Correspondence to: Michelle Holmes, M.D., Dr.P.H., Brigham & Women's Hospital, Harvard Medical School, Channing Laboratory, 181 Longwood Ave., Boston, MA 02115.
We wish to comment on the meta-analysis by Wu et al. (1) on dietary fat, estrogen levels, and breast cancer risk. The validity of a meta-analysis depends on the validity of the component studies. We have serious concerns about the merits of the 13 individual studies in this analysis.
The use of a control group to guard against unintentional effects introduced by the experimental milieu is a basic tenet of experimental science. Only one of 13 component studies had a simultaneous control group.
A positive association between postmenopausal estrogen levels and adiposity has been reported (2). Women in six of 13 studies experienced statistically significant weight loss during the intervention, including those in three of four studies of postmenopausal women. In the study with the lowest fat intake and greatest estrogen reduction, the magnitude of weight loss suggests a negative energy balance of approximately 1000 Kcal/day. A low-fat diet may cause a small transient weight loss because of a lower caloric intake, so short-term studies that are not isocaloric can be misleading (3).
Fiber intake may decrease breast cancer risk by decreasing serum estrogen levels. In four of 13 studies, an increase in fiber intake was an explicit goal; one study reported a statistically nonsignificant increase in fiber intake although it was not a goal.
Regrettably, the quality of dietary interventions to affect hormone levels is decades behind the standards in research for modifying blood lipid levels, in which randomization, use of control groups, and isocaloric diets are the norm. Such research has clearly established the associations between dietary fats and blood lipids. Also, examining the relationship between dietary fat and estrogen levels alone will not allow observers to draw meaningful conclusions about the relation between fat intake and breast cancer. Other hormonesincluding insulin-like growth factor 1 and prolactinare also likely to influence breast cancer, and the effects of dietary fat on levels of these hormones could differ. For this reason, data directly relating fat intake to breast cancer risk are essential.
We feel that these limitations make it imprudent to conclude that dietary fat reduction can reduce estradiol levels and, consequently, breast cancer risk.
Wu et al. (1) raise the issue of measurement error for fat intake that is less than 20% of energy in the international pooled analysis of diet and breast cancer (4). The number of women with intake that low is too few to allow for correction by use of standard matrix methods. However, the inverse matrix method of Marshall is more stable (5). Applying this method, the estimated odds ratios for fat intake less than 20%, 20%-30%, and greater than 35%compared with 30%-35% as the referentwent from 1.10, 0.98, and 0.98, respectively, to 0.98, 0.98, and 1.0, respectively. As with the continuous measurement error correction previously published (4), correction for misclassification does not produce estimates consistent with the international correlation data. Also, in the lowest fat intake group (<15% of energy from fat), risk of breast cancer was significantly increased. Thus, standard correction for measurement error would move the relative risk further away from a risk reduction. The same applies to the 14-year follow-up of the Nurses' Health Study (6), in which the highest risk of breast cancer was seen for women reporting at most 20% of energy from fat, and the overall trend was significantly inverse.
REFERENCES
1
Wu AH, Pike MC, Stram DO. Meta-analysis: dietary fat intake,
serum estrogen levels, and the risk of breast cancer. J Natl Cancer Inst 1999;91:529-34.
2 Hankinson SE, Willett WC, Manson JE, Hunter DJ, Coldtiz GA, Stampfer MJ, et al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 1995;87:1297-302.[Abstract]
3 Willett WC. Is dietary fat a major determinant of body fat? Am J Clin Nutr 1998; 67(3 Suppl):556S-62S.[Abstract]
4
Hunter DJ, Spiegelman D, Adami HO, Beeson L, van den Brandt
PA, Folsom AR, et al. Cohort studies of fat intake and the risk of breast cancera pooled
analysis. N Engl J Med 1996;334:356-61.
5 Morrissey MJ, Spiegelman D. Matrix methods for estimating odds rations with misclassified exposure data: extensions and comparisons. Biometrics 1999;55:338-44.[Medline]
6
Holmes MD, Hunter DJ, Colditz GA, Stampfer MJ, Hankinson
SE, Speizer FE, et al. Association of dietary intake of fat and fatty acids with risk of breast
cancer. JAMA 1999;281:914-20.
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