We aim to measure sex hormones, indicators of resistance to insulin and indicators of inflammation in stored blood samples to see whether these markers predict women’s risk of breast cancer.
Mechanisms underlying the effect of body fatness on risk of postmenopausal breast cancer: a nested case-control with causal mediation analysis
There is convincing evidence that adult body fatness (“adiposity”) increases the risk of postmenopausal breast cancer. The mechanisms by which adiposity causes postmenopausal breast cancer are uncertain, but may be due to metabolic dysfunction and inflammation related to increased mass and activity of adipose tissue.
Adipose tissue of obese individuals secretes higher levels of pro-inflammatory cytokines and free fatty acids, and less anti-inflammatory cytokines, compared with lean women. It also disturbs the production of sex steroid hormones and cellular sensitivity to insulin. These factors can affect cell proliferation, apoptosis and angiogenesis, which are hallmarks of cancer.
Observational epidemiological studies can assess mechanistic pathways by measuring relevant biomarkers and performing modern causal mediation analyses. Effects for each pathway can be estimated simultaneously. To explain (mediate) the effect of adiposity on breast cancer risk, markers of the pathway must be associated with breast cancer and with adiposity.
Our first aim is to measure associations between markers of the adipose tissue-related pathways and risk of postmenopausal breast cancer. For the pathways that show associations, our second aim is to assess the proportion of the effect of adiposity on risk of postmenopausal breast cancer that is mediated by the pathways, singly and together.
Our objectives for this aim are to estimate the absolute risk of breast cancer associated with markers in each of the pathways, thereby also establishing the relative importance of each of the mechanistic pathways.
This research is set within the Melbourne Collaborative Cohort Study (MCCS), a cohort including 24,469 women recruited from 1990–94. A second wave of data collection (Wave2) took place from 2003–07. At both waves, height, weight and waist and hip circumferences were measured and a blood sample was collected. Participants were interviewed about diet, physical activity and other lifestyle factors and for women, reproductive history.
The proposed biomarker study is a nested case-control study of postmenopausal MCCS female participants who attended Wave2. Women will be eligible if at Wave2 they were postmenopausal, not using hormone therapy, not taking antihyperglycaemic medication, and had no history of cancer. Cases will be women with incident adenocarcinoma of the breast diagnosed after Wave2; we anticipate 515 cases. Using plasma samples collected at Wave2, we will measure biomarkers of each of the three pathways.
The associations between the biomarkers and breast cancer risk will be assessed using logistic regression. The indirect and direct effects will be estimated using causal mediation methods for multiple mediators, which permit estimation of indirect effects for each of the pathways simultaneously. These methods also permit identifying indirect effects for interrelated pathways.
Few epidemiological studies have attempted to determine what biological mechanisms mediate the association between adiposity and breast cancer and no study has estimated indirect effects for multiple mediators simultaneously. Indirect effects quantify the risk mediated through each pathway, thus estimating the potential public health benefit of intervening in those pathways.
Formal mediation analyses involving multiple mediators adds substantial weight to inferences of causality. Establishing that an exposure such as adiposity asserts its carcinogenic effect through specific biological pathways is strong evidence of a causal effect.
