For green leafy vegetables, no evidence of a nonlinear association was detected (P = 0.11), the pooled RRs of linear association (0.2 serving increment a day) were 0.98 (95%CI: 0.96, 0.99; P < 0.01; I2 = 0.0%; Power = 0.76; see Figure S1, Supplemental Digital Content 2, http://links.lww.com/MD/A258, which demonstrates the forest plot of results). For citrus, the summarized RR was 1.00 (95%CI: 1.00, 1.00; P = 0.83; I2 = 0.0%); for cruciferous vegetables, the pooled RR was 0.97 (95%CI: 0.93, 1.01; P = 0.19; I2 = 55.8%), respectively (see Figures S2 and S3, Supplemental Digital Content 2, http://links.lww.com/MD/A258, which demonstrate the forest plot of the results of citrus and cruciferous, respectively).
We conducted sensitivity analysis by omitting those studies with special population (such as Adventist), special exposure (such as fried vegetables, high smoking rate [>40%]), or low quality each time on a random-effect model to detect whether these confounders influence our results or not. Sensitivity analysis was also used to test the influence of individual studies on the overall results. After the omitting, for total fruits, vegetables, and both FVs intake, the summarized RRs of remaining studies kept consistency with before (Table 4). But for cruciferous intake, study47 influenced the result obviously. For green leafy vegetables intake, study50 influenced the result obviously (see Table S2, Supplemental Digital Content 3, http://links.lww.com/MD/A258, which demonstrates the results of sensitivity analyses of citrus, cruciferous, and green leafy vegetables).
In present dose-response meta-analysis, we confirmed no associations between total fruits intake, vegetables intake, both FVs intake and risk of BC. We also found no obvious association between citrus, cruciferous vegetables intake and risk of BC. However, we observed inverse association between green leafy vegetables intake and risk of BC. That is, per 0.2 serving increment of daily green leafy vegetables intake is associated with 2% decrease of BC risk.
The results for total fruits, vegetables, and both FVs were credible. It is similar to another meta-analysis of cohort studies,12 although studies in the meta-analysis were insufficiently included. Our subgroup analysis and sensitivity analysis also showed consistent results, which supported the conclusions.
The results of cruciferous vegetables and green leafy vegetables should be treated with caution. In our meta-analysis, we analyzed some subtypes of fruits or vegetables and the risk of BC. We observed unstable results in cruciferous vegetables and green leafy vegetables when conducting sensitivity analysis. Study47,50 influenced the results of cruciferous and green leafy vegetables, respectively. Interestingly, the cases in reference47 were all males while in reference50 were all females. This suggested that, there were some differences between male and female of the prevention effect of some specific vegetables. But we have no sufficient, available data for further subgroup analysis by sex in our included studies. Another possibility may be that different stage or grade of BC may influence the results. We found that, in the study,50 the outcome was invasive BC. But there were no sufficient evidence to verify it since other studies did not subgroup the results by cancer stage or grade.
To our knowledge, this was the first meta-analysis that found green leafy vegetables were associated with reduced risk of BC. Although sensitivity analysis tested unstable result, we have evaluated the statistic power of it and it showed a reasonable amount of power (P = 0.76). We recommend a high green leafy vegetables diet instead of other types of FVs for BC prevention.
Green leafy vegetables contain high concentrations of vitamins such as β-carotene, ascorbic acid, and folic acid.58 These bioactivators are beneficial for immune function, antioxidant status and can protect DNA from oxidative damage4–6 which may help prevent BC. But it is hard to explain why total fruits or vegetables are not associated with reduced BC risk. Research has found that orange fruit is more effective than dark-green leafy vegetables in increasing serum concentrations of β-carotene.59 Further studies were needed.
We detected moderate heterogeneity in our meta-analysis. We found parts of the source of heterogeneity by sensitivity analysis. According to the results of sensitivity analysis, the outcomes, sex, processed fruits or vegetables (such as juice, cooked vegetables), and smoking status consist of the main source of heterogeneity. When omitting the studies with these characteristics, the heterogeneity reduced to a low level.
In our meta-analysis, we detected obvious asymmetry in publication bias analysis of fruit intake and risk of BC. However, our further trim and fill method showed no substantial changes of the results in both fixed- and random-effect model, which suggested that the asymmetry may not be caused by publication bias.
There were some limitations in present meta-analysis. First, smoking is the main risk factor for BC.1 We observed a borderline statistical significant result (P = 0.06) in vegetables when omitting the population with high current smoking rate (>40%), which suggested that smoking may influence our results. Some studies have reported the association between smoker and nonsmoker intake of fruits or vegetables and risk of BC; but we did not pool the results for there were limited studies (n ≤ 5). The influence of smoking on our results should be treated with caution. Second, there did have selection bias in our dose-response meta-analysis—we excluded 2 cohort studies56,57 with the data were not available that may influence our results. Third, as for analyses that with <10 studies, we did not test the publication bias, the influence of publication bias on the results should be noted. Fourth, we did not test the nonlinearity association between citrus, cruciferous vegetables and risk of BC since there were several studies only reported the linear association, which may lead to reporting bias. Moreover, the cases of included studies were only distributed in European, America, and Asian; so, the results of our meta-analysis may suit better for these areas.
Current published evidence suggests no association between fruits intake, vegetables intake, both FVs intake and risk of BC. No evidence support citrus is benefit for BC prevention. The effect of cruciferous vegetables on BC prevention is inconsistent. Green leafy vegetables may be associated with reduced risk of BC. Studies should provide more detailed data for further analysis.
We thank Prof. Kwong Joey Sum Wing for providing statistical consultation for our meta-analysis.
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