December 30, 2008 — There is a "strong positive association" between fasting insulin levels and the risk for breast cancer among postmenopausal women, according to a new analysis of 1651 women who were both hormone-replacement-therapy users and nonusers in the Women’s Health Initiative Observational Study.
The new study appears in the January 7 issue of the Journal of the National Cancer Institute.
Women with the highest insulin levels had a nearly 1.5-fold higher risk of developing breast cancer than women with the lowest insulin levels, when the women were divided into insulin-level quartiles, according to lead author Marc Gunther, PhD, assistant professor of epidemiology and population health at the Albert Einstein College of Medicine, in the Bronx, New York.
Among a subset of women who did not use hormone-replacement therapy, those individuals with the highest insulin levels had a nearly 2.5-fold increased risk of developing breast cancer compared with those with the lowest levels, Dr. Gunther told Medscape Oncology.
"Everyone has insulin. We see an incremental increase in breast cancer risk as insulin levels go up," said coauthor Howard Strickler, MD, who also participated in an interview with Medscape Oncology and is a professor in the same department at Albert Einstein.
Interventions aimed at lowering fasting insulin levels may reduce the risk for breast cancer in postmenopausal women, note the authors.
Dr. Stringer believes that research in this area is poised to take off. "Clinicians can look forward to fast progress in identifying methods for mitigating the insulin pathways related to breast cancer," he said.
The new study also supports laboratory findings in which insulin has been shown to stimulate cell proliferation in breast cancer cell lines, suggested Dr. Strickler. "There is now a confluence of data between lab scientists showing biologic plausibility and molecular epidemiologists showing the existence of associations in human beings," he commented.
First Study to Control for Estrogen Levels
Previous epidemiological studies into the association between circulating insulin levels and the risk for breast cancer have had inconsistent findings. Two studies that included women who were using hormone-replacement therapy reported no association. A third study, which was conducted among nonusers of hormone-replacement therapy, found a positive association between hyperinsulinemia and postmenopausal breast cancer, but only among women who were overweight or obese.
Notably, the new study is the first to prospectively examine the role of insulin in breast cancer while controlling for estrogen levels. "It is widely hypothesized that the association between obesity and postmenopausal breast cancer partly reflects the higher-than-average circulating estrogen levels present in obese women," write the authors.
In this study, Drs. Gunter, Strickler, and colleagues examined the association between incident breast cancer and the baseline serologic factors, including fasting insulin, insulinlike growth factor-I (IGF-I), and endogenous estradiol levels, as well as body-mass index (BMI). They compared these factors in 835 women enrolled in the Women's Health Initiative Observational Study who developed breast cancer and a randomly selected sample of 816 women in the study who did not develop breast cancer.
Fasting levels of insulin and endogenous estradiol were associated with a statistically significantly increased risk for incident breast cancer (hazard ratio [HR] for the highest vs lowest quartile of insulin, 1.46; 95% CI, 1.00 – 2.13; P = .02; HR for highest vs lowest quartile of endogenous estradiol, 1.59; 95% CI, 1.00 – 2.55; P = .04). The hazard ratios were adjusted for a wide range of breast cancer risk factors, including age, onset of menopause, smoking, physical activity, and use of contraceptives and nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, BMI was not associated with an increased risk for breast cancer in this model.
The new study also separately looked at a subset of women who did not use hormone-replacement therapy. This was important because the therapy "makes the analysis of insulin complicated due to the way it impacts the hormonal milieu," said Dr. Strickler.
Among these women, fasting insulin level was associated with an even greater statistically significantly increased risk for incident breast cancer among nonusers of hormone-replacement therapy (HR for highest vs lowest quartile of insulin, 2.48; 95% CI, 1.38 – 4.47; P < .001).
In addition, among nonusers of hormone-replacement therapy, high BMI was associated with an increased risk for breast cancer in multivariable models that adjusted for breast cancer risk factors (HR for BMI ≥ 30 kg/m2 vs 18.5 to <>2, 2.12; 95% CI, 1.26 – 3.58; P = .003). When estradiol levels were incorporated into these models, there was only a "modest" 10% reduction in the BMI–breast cancer association (HR for BMI ≥ 30 kg/ m2 vs 18.5 to <>2, 1.91; 95% CI, 1.11 – 3.27; P = .02). However, adjustment for insulin levels attenuated this association by 30% (HR for BMI ≥ 30 kg/m2 vs 18.5 to <>2, 1.50; 95% CI, 0.80 – 2.83; P = .40).
"Insulin explains much of the relationship here [between the risk for breast cancer and BMI]," commented Dr. Gunter.
There was no association between fasting insulin level and incident breast cancer among women who used estrogen and progestin (HR for highest vs, lowest quartile of insulin, 1.15; 95% CI, 0.34 – 3.84; P = .40) and a possible inverse association among those who used estrogen alone (HR for highest vs lowest quartile of insulin, 0.33; 95% CI, 0.12 – 0.92; P = .31).
"Our data indicate that hyperinsulinemia and high endogenous estradiol levels are independent risk factors for breast cancer and largely explain the relationship between obesity and the risk for breast cancer in postmenopausal women," the authors conclude.
The insulin pathway is "obviously important" in part because the related problem of obesity is so common, noted Dr. Strickler. "The doubling of risk related to a common exposure [high levels of insulin often due to obesity] means that this pathway can explain a substantial portion of breast cancer in postmenopausal women," he said.
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