Discussion
In this NLCS analysis, sex-specific associations of a priori defined Mediterranean diet adherence with risks of overall cancer and cancer subgroups defined by relations with 3 major cancer risk factors (tobacco smoking, obesity, and alcohol consumption) were investigated. In women, middle compared with low aMEDr values were significantly associated with a reduced risk of overall cancer and the majority of the cancer subgroups investigated. Other associations in women were not statistically significant after full adjustment for confounding, but all estimates were below 1. No association was observed between aMEDr and risk of overall cancer or any of the cancer subgroups in men. Inclusion of alcohol in the Mediterranean diet score diminished the model performance.
Even though the association of Mediterranean diet adherence with overall cancer risk is comprised of a combination of potentially diverging associations with individual cancer (sub)types, overall cancer risk is an interesting end point for epidemiological studies. It provides insight in the overall possible benefits of Mediterranean diet adherence and the potential of the Mediterranean diet as a dietary strategy for cancer prevention. Findings of previously conducted prospective studies evaluating the relation between a priori defined Mediterranean diet adherence and overall cancer risk have been inconclusive and were rarely specified by sex.
A priori defined Mediterranean diet adherence has previously significantly been associated with a reduced overall cancer risk in the total European Prospective Investigation into Cancer and Nutrition (EPIC) cohort as well as the Greek EPIC cohort., Comparing the highest with the lowest Mediterranean diet adherence category in the total EPIC cohort, HRs (95% CIs) of 0.93 (0.88-0.99) and 0.93 (0.89-0.96) were observed for men and women, respectively. Although inverse associations were also suggested for both sexes in the Greek EPIC cohort, only effect estimates obtained in women reached statistical significance (HRhigh vs low [95% CI]: 0.83 [0.63-1.09] for men and 0.73 [0.56-0.96] for women). In addition to the previously mentioned EPIC studies, weak inverse associations between Mediterranean diet adherence and overall cancer risk were observed in men (HRper tertile increase [95% CI]: 0.97 [0.94-1.01]) and women (HRper tertile increase [95% CI]: 0.97 [0.93-1.00]) participating in the Swedish prospective Västerbotten Intervention Programme. In the present analysis of the NLCS cohort, a priori defined Mediterranean diet adherence was not associated with overall cancer risk in men. In regard to women, although the multivariable-adjusted associations in female NLCS participants were not statistically significant in most cases, effect estimates were stronger inverse than those observed for women in the total EPIC cohort, which did reach statistical significance possibly due to the larger number of cases. Additional cohort studies in Germany and France have investigated the association between Mediterranean diet adherence and overall cancer risk in men and women together and did not observe an association., Besides the prospective cohort evidence, a reduced overall cancer risk (borderline significant, P = .05) was indicated in patients with coronary heart disease who followed an α-linolenic acid-rich Mediterranean-type diet as opposed to a control diet close to the step 1 prudent diet of the American Heart Association in the randomized Lyon Diet Heart Study. However, results should be interpreted with caution because they were based on only 24 incident cancer cases.
Differential adjustment for potential confounding factors and residual confounding, particularly by tobacco smoking and female reproductive factors, may have contributed to the varying associations between a priori defined Mediterranean diet adherence and overall cancer risk that have been reported thus far. Other potentially contributing factors include differences in the method of Mediterranean diet assessment, the composition of the study population, and the time period and/or geographical region in which the study was conducted. The distribution of the specific cancer types in the overall cancer outcome is likely to vary over time and between countries because of, for example, different distributions of risk factors and the introduction of cancer screening programs. Some specific cancer types are inversely associated with Mediterranean diet adherence, whereas null associations have been observed for others. For example, Mediterranean diet adherence has inversely been associated with risks of postmenopausal breast cancer (particularly of the estrogen receptor negative subtype) and subtypes of esophageal and gastric cancer in previous NLCS analyses., However, no association was found with colorectal cancer risk and a positive association with nonadvanced prostate cancer risk., Therefore, differences in the relative incidence of specific cancer types could also (partly) be responsible for the inconsistent findings concerning overall cancer risk.
Results of the present study indicated that the inverse association between Mediterranean diet adherence and overall cancer risk, if present, might be restricted to women. In line with these findings, slightly stronger inverse associations were observed in female participants of EPIC-Greece, though the interaction by sex did not reach statistical significance. Cancers arising in men and women may etiologically differ. The sex-specific levels of sex hormones may influence tumor development and could therefore potentially modulate the association of dietary factors with cancer risk., , , , Apart from other factors, sex-related differences may also exist in exposure levels to risk factors and carcinogen metabolism.,, , Furthermore, the disparate associations of Mediterranean diet adherence with commonly diagnosed sex-specific cancers (ie, postmenopausal breast and prostate cancer) are likely to have contributed to the heterogeneous relations of Mediterranean diet adherence with overall cancer risk for men and women. It should be noted that other studies did not observe clear differences in associations between the sexes,, stressing the importance of additional research on this topic.
Associations with Mediterranean diet adherence among women in the present study appeared comparable for overall cancer risk and risks of cancer subgroups defined by the presence of a relation with tobacco smoking, obesity, or alcohol consumption. In contrast to the findings for women, significant heterogeneity was observed in all subgroup comparisons in men. However, associations with Mediterranean diet adherence did not reach statistical significance for any of the subgroups in men and the differences did not seem to be relevant. The statistical power in the present study was high, especially for men, which increased the likelihood for small and irrelevant differences to become statistically significant. Additionally, one should realize that the distribution of the individual cancer types differs between the subgroups in men and women, and that in certain subgroups a substantial proportion can be comprised by sex-specific cancers.
Regarding cancers related vs not related to obesity and alcohol consumption, similar results were obtained in previous studies., The inverse association with Mediterranean diet adherence was stronger for smoking-related cancers compared with cancers not related to tobacco smoking in the total EPIC cohort, whereas the opposite was observed in the Greek EPIC cohort. Furthermore, associations did not seem to differ in a Swedish cohort. These contrasting findings may have resulted from differences in the classification of cancer types as being related to tobacco smoking or not. For example, although cancers of the colorectum/large bowel were classified as being smoking-related in the studies by Couto et al and Bodén et al, they were considered not being related to smoking in the study by Benetou et al. Moreover, the subgroup of cancers not being related to tobacco smoking constituted all cancers not classified as being related to smoking in one study, whereas the 2 other studies selected specific cancer types.,
The cancer-preventive effect of the Mediterranean diet seems biologically plausible. The high intake of dietary antioxidants in the Mediterranean diet (eg, polyphenols and vitamins from plant foods and olive oil) and the resulting higher total antioxidant capacity that has been associated with adherence to this dietary pattern may defend the body against the DNA-damaging effects of free radicals and other oxidants., , Moreover, the anti-inflammatory effects of polyphenols and the favorable fatty acid profile of the Mediterranean diet (high in anti-inflammatory omega-3 polyunsaturated fatty acids) may reduce inflammation., Several additional mechanisms have been proposed for the cancer-preventive effect of the Mediterranean diet, which were among others related to body weight regulation and the low consumption of red and processed meats.,
Important strengths of the NLCS include the large sample size, prospective design, and nearly complete follow-up of 20.3 years, which make information and selection biases unlikely. The statistical power was adequate to perform sex-specific analyses for overall cancer risk as well as risks of cancer subgroups defined by relations with three major cancer risk factors. The possibility of residual confounding was minimized through comprehensive adjustment for cigarette smoking and other potential confounders, including reproductive factors in women.
Limitations of this study include the lack of updated dietary information during follow-up and possible measurement errors in the exposure assessment, which may have attenuated some associations. The use of cohort-specific cutoffs in the assessment of Mediterranean diet adherence may pose a final weakness. Participants with high aMEDr values in the non-Mediterranean study population of the NLCS could potentially be classified in intermediate or low adherence categories in populations with higher intakes of typically Mediterranean foods. As expected, intakes of typically Mediterranean food groups (eg, vegetables, fruits [including nuts], and legumes) were lower in NLCS subcohort members compared with participants of the Greek EPIC cohort, whereas the opposite was observed for the intake of meat. Among men, median daily intakes were 207 and 550 g/d for vegetables, 166 and 363 g/d for fruits (including nuts), 6 and 9 g/d for legumes, and 141 and 121 g/d for meat (all types) in the NLCS subcohort and EPIC-Greece, respectively. The respective intakes among women were 219 and 500 g/d for vegetables, 215 and 356 g/d for fruits, 5 and 7 g/d for legumes, and 124 and 90 g/d for meat.
Conclusions
Mediterranean diet adherence was not associated with risk of overall cancer or any of the cancer subgroups in male participants of the prospective NLCS. Multivariable-adjusted HR estimates in women pointed in the inverse direction, but were only statistically significant when comparing the middle with the lowest aMEDr category. Associations of Mediterranean diet adherence with subgroups of cancer defined by relations with tobacco smoking, obesity, and alcohol consumption closely resembled the results obtained for overall cancer risk in women.
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