TY - JOUR
T1 - Quantifying mediating effects of endogenous estrogen and insulin in the relation between obesity, alcohol consumption, and breast cancer
AU - Hvidtfeldt, Ulla A.
AU - Gunter, Marc J.
AU - Lange, Theis
AU - Chlebowski, Rowan T.
AU - Lane, Dorothy
AU - Farhat, Ghada N.
AU - Freiberg, Matthew S.
AU - Keiding, Niels
AU - Lee, Jennifer S.
AU - Prentice, Ross
AU - Tjønneland, Anne
AU - Vitolins, Mara Z.
AU - Wassertheil-Smoller, Silvia
AU - Strickler, Howard D.
AU - Rod, Naja H.
PY - 2012/7
Y1 - 2012/7
N2 - Background: Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting. Methods: We combined data from two case-cohort studies based in the Women's Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model. Results: A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2-76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9-68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6-273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8-161.1) for BMI when restricted to estrogen receptor positive (ER+) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8-284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER+ breast cancers. Conclusions: The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin. Impact: The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.
AB - Background: Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting. Methods: We combined data from two case-cohort studies based in the Women's Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model. Results: A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2-76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9-68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6-273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8-161.1) for BMI when restricted to estrogen receptor positive (ER+) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8-284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER+ breast cancers. Conclusions: The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin. Impact: The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.
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U2 - 10.1158/1055-9965.EPI-12-0310
DO - 10.1158/1055-9965.EPI-12-0310
M3 - Article
C2 - 22564867
AN - SCOPUS:84863585013
SN - 1055-9965
VL - 21
SP - 1203
EP - 1212
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 7
ER -