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Randomized Controlled Trial
. 2024 Jun 30;16(13):2098.
doi: 10.3390/nu16132098.

A Mediation Analysis of Obesity and Adiponectin Association with Postmenopausal Breast Cancer Risk: A Nested Cohort Study in the International Breast Cancer Intervention Study II (IBIS-II) Prevention Trial

Debora Macis  1 , Federica Bellerba  2 , Valentina Aristarco  1 , Harriet Johansson  1 , Aliana Guerrieri-Gonzaga  1 , Matteo Lazzeroni  1 , Ivana Sestak  3 , Jack Cuzick  3 , Andrea DeCensi  3   4 , Bernardo Bonanni  1 , Sara Gandini  2
Affiliations
Randomized Controlled Trial

A Mediation Analysis of Obesity and Adiponectin Association with Postmenopausal Breast Cancer Risk: A Nested Cohort Study in the International Breast Cancer Intervention Study II (IBIS-II) Prevention Trial

Debora Macis et al. Nutrients. .

Abstract

Obesity is a risk factor for postmenopausal breast cancer (BC), and evidence suggests a role for adiponectin in the relationship between obesity and BC. We investigated whether adiponectin or other biomarkers mediate the effect of body mass index (BMI) on postmenopausal BC risk in a cohort study nested in the IBIS-II Prevention Trial. We measured adiponectin, leptin, IGF-I, IGFBP-1, high-sensitivity C-reactive protein, glycemia, insulin, HOMA-IR index, and SHBG in baseline and 12-month serum samples from 123 cases and 302 matched controls in the placebo arm of the IBIS-II Prevention trial. We conducted the main mediation analysis considering baseline BMI as an exposure and the 12-month adiponectin increase as a mediator after adjustment for the Tyrer-Cuzick score and the lipid-lowering medications/supplements use. In the multivariable Cox model, both the 12-month adiponectin increase (HR, 0.60; 95%CI, 0.36-1.00) and BMI were associated with BC risk (HR, 1.05; 95%CI, 1.00-1.09), with a 40% reduction in women with a 12-month increase in adiponectin. A significantly higher cumulative hazard of BC events was observed in obese women (BMI > 30) with decreased adiponectin (p = 0.0087). No mediating effect of the adiponectin increase on the total effect of BMI on BC risk was observed (natural indirect effect: HR, 1.00; 95%CI, 0.98-1.02). Raising adiponectin levels might be an attractive target for postmenopausal BC prevention.

Keywords: BMI; adiponectin; breast cancer prevention; breast cancer risk; mediation analysis.

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Conflict of interest statement

J.C. received funding for the IBIS-II study from Cancer Research UK and AstraZeneca. The funders had no role in the study design, collection, analyses, or interpretation of data, writing of the manuscript, or decision to publish the results. The other authors have no relevant financial or nonfinancial interests to disclose.

Figures

Figure 1
Figure 1
Cumulative incidence curves of breast cancer according to the increase in adiponectin between baseline and 12 months (a) and quartiles of adiponectin change between baseline and 12 months (b). p-value: log-rank test.
Figure 2
Figure 2
Breast cancer in high-risk postmenopausal women: the role of body mass index (BMI) and adiponectin in IBIS-II Prevention cohort study. Main directed acyclic graph (DAG) for mediation analysis (a). The results from single-mediator mediation analysis (b) and from the Cox proportional hazards model including baseline BMI and adiponectin increase as independent factors (c). The blue arrows indicate the effect of confounders, while the red arrows indicate the pathway through the mediator.
Figure 3
Figure 3
Cumulative incidence curves of breast cancer according to the increase in adiponectin between baseline and 12 months and obesity status (BMI > 30) at baseline. p-value: log-rank test.
See this image and copyright information in PMC

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