Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis

Abstract

Background: Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found exclusively in animal-sourced foods, is suggested to have a more detrimental effect. Epidemiological evidence of the association between iron and breast cancer risk remains inconclusive and has not been comprehensively summarized. This systematic review and meta-analysis evaluated associations between both iron intake and body iron status and breast cancer risk.

Methods: Four electronic databases (MEDLINE, EMBASE, CINAHL, and Scopus) were searched up to December 2018 for studies assessing iron intake and/or biomarkers of iron status in relation to breast cancer risk. Using random-effects meta-analyses, pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated comparing the highest vs. lowest category of each iron measure. Dose-response meta-analyses were also performed to investigate linear and nonlinear associations.

Results: A total of 27 studies were included in the review, of which 23 were eligible for meta-analysis of one or more iron intake/status measures. Comparing the highest vs. lowest category, heme iron intake was significantly associated with increased breast cancer risk, with a pooled RR of 1.12 (95% CI: 1.04-1.22), whereas no associations were found for dietary (1.01, 95% CI: 0.89-1.15), supplemental (1.02, 95% CI: 0.91-1.13), or total (0.97, 95% CI: 0.82-1.14) iron intake. Associations of iron status indicators with breast cancer risk were generally in the positive direction; however, a significant pooled RR was found only for serum/plasma levels (highest vs. lowest) of iron (1.22, 95% CI: 1.01-1.47), but not for ferritin (1.13, 95% CI: 0.78-1.62), transferrin saturation (1.16, 95% CI: 0.91-1.47), or total iron-binding capacity (1.10, 95% CI: 0.97-1.25). In addition, a nonlinear dose-response was observed for heme iron intake and serum iron (both P_nonlinearity < 0.05).

Conclusions: Heme iron intake and serum iron levels may be positively associated with breast cancer risk. Although associations were modest, these findings may have public health implications given the widespread consumption of (heme) iron-rich foods. In light of methodological and research gaps identified, further research is warranted to better elucidate the relationship between iron and breast cancer risk.

Keywords: Breast cancer; Dose-response; Ferritin; Heme iron; Iron intake; Iron status; Meta-analysis; Systematic review.

Fig. 1

Flow diagram of study selection for the systematic review and meta-analysis. *One study reporting on toenail iron [69] and the other on breast tissue iron [70] as the only iron measure

Fig. 2

Forest plot of associations between iron intake (highest vs. lowest category) and breast cancer risk. The diamonds represent the pooled relative risks and corresponding 95% confidence intervals obtained from random-effects meta-analyses. The dots and horizontal lines represent the relative risks and corresponding 95% confidence intervals of individual studies, and the sizes of shaded squares are proportional to the weight contributed by each study to the pooled estimate. I² is the proportion of the total variability attributable to between-study heterogeneity, and P is from Cochran’s Q test evaluating the presence of heterogeneity

Fig. 3

Dose-response curves for intakes of (a) dietary iron; (b) total iron; and (c) heme iron in relation to breast cancer risk. Data were modeled using random-effects restricted cubic spline models with three knots fixed at the 10th, 50th, and 90th percentiles. The solid lines represent the fitted relative risks for the nonlinear trend, and the dashed lines represent pointwise 95% confidence intervals

Fig. 4

Forest plot of associations between serum/plasma indicators of body iron status (highest vs. lowest category) and breast cancer risk. The diamonds represent the pooled relative risks and corresponding 95% confidence intervals obtained from random-effects meta-analyses. The dots and horizontal lines represent the relative risks and corresponding 95% confidence intervals of individual studies, and the sizes of shaded squares are proportional to the weight contributed by each study to the pooled estimate. I² is the proportion of the total variability attributable to between-study heterogeneity, and P is from Cochran’s Q test evaluating the presence of heterogeneity. *Stevens et al. 2011 [71] reported separate estimates for premenopausal (pre/post) and postmenopausal (post/post) ferritin levels in relation to postmenopausal breast cancer risk; Gaur et al. 2013 [72] reported separate estimates for premenopausal (pre) and postmenopausal (post) breast cancer

Fig. 5

Dose-response curves for serum/plasma (a) ferritin and (b) iron in relation to breast cancer risk. Data were modeled using random-effects restricted cubic spline models with three knots fixed at the 10th, 50th, and 90th percentiles. The solid lines represent the fitted relative risks for the nonlinear trend, and the dashed lines represent pointwise 95% confidence intervals