Dietary Iron and Heme Iron Intake and Risk of Breast Cancer: A Prospective Cohort Study

Introduction

Free iron is associated with oxidative DNA damage and lipid peroxidation (1-4), both of which are thought to contribute to breast carcinogenesis (5-11). Iron has been shown to enhance chemically initiated mammary carcinogenesis (12, 13) and may potentiate the effects of two established risk factors for breast cancer (i.e., alcohol and exogenous estrogens). Both alcohol and estrogen are capable of inducing oxidative DNA damage, and both may disturb iron homeostasis by releasing iron from its bound form, further contributing to the production of reactive oxygen species (2, 14). Intake of red meat, an important source of the more bioavailable heme iron, has shown an inconsistent association with breast cancer (15). However, to date, only one report (16) has assessed intake of heme iron in relation to breast cancer risk, reporting a positive association of iron and heme iron intake with postmenopausal breast cancer in women consuming 20+ g of alcohol per day but no overall association. Given the limited epidemiologic evidence currently available, we used data from a large cohort study of Canadian women to assess breast cancer risk in association with total iron intake and heme iron intake.

Materials and Methods

Our study was conducted in the Canadian National Breast Screening Study, a randomized controlled trial of screening for breast cancer involving 89,835 women ages 40 to 59 at baseline enrolled between 1980 and 1985 (17, 18). Starting in 1982, dietary information was obtained by means of a food frequency questionnaire completed by women attending participating screening centers (19). The food frequency questionnaire elicited information on usual portion size and consumption of 86 food items and included photographs of portion sizes to assist respondents in quantifying intake. A total of 49,654 dietary questionnaires was returned. Data from the food frequency questionnaire were used to calculate total dietary iron intake using a database described elsewhere (19). The values for iron intake presented here are for dietary sources alone because data on iron supplements were not collected. Total intake of meat iron was calculated from the reported intake of 22 meat items and 2 mixed dishes containing meat. Heme iron intake was computed by two different methods using different proportions for heme iron from different types of meat: 69% for beef; 39% for pork, ham, bacon, pork-based luncheon meats, and veal; 26% for chicken and fish; and 21% for liver (20); and, alternatively, using 40% as the average proportion of heme iron in all meats (21). Results were similar for both methods, and we present data using the first approach. Total iron and heme iron intake were calorie adjusted using the residuals method (22). In addition, we assessed meat iron intake and red meat intake.

During an average follow-up of 16.4 years through the end of December 2000, 2,545 breast cancer cases were identified by means of record linkage to the Canadian Cancer Registry. We excluded 947 women with extreme energy intake values (<730 or >6,485 kcal/d) and women whose body mass index was <15 kg/m² or >50 kg/m² or who were missing information on body mass index. In addition, 4 women with prevalent breast cancer were excluded, leaving 48,662 women, including 2,491 cases, available for analysis.

Cox proportional hazards models (using age as the time scale) were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between iron intake and breast cancer risk. Quintiles and deciles of iron-related variables were derived based on their distribution in the total population. All multivariate models included covariates shown in the footnotes to Tables 1 and 2 . We also examined the associations within strata of alcohol consumption (nondrinker versus drinkers of 30+ g/d) and hormone replacement therapy (HRT) use (ever versus never), and we tested for interactions using likelihood ratio tests. To test for trends in risk with increasing levels of exposure, we assigned the median value for each quintile (or decile) and then fitted the medians as a continuous variable in the risk models. We then evaluated the statistical significance of the corresponding coefficient using the Wald test (23). All analyses were done using Statistical Analysis System version 9 (SAS Institute). Use of the lifetest procedure in Statistical Analysis System showed that the proportional hazards assumption was met in this data set. All tests of statistical significance were two sided.

Results

In multivariate models, quintiles of total iron intake, heme iron intake, iron intake from meat, and red meat intake showed no association with breast cancer risk in premenopausal women, postmenopausal women, or all women combined (Table 1). Non–heme iron intake also was not associated with breast cancer risk (data not shown). Furthermore, no associations or trends were seen when iron-related variables were categorized by deciles or treated as continuous variables (data not shown).

In this study population, alcohol was associated with increased risk of breast cancer (HR for an intake of ≥40 g/d, 1.20; 95% CI, 0.96-1.51; P for trend = 0.04), whereas HRT use was not (HR, 0.98; 95% CI, 0.89-1.09). There was no association between iron intake or heme iron intake and breast cancer risk within strata defined by alcohol consumption or HRT use (Table 2). Tests for heterogeneity in the association between subgroups were not statistically significant.

Discussion

Consistent with the cohort data of Lee et al. (16), we found no overall association between dietary iron or heme iron intake and breast cancer risk. However, the prior report did find a significant association of both iron intake and heme iron intake in women consuming 20+ g of alcohol per day. With ∼2,500 incident breast cancer cases ascertained over 16 years of follow-up, our study had excellent statistical power to detect a main effect of iron and heme iron on breast cancer. Specifically, we had 87% power to detect a HR of 1.2 for extreme quintiles with a two-sided α-level of 5%. In the subgroup with the smallest number of breast cancer cases (women who reported drinking 30+ g/d of alcohol at baseline), we had 86% power to detect a HR of 1.8 for extreme quintiles. Two limitations of this study should be mentioned. First, information on use of iron supplements was not available. However, in their studies on heme iron, Lee et al. al. (21, 24) seem to have based their estimates on dietary data only. Second, our dietary data were limited to intake reported at baseline, and changes in dietary intake over the long follow-up period could have led to misclassification of exposure, thereby reducing our ability to detect an association.

Considering the biological plausibility of an association between iron and breast cancer risk, further investigation is warranted given the limited data currently available. Of particular importance are cohort studies with repeated measurement of iron intake. If elevated iron intake is found to contribute to breast carcinogenesis, preventive strategies might include dietary modification, avoidance of iron supplements, and chelation (25).