Original Article
Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status Ulla Arthur Hvidtfeldt,a Anne Tjønneland,b Niels Keiding,c Theis Lange,c Ingelise Andersen,a Thorkild I. A. Sørensen,d Eva Prescott,e Åse Marie Hansen,a,f Morten Grønbæk,g Stig Egil Bojesen,h Finn Diderichsen,a and Naja Hulvej Rod a Background: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of “high-risk” users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. Methods: Two Danish prospective cohorts were pooled, including 30,789 women ages 50+ years (study period 1981 to 2009). Information on risk factors was obtained in baseline questionnaires. We performed analyses using the Aalen additive hazards model. Serum estradiol and testosterone measurements were obtained in a subsample of approximately 1000 women. Results: During 392,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone
Submitted 2 July 2014; accepted 30 December 2014. a Social Medicine Section, Department of Public Health, University of Copenhagen, Denmark; bDanish Cancer Society Research Centre, Copenhagen, Denmark; cSection of Biostatistics, Department of Public Health, University of Copenhagen, Denmark; dDepartment of Public Health, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Frederiksberg, Denmark; eDepartment of Cardiology and The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark; fNational Research Centre for the Working Environment, Copenhagen, Denmark; gNational Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; and hDepartment of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. Supported by the Danish Cancer Society, Commission of Social Inequality in Cancer (grant no. SU08004). Disclosure: The authors report no conflicts of interest. Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author. Correspondence: Ulla Arthur Hvidtfeldt, Social Medicine Section, Department of Public Health, University of Copenhagen, CSS, Oster Farimagsgade 5, DK-1014 Copenhagen, Denmark. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1044-3983/15/2603-0353 DOI: 10.1097/EDE.0000000000000261
Epidemiology • Volume 26, Number 3, May 2015
therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. Conclusion: These analyses suggest an increased risk of breast cancer associated with hormone therapy use—a risk that may be particularly strong among women consuming alcohol. (Epidemiology 2015;26: 353–361)
F
ollowing the publication of the Women’s Health Initiative (WHI) report,1 as well as several observational studies,2 in which postmenopausal hormone therapy use was found to increase the risk of breast cancer and coronary heart disease, the general use of hormone therapy has declined worldwide.3 Many women, however, suffer from menopausal symptoms, and hormone therapy is effective for the relief of these symptoms, in addition to osteoporosis prevention. It, therefore, becomes relevant to investigate whether other risk factors modify the effect of hormone therapy use on breast cancer risk. Such findings are important to identify subgroups of patients at particularly high risk—information that can be used to guide hormone therapy prescription practices in clinical settings. Although the individual effects of lifestyle factors on postmenopausal breast cancer have been established in multiple studies,4,5 their combined effects—and the hormonal pathways underlying them—are not understood in depth. Obesity is expected to affect the risk through conversion of androgens into estrogens in adipose tissue, leading to increased estrogen levels.6 An independent role of testosterone has also been suggested.7 In addition, hyperinsulinemia, which is closely www.epidem.com | 353
Hvidtfeldt et al
related to obesity, lowers the levels of sex-hormone binding globulin, leading to increased levels of estradiol and testosterone.7 Likewise, alcohol consumption has been associated with increased serum sex-hormone levels.8 Because hormone therapy use, alcohol consumption, and obesity may take effect through similar hormonal pathways,9–11 biological interactions between these factors in the pathogenesis of postmenopausal breast cancer are possible and worth investigating further. Although several studies have addressed the combined effects of high body mass index (BMI) and hormone therapy use on breast cancer risk,2,12–17 the issue remains controversial. Previous studies have suggested that, among never-users of hormone therapy, the risk of postmenopausal breast cancer increases with increasing BMI.12–14 In contrast, others have shown that the risk among users of hormone therapy may be greater in women with low relative weight compared with that in women with high relative weight.2,12,15–17 However, in a joint analysis of BMI and hormone therapy use from the large European Investigation into Cancer and Nutrition study, a more than two-fold higher risk was observed across all BMIstrata in current users of hormone therapy compared with normal-weight never-users of hormone therapy,12 indicating that high BMI has no direct effect on breast cancer risk among hormone therapy users. In addition, some evidence suggests that alcohol may interact with hormone therapy use, leading to a markedly higher risk among women combining the two.18–20 For instance, a prospective study found a more than 4 times higher risk of breast cancer among women with a combined high alcohol intake and hormone therapy use, which was more than expected from the combination of the individual effects.18 Another study found similar interactions, but restricted to estrogen-receptor-positive and progesterone-receptor-positive (ER+/PR+) breast cancers.19 However, most previous studies have had insufficient statistical power to address the alcohol– hormone therapy interactions.21–25 An overview of previous studies on interactions between these factors is provided in eAppendix 4 (http://links.lww.com/EDE/A882). In most of the previous literature, interactions have been evaluated as ratios of relative effects, but from a public health perspective and especially for individual/clinical decisionmaking, differences in absolute risks across groups are more informative.26 Absolute risk measures can, unlike relative measures, be directly compared across subgroups, and therefore, provide a more relevant effect measure when addressing the risk associated with hormone therapy use according to other risk factor subgroups. Another feature distinguishing this study from most previous studies on this topic is the focus on joint effects. This study examines combined effects of hormone therapy use, alcohol consumption, and high BMI on hormone-receptor-defined subtypes of postmenopausal breast cancer in a large pooled cohort; the joint reference category allows us to compare each combination of BMI/hormone therapy and alcohol/hormone therapy according to the same 354 | www.epidem.com
Epidemiology • Volume 26, Number 3, May 2015
baseline hazard. In addition, we had a unique opportunity to directly test our underlying hypothesis of a biological pathway through sex-steroid hormones by addressing the association between hormone therapy use, alcohol consumption, and BMI-strata combined and serum levels of estradiol and testosterone in a subset of the population.
METHODS The study was based on the Social Inequality in Cancer database derived by pooling several large cohorts as described previously.27 This analysis included data from the 2 cohorts with information on current hormone therapy use: The Diet, Cancer, and Health Study28 and The Copenhagen City Heart Study.29 Information from self-administered questionnaires on health status, health behaviors, and reproductive factors at baseline was harmonized and linked to sociodemographic information from Statistics Denmark from 1980 onward. We included postmenopausal women defined as women ages 50+ years at baseline. We excluded women with a history of cancer (other than nonmelanoma skin cancer) and women born before 1921 because the central registries do not contain information on education for these birth cohorts. After exclusion of women with missing information on current hormone therapy use (n = 1,334), BMI (n = 33), alcohol consumption (n = 26), and covariates (n = 473), the total study included 30,789 women. In both studies, current hormone therapy use (yes/no) was self-reported. Alcohol was assessed as consumption of beer, wine, and spirits (“never/almost never,” “monthly,” “weekly,” and “daily”) and average number of drinks per week within these categories. We categorized the total intake in groups of
Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status Ulla Arthur Hvidtfeldt,a Anne Tjønneland,b Niels Keiding,c Theis Lange,c Ingelise Andersen,a Thorkild I. A. Sørensen,d Eva Prescott,e Åse Marie Hansen,a,f Morten Grønbæk,g Stig Egil Bojesen,h Finn Diderichsen,a and Naja Hulvej Rod a Background: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of “high-risk” users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. Methods: Two Danish prospective cohorts were pooled, including 30,789 women ages 50+ years (study period 1981 to 2009). Information on risk factors was obtained in baseline questionnaires. We performed analyses using the Aalen additive hazards model. Serum estradiol and testosterone measurements were obtained in a subsample of approximately 1000 women. Results: During 392,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone
Submitted 2 July 2014; accepted 30 December 2014. a Social Medicine Section, Department of Public Health, University of Copenhagen, Denmark; bDanish Cancer Society Research Centre, Copenhagen, Denmark; cSection of Biostatistics, Department of Public Health, University of Copenhagen, Denmark; dDepartment of Public Health, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Frederiksberg, Denmark; eDepartment of Cardiology and The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark; fNational Research Centre for the Working Environment, Copenhagen, Denmark; gNational Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; and hDepartment of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. Supported by the Danish Cancer Society, Commission of Social Inequality in Cancer (grant no. SU08004). Disclosure: The authors report no conflicts of interest. Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author. Correspondence: Ulla Arthur Hvidtfeldt, Social Medicine Section, Department of Public Health, University of Copenhagen, CSS, Oster Farimagsgade 5, DK-1014 Copenhagen, Denmark. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1044-3983/15/2603-0353 DOI: 10.1097/EDE.0000000000000261
Epidemiology • Volume 26, Number 3, May 2015
therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. Conclusion: These analyses suggest an increased risk of breast cancer associated with hormone therapy use—a risk that may be particularly strong among women consuming alcohol. (Epidemiology 2015;26: 353–361)
F
ollowing the publication of the Women’s Health Initiative (WHI) report,1 as well as several observational studies,2 in which postmenopausal hormone therapy use was found to increase the risk of breast cancer and coronary heart disease, the general use of hormone therapy has declined worldwide.3 Many women, however, suffer from menopausal symptoms, and hormone therapy is effective for the relief of these symptoms, in addition to osteoporosis prevention. It, therefore, becomes relevant to investigate whether other risk factors modify the effect of hormone therapy use on breast cancer risk. Such findings are important to identify subgroups of patients at particularly high risk—information that can be used to guide hormone therapy prescription practices in clinical settings. Although the individual effects of lifestyle factors on postmenopausal breast cancer have been established in multiple studies,4,5 their combined effects—and the hormonal pathways underlying them—are not understood in depth. Obesity is expected to affect the risk through conversion of androgens into estrogens in adipose tissue, leading to increased estrogen levels.6 An independent role of testosterone has also been suggested.7 In addition, hyperinsulinemia, which is closely www.epidem.com | 353
Hvidtfeldt et al
related to obesity, lowers the levels of sex-hormone binding globulin, leading to increased levels of estradiol and testosterone.7 Likewise, alcohol consumption has been associated with increased serum sex-hormone levels.8 Because hormone therapy use, alcohol consumption, and obesity may take effect through similar hormonal pathways,9–11 biological interactions between these factors in the pathogenesis of postmenopausal breast cancer are possible and worth investigating further. Although several studies have addressed the combined effects of high body mass index (BMI) and hormone therapy use on breast cancer risk,2,12–17 the issue remains controversial. Previous studies have suggested that, among never-users of hormone therapy, the risk of postmenopausal breast cancer increases with increasing BMI.12–14 In contrast, others have shown that the risk among users of hormone therapy may be greater in women with low relative weight compared with that in women with high relative weight.2,12,15–17 However, in a joint analysis of BMI and hormone therapy use from the large European Investigation into Cancer and Nutrition study, a more than two-fold higher risk was observed across all BMIstrata in current users of hormone therapy compared with normal-weight never-users of hormone therapy,12 indicating that high BMI has no direct effect on breast cancer risk among hormone therapy users. In addition, some evidence suggests that alcohol may interact with hormone therapy use, leading to a markedly higher risk among women combining the two.18–20 For instance, a prospective study found a more than 4 times higher risk of breast cancer among women with a combined high alcohol intake and hormone therapy use, which was more than expected from the combination of the individual effects.18 Another study found similar interactions, but restricted to estrogen-receptor-positive and progesterone-receptor-positive (ER+/PR+) breast cancers.19 However, most previous studies have had insufficient statistical power to address the alcohol– hormone therapy interactions.21–25 An overview of previous studies on interactions between these factors is provided in eAppendix 4 (http://links.lww.com/EDE/A882). In most of the previous literature, interactions have been evaluated as ratios of relative effects, but from a public health perspective and especially for individual/clinical decisionmaking, differences in absolute risks across groups are more informative.26 Absolute risk measures can, unlike relative measures, be directly compared across subgroups, and therefore, provide a more relevant effect measure when addressing the risk associated with hormone therapy use according to other risk factor subgroups. Another feature distinguishing this study from most previous studies on this topic is the focus on joint effects. This study examines combined effects of hormone therapy use, alcohol consumption, and high BMI on hormone-receptor-defined subtypes of postmenopausal breast cancer in a large pooled cohort; the joint reference category allows us to compare each combination of BMI/hormone therapy and alcohol/hormone therapy according to the same 354 | www.epidem.com
Epidemiology • Volume 26, Number 3, May 2015
baseline hazard. In addition, we had a unique opportunity to directly test our underlying hypothesis of a biological pathway through sex-steroid hormones by addressing the association between hormone therapy use, alcohol consumption, and BMI-strata combined and serum levels of estradiol and testosterone in a subset of the population.
METHODS The study was based on the Social Inequality in Cancer database derived by pooling several large cohorts as described previously.27 This analysis included data from the 2 cohorts with information on current hormone therapy use: The Diet, Cancer, and Health Study28 and The Copenhagen City Heart Study.29 Information from self-administered questionnaires on health status, health behaviors, and reproductive factors at baseline was harmonized and linked to sociodemographic information from Statistics Denmark from 1980 onward. We included postmenopausal women defined as women ages 50+ years at baseline. We excluded women with a history of cancer (other than nonmelanoma skin cancer) and women born before 1921 because the central registries do not contain information on education for these birth cohorts. After exclusion of women with missing information on current hormone therapy use (n = 1,334), BMI (n = 33), alcohol consumption (n = 26), and covariates (n = 473), the total study included 30,789 women. In both studies, current hormone therapy use (yes/no) was self-reported. Alcohol was assessed as consumption of beer, wine, and spirits (“never/almost never,” “monthly,” “weekly,” and “daily”) and average number of drinks per week within these categories. We categorized the total intake in groups of
