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We investigated the association between dietary intake of citrus fruits and breast cancer risk.
The PubMed and EMBASE were searched for relevant articles on diet and breast cancer up to January 2012. All of the epidemiological studies that assessed dietary intake of citrus fruits and presented risk estimates of the association between citrus fruits intake and risk of breast cancer were reviewed. Multivariable-adjusted odds ratios (OR) and associated 95% confidence intervals (CI) for highest versus lowest intake of dietary citrus fruits level were extracted. Overall summary OR was calculated by using a fixed-effect meta-analysis.
Six case-control studies out of five articles were eligible. Overall summary OR showed a 10% reduction in risk of breast cancer associated with high intake of citrus fruits (summary OR, 0.90; 95% CI, 0.85-0.96;
Pooled results from observational studies showed an inverse association between citrus fruits intake and the risk of breast cancer.
Breast cancer was one of the most common cancers in 2008 and overtook stomach cancer as the cancer with the highest incidence in Korean women in 2001 [
Diet and nutrition have been emphasized as a modifiable risk factor for breast cancer, while most of the other factors, i.e., reproductive history, lactation, menstrual history, adult-attained height and obesity, are generally difficult to modify [
Recently, a systematic review reported on the protective effects of high citrus fruit intake on stomach cancer risks [
An electronic literature search was conducted in PubMed (U.S. National Library of Medicine, Bethesda, USA) and EMBASE (Reed Elsevier PLS, Amsterdam, The Netherlands) to identify human adult studies written in the English language and published up to January 2012 that included the following keywords or phrases: breast, breast neoplasms, fruit, citrus, diet, dietary, prevention and control, etiology, epidemiology, humans, and adult. The search terms used were: ("Breast Neoplasms/diet therapy"[Majr] OR "Breast Neoplasms/epidemiology"[Majr] OR "Breast Neoplasms/etiology"[Majr] OR "Breast Neoplasms/prevention and control"[Majr]) AND ("Fruit" [Mesh] OR "Citrus"[Mesh]) AND ("humans"[MeSH Terms] AND Comparative Study[ptyp] AND "adult"[MeSH Terms]) for PubMed; and breast AND [(neoplasm) OR (cancer)] AND [(FRUIT) OR (CITRUS)] AND [(PREVENTION) OR (RISK) OR (ETIOLOGY)] for EMBASE. In addition, we reviewed the references cited in the full-text articles and in the relevant review articles or meta-analyses identified in the search.
We applied the following inclusion criteria [
The following information was extracted from all of the eligible studies: study design, country of origin, years of enrollment, sampling frame, number of participants, range of age, kinds of citrus fruits, level of comparison, and potential confounding variables that had been adjusted for. From the eligible studies that met the inclusion criteria, estimates of the odds ratio (OR)/relative risk (RR), and their associated 95% confidence intervals (CIs), were calculated for the data relating to the intake of citrus fruits. If separate articles from the same study were published, the article containing the more detailed information on the case and control was selected for inclusion.
Using general variance-based methods, study-specific OR/RR and 95% CIs for the highest versus the lowest intake of citrus fruits level were extracted from each article. For all studies, the reported OR/RR estimate was adjusted for age. SE=[ln (OR/RR upper limit)-ln (OR/RR lower limit)]/2×1.96. Where OR were given by menopause status (e.g., premenopausal or postmenopausal) [
Heterogeneity was tested with a chi-square test and measured by using the
The computerized search yielded 157 articles, and 321 articles that had been identified from the citations were added. Of the 335 articles that were obtained for full-text review, we excluded 330 articles based on the exclusion criteria (
The six studies included in the final analysis had 8,393 participants: 3,789 cases and 4,705 controls. Some details of the selected studies are shown in
Four studies adjusted for age [
In all of the studies, intake of citrus fruits was part of a broader dietary assessment, and the relationship between citrus fruit intake and breast cancer was not a primary hypothesis. The adjusted OR for the highest category for citrus fruit intake varied considerably, with the ORs ranging from 0.68 to 1.1. One study reached the usual threshold
There was no significant heterogeneity among the study results (
No publication bias was observed in the selected studies. Visualization of Begg's funnel plot was symmetrical (
The results indicate that a higher intake of citrus fruits may decrease breast cancer risks. To the best of our knowledge, this is the first systemic review and meta-analysis of breast cancer and citrus fruit intake. When the latest World Cancer Research Fund report was published in 2007, there was no convincing evidence for individual foods and nutrients modifying the risk of breast cancer except for alcohol consumption. It was judged that the evidence was too limited to reach a conclusion on the effect of fruits on breast cancer risk [
The results of this quantitative meta-analysis could be supported by the finding of the lowest age-standardized incidence rate of breast cancer in Korea occurring in the population of Jeju who simultaneously consumed the highest amount of tangerines in Korea [
The following study limitations are considered. Firstly, although the selected studies for this meta-analysis were homogeneous with zero
Secondly, the apparent association of this pooled result is restricted to the case-control studies. As retrospective studies are considered as more prone to overestimating the exposure effect due to recall and selection bias, it is possible that any true ORs are likely smaller than as shown in this analysis.
Thirdly, measurement error in a food frequency questionnaire (FFQ), such as inability to accurately capture the intake of all citrus fruits, should be considered. It has been shown that frequency of intake explains most of the variations in intake. While the FFQ may be an adequate, albeit imperfect, instrument for measuring relative fruit and vegetable intake, the nondifferential misclassification errors observed in the FFQ likely attenuate the estimates toward the null [
Environmental factors are important in the progression of the disease, although between 4% and 9% of breast cancer cases are hereditary with mutations in either the
Citrus fruits contain a complex mixture of constituents, all of which may also contribute to any effect [
In summary, pooled results from observational studies show an inverse association between citrus fruit intake and the risk of breast cancer. This statistical evidence helps to generate a new hypothesis of citrus fruits modifying the risks of breast cancer. However, the limitations as outlined above may present questions on showing a true association. As such, the need for well-designed prospective observational and intervention studies is highlighted by this study to clarify the role of citrus fruit intake and breast cancer.
The authors declare that they have no competing interests.
Literature flow.
DB=database.
Summary estimates of the association between citrus fruits intake and breast cancer risks sorted by effect estimate.
CI=confidence interval; df=degree of freedom; chi2=chi-square statistic;
Funnel plot of studies evaluating the association between citrus fruit intake and breast cancer risks. Dot lines are 95% pseudo-confidence intervals.
SE=standard error; OR=odds ratio.
Summary of case-control studies selected in meta-analysis
OR=odds ratio; CI=confidence interval; BMI=body mass index; Q1=baseline level by rank distribution; Q4=quartile level; Q5=quintile level; ND=not described.