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Hyperinsulinemia a Risk Factor for Breast Cancer in Non-HT Users
Abstract & Commentary
By Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University, School of Medicine, Atlanta, is Associate Editor for OB/GYN Clinical Alert.
Synopsis: Higher insulin levels were associated with an increased risk of breast cancer in postmenopausal women who participated in the observational arm of the Women's Health Initiative, but the association held only for women who did not use hormone therapy.
Source: Gunter MJ, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2009;101:48-60.
The above study involved a detailed analysis of data obtained in the observational arm of the Women's Health Initiative. As a rationale, the authors note that obesity is a well-established risk factor for breast cancer. While the customary explanation for this association has been that obesity raises estrogen levels, another candidate is insulin, which is a potent mitogen and is elevated by obesity. In this study, therefore, the investigators primarily sought to determine whether hyperinsulinemia was associated with breast cancer in postmenopausal women. To address this query, they conducted a prospective case-cohort study by drawing from a pool of 93,676 women in the observational arm of the Women's Health Initiative (WHI) and from the roughly 1800 women who developed incident breast cancer. The study group included 835 women without diabetes who developed incident breast cancer and 816 women who were randomly chosen using the same inclusion and exclusion criteria as the cases.
The investigators found that insulin levels more than estradiol levels were associated with the development of incident breast cancer, but only in women not using hormone therapy (HT) after menopause. Higher insulin levels were not associated with incident breast cancer in women using either unopposed estrogen therapy or estrogen + progestin therapy.
In non-users, fasting insulin levels were parsed into quartiles, with the highest quartile being women with fasting insulin levels ≥ 8.8 µIU/mL. A hazard ratio (HR) of 2.48 (confidence interval [CI], 1.38-4.47; P < 0.001) was reported for incident breast cancer when the top quartile was compared to the bottom quartile. There was no association between fasting glucose levels and breast cancer in HT users and non-users. In non-users, a body mass index (BMI) ≥ 30 kg/m2 (top quartile) was associated with a HR of 1.91 (CI, 1.11-3.27; P = 0.02). In non-users, an estradiol level in the top tertile was associated with a HR of 1.59 (CI, 1.00-2.55; P = 0.04). Thus, the investigators concluded that there was "a positive association between fasting insulin levels and the risk of postmenopausal breast cancer that was unaffected by adjustment for endogenous estradiol levels, supporting a mechanism that is independent of circulating estradiol." As for the lack of an association between insulin levels and breast cancer and between obesity and breast cancer in HT users, they note that insulin levels were significantly lower among HT users than non-users. Glucose and total and free IGF levels bore no consistent relationship with incident breast cancer in any group.
This is an important but dense study that is likely to receive a great deal of attention. The investigators state in the last line of the abstract that "hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship." So far, none of the various media releases about this study have explained that this relationship was seen only in non-users of HT, so I wanted to be sure that this aspect of the study came to your attention.
The study raises an important question about trade-offs and about our model of carcinogenesis. If hormone use after menopause reduces the risk of hyperinsulinemia and diabetes, will it also reduce the risk of breast cancer by this mechanism? The present investigation did not directly addresses this. Another interesting report that indirectly addresses this point involved a population-based study done in Korea in which ~1.3 million men and women age 30-95 were followed for 10 years.1 For persons with a diagnosis of diabetes or a fasting serum glucose ≥ 125 mg/dL, cancer incidence and mortality were generally elevated. However, as glucose levels rose, the impact was greater for men than for women; women did not show an elevated mortality until glucose ≥ 140 mg/dL as compared to ≥ 110 mg/dL for men. In women, age-adjusted mortality rate from breast cancer was increased only in those with diabetes but not hyperglycemia (HR = 2.23; CI, 1.49-3.33). Similarly, age-adjusted incidence of breast cancer was elevated only in women with diabetes but not for hyperglycemia (HR = 1.51; CI, 1.26-1.80). A BMI ≥ 23 kg/m2 augmented the hazard ratio associated with increasing glucose levels.
Insulin might well be the hormone of interest for the 21st century. Obesity is on the rise, with nearly 25% of Americans currently qualifying for the label "obese" (BMI ≥ 30 kg/m2). Obesity elicits hyperinsulinemia and a myriad of clinical sequelae, including gestational diabetes and polycystic ovary syndrome. Thus, the associations noted above are likely to have clinical significance and may serve to guide screening protocols for all, including postmenopausal women. Of course, prevention is the key and lifestyle measures are critical to prevention.
This study raises the question as to whether we should recommend postmenopausal hormone use to reduce the likelihood of hyperglycemia and hyperinsulinemia in aging women. Should we see postmenopausal hormone use as one of the strategies to maintain body composition and decrease the risk of diabetes and its clinical consequences in older women? The authors did not emphasize this point, but the WHI also showed that HT use reduced the risk of diabetes (HR = 0.79 [0.67-0.93]; P = 0.004 for the E+P arm; and HR = 0.88 [0.77-1.01]; P = 0.07 for the E alone arm).2,3 The WHI also found that the low-fat diet intervention reduced the risk of diabetes, but only when the diet caused weight loss, leading the authors to opine that "weight loss, rather than macronutrient composition, may be the dominant predictor of reduced risk of diabetes." Only time will tell, but we may yet come full circle in our attitudes towards postmenopausal hormone therapy as our population and individual needs change and hyperinsulinemia becomes the specter that heralds accelerated aging and its concomitants such as cardiovascular disease and breast cancer.