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Mechanisms underlying social inequality in post-menopausal breast cancer.

This thesis is based on studies conducted in the period 2010-2014 at Department of Public Health, University of Copenhagen and at Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York. The results are presented in three scientific papers and a synopsis. The main objective of the thesis was to determine mechanisms underlying social inequality (defined by educational level) in postmenopausal breast cancer (BC) by addressing mediating effects through hormone therapy (HT) use, BMI, lifestyle and reproductive factors. The results of previous studies suggest that the higher risk of postmenopausal BC among women of high socioeconomic position (SEP) may be explained by reproductive factors and health behaviors. Women of higher SEP generally have fewer children and give birth at older ages than women of low SEP, and these factors have been found to affect the risk of BC - probably through altered hormone levels. Adverse effects on BC risk have also been documented for modifiable health behaviors that may affect hormone levels, such as alcohol consumption, high BMI, physical inactivity, and HT use. Alcohol consumption and HT use are likewise more common among women of higher SEP. The analyses were based on the Social Inequality in Cancer (SIC) cohort and a subsample of the Women's Health Initiative Observational Study (WHI-OS). The SIC cohort was derived by pooling 6 individual studies from the Copenhagen area including 33,562 women (1,733 BC cases) aged 50-70 years at baseline. The subsample of WHI-OS consisted of two case-cohort studies with measurements of endogenous estradiol (N = 1,601) and insulin (N = 791). Assessment of mediation often relies on comparing multiplicative models with and without the potential mediator. Such approaches provide potentially biased results, because they do not account for mediator-outcome confounding, exposure-dependent mediator-outcome confounding, exposure-mediator interaction and interactions between mediators. In addition, these simple methods do not allow for a decomposition of the total effect into direct and indirect pathways. The counterfactual-based methods for quantifying mediating effects in this thesis were developed specifically for this project taking into account some of the shortcomings of previous methods. The results of this thesis showed that a high versus low educational level was associated with a higher risk of postmenopausal BC and that this effect was partly mediated through HT use, fertility patterns and alcohol consumption in the SIC data. Overall BMI did not mediate the education-BC relation. The results from the WHI-OS for the effect of alcohol consumption on BC risk did not - as hypothesized - seem to be mediated by endogenous estradiol levels; however, the observed higher risk of BC with higher levels of alcohol was restricted to estrogen-receptor positive cases, which indicates a role of estrogens in this relation. In the WHI-OS subsample of non-HT users, a higher risk of BC was found with higher levels of BMI; both estradiol and insulin mediated the effect of BMI on BC. The effect of HT use on BC interacted synergistically with alcohol consumption and this combination appeared to be associated with very high serum levels of estradiol in the SIC data. For BMI combined with HT use, a modest positive association was observed for non-HT users whereas markedly higher risks were observed across all BMI groups in current HT-users with a tendency towards a U-shaped relation. In conclusion, the social inequality in postmenopausal BC seems to be largely mediated by HT use, alcohol consumption and reproductive factors. Various sources of bias - especially misclassification of mediators, but also exposure-dependent confounding - raise some concern about the observed relations. Future studies should focus on life-course perspectives to identify certain windows of susceptibility and collect data on repeated measurements of mediators to enable health behavior trajectories over time. In addition, there is a need for further development of the methodology for the quantification of mediating effects to handle current shortcomings such as exposure-dependent confounding and the potential interactions between mediators.