Glycemic load, glycemic index and breast cancer risk in a prospective cohort of Swedish women Susanna C. Larsson 1 * , Leif Bergkvist 2 and Alicja Wolk 1 1 Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 2 Department of Surgery and Centre for Clinical Research, Central Hospital, V€ aster ˚ as, Sweden High-glycemic load diets have been hypothesized to increase the risk of breast cancer but epidemiologic studies have yielded incon- sistent findings. We examined the associations of carbohydrate intake, glycemic index and glycemic load with risk of overall and hormone receptor-defined breast cancer in the Swedish Mammog- raphy Cohort, a population-based cohort of 61,433 women who completed a food frequency questionnaire at enrollment in 1987– 1990. During a mean follow-up of 17.4 years, we ascertained 2,952 incident cases of invasive breast cancer. Glycemic load but not carbohydrate intake or glycemic index was weakly positively associated with overall breast cancer risk (p for trend 5 0.05). In analyses stratified by estrogen receptor (ER) and progesterone receptor (PR) status of the breast tumors, we observed statistically significant positive associations of carbohydrate intake, glycemic index and glycemic load with risk of ER1/PR2 breast cancer; the multivariate relative risks comparing extreme quintiles were 1.34 [95% confidence interval (CI) 5 0.93–1.94; p for trend 5 0.04] for carbohydrate intake, 1.44 (95% CI 5 1.06–1.97; p for trend 5 0.01) for glycemic index and 1.81 (95% CI 5 1.29–2.53; p for trend 5 0.0008) for glycemic load. No associations were observed for ER1/PR1 or ER2/PR2 breast tumors. These findings sug- gest that a high carbohydrate intake and diets with high glycemic index and glycemic load may increase the risk of developing ER1/ PR2 breast cancer. ' 2009 UICC Key words: breast cancer; carbohydrate; cohort studies; diet; epidemiology; glycemic load There is a growing recognition that breast cancer may be pro- moted by insulin resistance and hyperinsulinemia. Overweight and obesity are important determinants of insulin resistance and hyperinsulinemia and are related to an increased risk of postmeno- pausal breast cancer. 1 Furthermore, an increased risk of breast cancer has been observed among women with type 2 diabetes, 2 which is characterized by hyperglycemia and insulin resistance. Elevated insulin concentrations may affect breast cancer risk either directly, by stimulating insulin receptors in breast tissue, or indirectly, by increasing the bioactivity of insulin-like growth factor-I (IGF-I), which stimulates cell proliferation and inhibits apopotosis. 3 Furthermore, there is evidence that both insulin and IGF-I stimulate the synthesis of sex steroids, particularly andro- gens, and decrease the concentration of sex-hormone-binding globulin. 3 The increase in bioavailable androgens may be a major cause of increased tissue concentrations of estrogens, formed by local conversion of the androgens. 3 The amount, type and rate of digestion of dietary carbohydrate influence postprandial glycemia, insulin secretion and average in- sulin concentrations. 4–6 Hence, the quantity and quality of carbo- hydrate consumed could have a role in breast carcinogenesis. In 1981, Jenkins et al. 7 introduced the concept of the glycemic index, which is a means to quantify the glycemic response to carbohy- drates in various foods. A related measure, the glycemic load, is the product of the glycemic index of the food and carbohydrate content of the portion ingested. 8 The glycemic load thus quantifies the overall glycemic effect and insulin demand induced by a serv- ing of food. Epidemiologic studies of glycemic index and glycemic load in relation to breast cancer risk have yielded inconsistent results. 9–11 Few studies have assessed the associations stratified by hormone receptor status, 12–14 although breast cancers classified by estrogen receptor (ER) and progesterone receptor (PR) expression likely have different etiology. 15 We examined the associations of carbo- hydrate intake, glycemic index and glycemic load with the inci- dence of breast cancer, overall and stratified by ER and PR status of the tumor, in a population-based prospective cohort of Swedish women. Material and methods Study cohort The Swedish Mammography Cohort was established in 1987– 1990 when 66,651 women (74% of the source population) born between 1914 and 1948 and residing in central Sweden completed a questionnaire about diet, weight, height, reproductive factors and other factors. After exclusion of women with an erroneous or missing National Registration Number, those with implausible values for total energy intake (i.e., 3SDs from the log e -trans- formed mean energy intake) and those with a previous cancer diagnosis (except nonmelanoma skin cancer), 61,433 women remained for analysis. A second questionnaire was sent to all 56,030 women who were still alive and residing in the study area in the late autumn of 1997; 39,227 women (70%) responded to this questionnaire. The study was approved by the ethics commit- tees at the Uppsala University Hospital and the Karolinska Institu- tet in Sweden. Dietary assessment A food frequency questionnaire (FFQ) with 67 and 96 food items was sent to participants at baseline and in 1997, respec- tively. In these questionnaires, women were asked to report how often, on average, they had consumed each food item during the previous 6 months (baseline FFQ) or the previous year (1997 FFQ). The FFQs had 8 mutually exclusive predefined categories for frequency of consumption, ranging from ‘‘never/seldom’’ to ‘‘4 or more times per day’’ (baseline FFQ) or ‘‘3 or times per day’’ (1997 FFQ). Carbohydrate intake was calculated by multiplying the frequency of consumption of each food item by its carbohy- drate content per age-specific serving, using food composition val- ues from the Swedish National Food Administration Database. 16 The age-specific serving sizes were based on mean values obtained from 213 randomly selected women from the study area who weighed and recorded their food intake for a mean of 27.8 days. Glycemic index values of foods were obtained from international tables. 17 We calculated the average glycemic load for each participant by multiplying the carbohydrate content (grams per serving) of each food by its glycemic index; multiply- ing that product by the frequency of consumption (servings of that food per day), and summing the values from all foods. Each unit Grant sponsors: Swedish Cancer Foundation and the Swedish Research Council for Infrastructure. *Correspondence to: Division of Nutritional Epidemiology, the National Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-17177 Stockholm, Sweden. Fax: 146-8-304571. E-mail: susanna.larsson@ki.se Received 18 November 2008; Accepted after revision 16 January 2009 DOI 10.1002/ijc.24310 Published online 3 February 2009 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 125, 153–157 (2009) ' 2009 UICC Publication of the International Union Against Cancer