Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214
We read with great interest the article by Mink et al. (1) on the association of insulin and glucose with breast cancer risk. The authors examined the association in an incident study on 187 breast cancer patients derived from a cohort study of 7,894 women aged 4564 years from US communities, the Atherosclerosis Risk in Communities (ARIC) Study. The authors reported lack of association of breast cancer with insulin and glucose and a mild increase in breast cancer incidence among women who were diabetics at recruitment in comparison with those characterized by fasting glucose levels lower than 100 mg/dl.
Given that the study relied upon a prospective design and a relatively good sample size, the report could make a substantive contribution to the literature related to potential metabolic determinants of breast cancer. However, there are some weaknesses in the study. First, glucose determinations can be affected by several sources of variability. Previous studies showed, for instance, that the glucose concentration in blood samples decreases by time from the collection to the biochemical analysis (2, 3). In addition, "a short-term storage effect" reportedly affects glucose even in frozen samples (4). In the article, the authors did not describe how the blood samples were handled and how they dealt with that source of variability.
Second, it is not clear whether or not the samples in the study were collected while subjects were fasting. In the first part of the Materials and Methods section, the authors reported, "A fasting blood sample was taken from each participant" (1, p. 350), while later in the same section they reported, "Women were considered to have prevalent diabetes if ... they had ... a nonfasting glucose level of at least 200 mg/dl" (1, p. 350). The clarification of this issue is very relevant to the interpretation of the study findings.
Third, it is not clear why the authors decided to exclude from the analyses on insulin women with unknown diabetes (those with fasting glucose levels of 126 mg/dl or a nonfasting glucose level of at least 200 mg/dl), but they kept the same women for the analyses on glucose.
Fourth, one of the most relevant aspects of breast cancer etiology is the effect of menopausal status. For instance, the effect of reproductive factors and particularly of body mass index, a key variable involved in glucose metabolism, differs according to menopausal status (58). This knowledge and data produced by other prospective cohort studies, showing that most of the evidence linking variables related to glucose metabolism was limited to premenopausal women (911), should have led the authors to conduct detailed separate analyses in premenopausal and postmenopausal women. Indeed, in a previously conducted study, we found a statistically significant effect modification due to menopausal status, where fasting serum glucose and insulin-like growth factor I were associated with breast cancer only in premenopausal women (12).
In conclusion, the studies of the relation between glucose metabolism and chronic disease are made particularly difficult by numerous sources of variability. Careful attention to these sources of variability should be given before conclusive statements can be made with regard to the possible lack of evidence of an association.
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