This quantitative summary of the published literature on the risk of breast cancer associated with dietary fat intake suggests that a higher intake of fat is associated with an increased risk of breast cancer. The summary relative risk for all studies that examined nutrient intake is calculated from the results of cohort and case–control studies, and in contrast to our previous publication, the results from these different designs for epidemiological investigation gave very similar results. This conclusion is based on 45 studies that contain a total of 25
015 cases of breast cancer and 580
000 control or comparison subjects. The summary risk estimates from all case–control and cohort studies were very similar, although neither was statistically significant. The combined estimate, however, was statistically significant as was the summary risk estimate for cohort studies that met 80% or more of the quality standards.
Other differences between our earlier analysis and the present findings are summarised in
. (The software used for our earlier analysis contained a programming error, which had a small influence on the results, but did not affect the conclusions of the paper. The table shows the corrected values of the published results.) Compared to the 1993 analysis, which was based on 23 studies, the present analysis based on 45 studies, gave smaller odds ratios for case–control studies, and slightly larger relatives risks for cohort studies. Neither study design gave significant estimates of risk in the previous or present analysis, but the combined estimates were significant in both. Among studies of higher quality, the estimate from cohort studies was significant in the present results, while the estimate from case–control studies was no longer significant. Strong evidence of substantial variation in results according to the geographical location of the study was present in both analyses. Point estimates of risk associated with fat intake were highest in Asia, lowest in North America and intermediate in Europe, findings that may be related to differences in the underlying variation in dietary fat intake in the populations in these regions.
Summary risks for 1993 and present meta-analyses
Different studies partitioned fat intake in different ways, but an examination of the results obtained suggested that partitioning by tertiles, quartiles or quintiles gave very similar estimates. Among the major subtypes of fat, we found that saturated fat was significantly associated with breast cancer risk in both case–control and cohort studies, and that results were significant in the present but not the previous analysis. Mono- and polyunsaturated fat were not significantly associated with breast cancer in either case–control or cohort studies, or in summaries of all studies in the present analysis.
Our conclusion about the relationship of dietary fat to risk of breast cancer is supported to some degree by studies of specific foods. Of the studies that examined intake of foods in relation to risk of breast cancer, the largest number had examined meat consumption, which was significantly associated with breast cancer risk in this meta-analysis, in the overall estimate of risk and in both case–control and cohort studies considered separately. Fewer studies examined milk and cheese intake in relation to breast cancer risk, and although point estimates for the summary relative risks of all studies were greater than unity for both foods, neither was statistically significant.
Although this meta-analysis was based on published results, we were able to generate results similar to those of a previously published combined analysis of a subset of the cohort studies examined here. The differences between the results obtained in case–control and cohort studies might be attributable to recall bias, but as similar results were found here in the two research designs it is not likely that this potential source of bias has a major influence.
The biological plausibility of an association between dietary fat and breast cancer risk is shown by the effect that dietary fat intake has on mammary carcinogenesis in animals (see, for reviews, Freedman et al, 1990
; Welsch, 1994
),which appears to be distinct from the effect of calories, as well as by the known biological effects of fat. Potential mechanisms include the generation from fatty acids of eicosanoids, the generation of free radicals and mutagenic compounds such as malondialdehyde by lipid peroxidation and the modulation of genes that are involved in mammary carcinogenesis (Cohen et al, 1986
Despite the strong evidence that breast cancer is influenced by environmental factors, and the consistency of the ecological analyses suggesting that dietary fat is one of these factors, epidemiological investigations of the relationship of dietary fat to breast cancer incidence based upon the measurement of dietary intakes in individuals with case–control and cohort studies, have given much less consistent results. However, in considering these results, and those given above in our quantitative summary of the published literature, we need to consider the effects of the relative homogeneity of fat intake within populations and error in the measurement of fat intake, both factors that are expected to attenuate any true association between dietary fat and breast cancer.
For example, homogeneity is shown by the range across quintiles of total fat intake in the Nurses Health Study (Willett et al, 1987
), a large cohort study in North America, which was only 32–44% of calories, compared to the international range of 15% or less to more than 40% of calories. This narrow range of fat intake is expected, from international data, to be associated with a relative risk of only 1.4 in the highest quintile of fat intake relative to the lowest. When the measurement error known to be associated with the food frequency questionnaire used is taken into account, this estimate of the relative risk is reduced to 1.16, a figure that is close to the summary relative risk of our meta-analysis (Prentice et al, 1988
Measurement error in the food frequency questionnaires used in most studies may lead to overestimation of the range of intakes and may also lead to attenuation of risk (Prentice, 2003
). The cohort study of Bingham et al (2003)
showed a small and nonsignificant increase in the risk of breast cancer when fat intake was estimated from a food frequency questionnaire, but a larger and significant increase when estimated from food records obtained from the same subjects.
Experimental trials, in which the range of fat intake is increased beyond that seen in most Western populations, are a means of overcoming the limitations of observational epidemiology that arise from homogeneity of intake and measurement error, and provide the strongest evidence available concerning a causal relationship of dietary fat intake to breast cancer risk. Further, such trials are the only means available to determine whether breast cancer risk in high-risk subjects can be reduced by changing dietary fat intake.