The insulinemia link between obesity and risk of increased breast cancer

Reference: Gunter MJ, Hoover DR, Herbert Y, Wassertheil-Smoller S, et al. Insulin, Insulin-Like Growth Factor-I, and the Risk of Breast Cancer in Postmenopausal Women. J Natl Cancer Inst. 2009;101(1):48-60.

Commentary by: Lise Alschuler, ND, FABNO

Design: Prospective case-cohort study

Participants: Nondiabetic postmenopausal women enrolled in the Women’s Health Initiative Observational Study (WHI-OS), a prospective cohort of 93,676 postmenopausal women aged 50-79 years recruited through 40 clinical centers across the U.S. between October 1993 and December 1998. The study group consisted of 835 subjects and the matched comparison group consisted of 816 subjects. Study Parameters Assessed: At study entry (baseline), participants provided completed questionnaires regarding demographic and behavioral factors, medical history and use of medications (including hormonal therapy). Each woman underwent a physical examination that included waist, hip, height and weight measurements. Each woman provided a blood sample after an overnight fast of at least 8 hours for measurements of insulin, glucose, estradiol, insulin-like growth factor (IGF-I), free IFG-I, and (insulin-like growth factor binding protein-3 (IGFBP-3). Cancer outcomes were assessed from annual self-administered questionnaires with all cancers confirmed with a review of pathology reports, discharge and consultant summaries.

Key Findings: Insulin levels and endogenous estradiol were positively associated with the risk of breast cancer (HR for highest vs lowest quartile of insulin level = 1.46, 95% CI = 1.00 to 2.13, Ptrend = 0.02; HR for highest vs lowest tertile of endogenous estradiol = 1.59, 95% CI = 1.00 to 2.55, Ptrend = .04). Controlling for multiple other risk factors for breast cancer including estradiol, insulin level was associated with breast cancer only among nonusers of hormone therapy (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI =1.30 to 4.41, Ptrend <0.01). These results support a strong positive association between the risk of breast cancer and fasting insulin levels in nondiabetic postmenopausal women who were not using hormone therapy. The breast cancer incidence was 2.4-fold greater among the women in the highest quartile compared with the lowest quartile of fasting insulin level after controlling for estradiol levels, body mass index (BMI), free IGF-I level and established breast cancer risk factors. The strong association between obesity and postmenopausal breast cancer was dependent upon the trend for insulin level, and to some extent, estradiol level, suggesting that insulin and estradiol explain the association between obesity and postmenopausal breast cancer in this study.

Practice Implications: This study lends good credence to the supposition that hyperinsulinemia is an independent risk factor for breast cancer and that high insulin levels may explain the link between obesity and increased breast cancer risk. With over 180,000 new cases of breast cancer diagnosed annually and over 40,000 deaths from breast cancer annually, a greater understanding of modifiable risk factors is essential. Obesity, now affecting over a third of all women over the age of 40 years (BMI >30kg/m2), has been clearly established as an independent risk factor for breast cancer. The working hypothesis underlying this association has been the higher level of endogenous hormones, namely estradiol, in obese women. However, hyperinsulinemia, itself the result of insulin resistance, is more common in obese women than normal weighted women. Insulin is an independent and potent cancer proliferant. Insulin has been shown to stimulate human breast cancer cells in in-vitro models. Insulin binds to insulin receptors on malignant cells, activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase pathways. Both of these signal transduction pathways result in cell proliferation and anti-apoptotic signaling.

Prior to this study, an emerging body of epidemiological evidence was softly suggestive of a link between hyperinsulinemia and breast cancer risk. Two small prospective studies (less than 200 subjects each) found no relationship between insulin levels and breast cancer risk [Mink, P et al. Am J Epidemiol, 2002 and Kaaks R, et al. Cancer Causes Control, 2002]. A third small (also under 200 subjects) prospective study [Muti P, et al, Cancer Epid Biomarkers Prev, 2002] found a positive relationship between hyperinsulinemia and postmenopausal breast cancers among nonusers of hormone therapy and with BMI >25kg/m2. Other studies have found a positive association with c-peptide, a marker of insulin secretion, and the risk of postmenopausal breast cancer. [Verheus M. et al. Int J Cancer, 2006 and Toniolo P et al. Int J Cancer, 2006 and Keinan-Boker L et al. Int J Cancer, 2003] However, c-peptide levels are not perfectly correlated with insulin levels. Two large prospective studies [Rinaldi S et al. Endocrin Relat Cancer, 2006 and Baglietto L et al. Cancer Epidemiol Biomarkers Prev, 2007] demonstrated positive associations between total IGF-I levels and the risk of breast cancer in women over 50 years of age. However these studies did not control for endogenous estradiol levels.

Limitations: Given the array of serologic factors tested, this study represents perhaps the most comprehensive prospective study to date on the relationship between insulin, obesity and estradiol levels on breast cancer risk in menopausal women. The observation of the strong association between the risk of breast cancer and fasting insulin levels, stronger even than that between endogenous estradiol levels, supports the idea of insulin resistance as a serious breast cancer risk factor. The clinical implications are significant. Controlling insulin resistance and reducing high insulin levels become primary breast cancer prevention strategies. This is particularly relevant in obese women. Treating insulin resistance while similar to treating obesity requires additional dietary, supplement and exercise interventions in order to be successful.

While compelling, this study does have limitations. Only baseline serological evaluations were done. Serial evaluations would have allowed more precise stratification of the associations. However, in other studies insulin, total IGF-I, free IGF-I, IGFBP-3 and estradiol have been shown to be stable over several years in postmenopausal women. Additionally, there may have been subclinical cases of breast cancer present in some of the women in the study. In an effort to minimize this effect, only women who developed breast cancer after at least 12 months of follow-up were included in the analysis. Finally, as an observational study, a cause-and-effect relationship between insulin, estradiol and breast cancer cannot be established.

About Dr. Lise Alschuler, ND, FABNO
Lise Alschuler, ND, FABNO, is the President of the American Association of Naturopathic Physicians. She is a naturopathic physician with board certification in naturopathic oncology and she practices at Naturopathic Specialists, LLC, in Scottsdale, Ariz. Dr. Alschuler earned her naturopathic medical doctorate from Bastyr University and received her BA with honors in anthropology from Brown University. She has authored many articles in professional and popular press publications and she is the co-author of the Definitive Guide to Cancer. For more information visit www.drlise.net.

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