

          Among a cohort of postmenopausal breast cancer survivors, we aimed to compare the risk of dementia associated with aromatase inhibitor (AI) therapy versus tamoxifen.

          Methods

          Using UK primary care electronic health records, we identified 14,214 postmenopausal breast cancer survivors (aged ≥ 54 years) with a first AI or tamoxifen prescription between January 2002 and December 2015 and no previous dementia diagnosis. Women were followed-up to identify incident cases of dementia. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to quantify the association between AI exposure (vs. tamoxifen) and dementia, adjusted for confounders.

          Results

          A total of 368 incident dementia cases was identified over 57,102 person-years of follow-up. The crude incidence rate of dementia was 7.46 per 1000 person-years (95% CI 6.43–8.65) among women starting endocrine treatment on an AI, and 6.32 per 1000 person-years (95% CI 5.34–7.47) among women starting on tamoxifen. After accounting for age differences and assessing other potential confounders, there was no evidence of a difference in dementia risk between exposure groups (HR for AI vs tamoxifen 1.04, 95% CI 0.83–1.03). There was no evidence of effect modification by age.

          Conclusion

          There was no evidence for a difference in dementia risk between AI and tamoxifen users among postmenopausal breast cancer survivors.

          Implications for Cancer Survivors

          Our findings suggest that there is no reason for concern about a difference in dementia risk with AI vs. tamoxifen, which is relevant to postmenopausal breast cancer patients recommended these treatments.

          Electronic supplementary material

          The online version of this article (10.1007/s11764-019-00782-w) contains supplementary material, which is available to authorized users.

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          Most cited references17

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          Is age at menopause increasing across Europe? Results on age at menopause and determinants from two population-based studies.

          To investigate the variability and determinants of menopause age in two European cohort studies, the European Respiratory Health Survey and the Swiss Air Pollution and Lung Disease in Adults Cohort. Age at menopause was estimated in 5,288 women, aged 30 to 60 years, randomly selected in nine European countries between 1998 and 2002. Determinants of natural and surgically induced menopause were investigated by Cox regression and heterogeneity by meta-analysis. Follicle-stimulating hormone and luteinizing hormone levels were assessed in a subsample. A quarter of the women were postmenopausal by age 50.8 years. Median age of natural menopause was 54 years. Hormone levels were within expected ranges for premenopausal and postmenopausal women. Surgically induced menopause was highly prevalent (22%-47%), associated with earlier timing of menopause. Determinants of earlier menopause were current smoking (hazard ratio [HR], 1.59; 95% CI, 1.27-1.98), body mass index greater than 30 kg/m (HR, 1.32; 95%, CI, 1.02-1.70), and low physical activity (HR, 1.37; 95%, CI, 1.12-1.67). The determinant for later menopause was multiparity (HR, 0.74; 95% CI, 0.62-0.89). Predictors were similar for naturally and surgically induced menopause. Oral contraceptive use yielded heterogeneous effects on timing of menopause. Later birth was associated with later menopause (HR, 0.934; 95% CI, 0.91-0.96). This evidence of a secular trend is heterogeneous across countries. Age at menopause varies across Europe, shifting toward higher ages. This secular trend seems paradoxical because several adult determinants, that is, overweight, smoking, sedentarity, and nulliparity, associated with early menopause are on the rise in Europe. The heterogeneity of the secular trend suggests additional country-specific factors not included in the study, such as improved childhood nutrition and health, that have an influence on reproductive aging.
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            Association between dementia and infectious disease: evidence from a case-control study.

            Inflammation plays a part in the etiology of dementia. Whether this is the primary pathogenesis, or a secondary reaction is unclear. We postulate that since systemic infection can provoke the enhanced synthesis of inflammatory mediators in the brain, such diseases may promote the onset of dementia. We carried out a nested case-control study using the General Practice Research Database. Cases were patients with incident dementia, and controls without such a diagnosis. Infectious episodes in the four years preceding diagnosis were counted using diagnostic codes, or prescription codes for anti-infective drugs. We considered age, sex, smoking, diabetes mellitus, and frequency of consultation as potential confounders. There were 9954 valid cases, and 9374 valid controls. Cases were on average older, more likely to be female, to smoke and to have diabetes, than the controls. There was an increased risk of diagnosis of dementia in those patients older than 84 with infections (OR for 2 or more infections compared with 0 or 1 = 1.4, 95% CI 1.2 to 1.7). Smoking and diabetes mellitus were also shown to markedly increase the risk of diagnosis of dementia. We have shown a positive association between episodes of infection and increased likelihood of diagnosis of dementia in the very elderly. Smoking and diabetes mellitus are associated with onset of dementia in the elderly. The evidence from this study may represent cause and effect, since there is a credible biologic explanation.
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              Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial.

              To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC). Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC. Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohen's d = .43) and executive functioning (P = .01; Cohen's d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohen's d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found. After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.
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                Author and article information

                Contributors
                susan.bromley@epimed.co.uk
                Journal
                J Cancer Surviv
                J Cancer Surviv
                Journal of Cancer Survivorship
                Springer US (New York )
                1932-2259
                1932-2267
                18 July 2019
                18 July 2019
                2019
                : 13
                : 4
                : 632-640
                Affiliations
                [1 ]GRID grid.8991.9, ISNI 0000 0004 0425 469X, Department of Non-communicable Disease Epidemiology, , London School of Hygiene and Tropical Medicine, ; London, UK
                [2 ]EpiMed Communications Ltd, Abingdon, UK
                [3 ]GRID grid.5072.0, ISNI 0000 0001 0304 893X, Royal Marsden NHS Foundation Trust, ; Sutton, Surrey UK
                Article
                782
                10.1007/s11764-019-00782-w
                6776493
                31321612
                e8ee3e3d-9bc1-4bc4-ae12-c99fa3f2845a
                © The Author(s) 2019, corrected publication 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 25 March 2019
                : 28 June 2019
                Funding
                Funded by: Sir Henry Dale Fellowship and Welcome Trust
                Award ID: 107731/Z/15/Z
                Award Recipient :
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Oncology & Radiotherapy
                breast cancer,dementia,aromatase inhibitors,clinical epidemiology
                Oncology & Radiotherapy
                breast cancer, dementia, aromatase inhibitors, clinical epidemiology

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