Short Communication Serum Fructosamine and Subsequent Breast Cancer Risk: A Nested Case-Control Study in the ORDET Prospective Cohort Study Mary Platek, 1 Vittorio Krogh, 6 Andrea Micheli, 6 Richard Browne, 5 Elisabetta Meneghini, 6 Sabina Sieri, 6 Holger J. Schu ¨ nemann, 2 Valeria Pala, 6 Maddalena Barba, 1 Gregory E. Wilding, 3 Franco Berrino, 6 and Paola Muti 4 Departments of 1 Exercise and Nutrition Sciences, 2 Medicine, 3 Biostatistics, and 4 Social and Preventive Medicine, 5 Clinical Science Laboratory, University at Buffalo, State University of New York, Buffalo, New York; and 6 Epidemiology Unit, Instituto Nazionale Per lo Studio e la Cura dei Tumori, Via Venezian, Milan, Italy Abstract There is evidence that abnormal glucose metabolism may contribute to the risk of breast cancer. The measurement of markers of glucose metabolism could help to identify women at risk for breast cancer. Serum fructosamine is one such marker. In this study, we investigated whether prediagnostic serum fructosamine was associated with breast cancer. Between 1987 and 1992, 10,786 women ages 35 to 69 were recruited in Italy for a prospective study. Women with a history of cancer or on hormone therapy were excluded at baseline. Blood samples were collected after 12 hours fasting from all participants at recruitment. After 5.5 years of follow-up, 144 breast cancer cases were identified and four matched controls were selected from the cohort; serum fructosamine levels were measured in both groups at baseline. Adjusted odds ratios (OR) for the highest tertile of serum fructosamine compared to the lowest was 1.60 [95% con- fidence interval (CI), 0.95-2.73]. In premenopausal women, the OR was 1.58 (95% CI, 0.76-3.40) and in postmenopausal women, the OR was 1.60 (95% CI, 0.76-3.48). Serum fructosa- mine levels tended to be positively associated with breast cancer risk independent of menopausal status. (Cancer Epidemiol Biomarkers Prev 2005;14(1):271 – 4) Introduction There is increasing evidence that obesity and diabetes mellitus are associated with increased risk of breast carcinomas. Biological evidence provides support for a role of glucose and other factors related to glucose metabolism, such as insulin and C-peptide, in breast cancer development. It is known that glucose favors the selection of malignant cell clones and that the neoplastic cell extensively uses glucose for proliferation (1). Insulin has been shown to be a potent mitogenic agent (2). Insulin also induces a dose-dependent growth response in breast cancer cell lines and acts through the insulin receptor (3, 4). Furthermore, insulin may also play a role in tumor promotion by up-regulation of ovarian steroid secretion (5-7). There is epidemiologic evidence supporting the relationship between abnormal glucose metabolism and breast cancer risk. There was an increase of breast cancer risk for women who had a diagnosis of diabetes mellitus at baseline in four prospective studies (8-11); however, a fifth did not corroborate the evidence. Furthermore, studies have shown a positive relationship between insulin and C-peptide levels and breast cancer incidence (12, 13). Additionally, variables related to insulin resistance, such as body mass index (BMI) and abdominal obesity have been related prospectively to breast cancer risk in postmenopausal women (14-16). Given the evidence that supports a relationship between abnormal glucose metabolism and breast cancer risk, the measurement of markers of insulin resistance may help to identify women at high risk for breast cancer. Serum fructos- amine, a product of protein glycation, may be suitable for the assessment of glucose metabolism in epidemiologic studies. The spontaneous, nonenzymatic condensation of glucose and proteins initially produces an unstable ketoamine, which is generally referred to as fructosamine due to its structural similarities to fructose (17). Glycated albumin usually accounts for 80% of the glycated serum proteins (18, 19). Serum fructosamine is more strongly correlated with habitual intake of sugar (r = 0.26, P = 0.05) than glycated hemoglobin (r = 0.001, P = 0.99). Thus, fructosamine can also be considered an index of the chronic exposure to sugar intake (20). The purpose of our study was to investigate the association between fructosamine and breast cancer cases in a prospective study. The primary hypothesis of the present study was that prediagnostic serum fructosamine, as a marker of glucose metabolism, was associated with subsequent breast cancer. Materials and Methods Between June 1987 and June 1992, 10,786 healthy women, ages 35 to 69 years, residents of Varese province in northern Italy, participated in a prospective study of hormones, diet and breast cancer risk: the Hormones and Diet in the Etiology of Breast Cancer Risk (ORDET) study (20, 21). All members of the cohort were volunteers recruited from the general population. The total number of women recruited in the cohort represented f7% of the general population of women in that age range in Varese province. A major focus of the ORDET study was endogenous hormones and their relation to breast cancer risk. Therefore, several sources of hormone variability were controlled for by Received 1/13/04; revised 6/16/04; accepted 9/21/04. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Paola Muti, Department of Social and Preventive Medicine, University at Buffalo, State University of New York, 270 Farber Hall, 3435 Main Street, 14214 Buffalo, NY. Phone: 716-829-2975; Fax: 716-829-2979. E-mail: muti@buffalo.edu Copyright D 2005 American Association for Cancer Research. 271 Cancer Epidemiol Biomarkers Prev 2005;14(1). January 2005 Cancer Epidemiology, Biomarkers & Prevention Research. on October 6, 2021. © 2005 American Association for Cancer cebp.aacrjournals.org Downloaded from