Affiliations of authors: E. Cho, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, Boston, MA; D. Spiegelman, Departments of Biostatistics and Epidemiology, Harvard School of Public Health, Boston; D. J. Hunter, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Harvard Center for Cancer Prevention, Boston; W. Y. Chen, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, and Department of Adult Oncology, Dana-Farber Cancer Institute, Boston; M. J. Stampfer, W. C. Willett, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, and Departments of Nutrition and Epidemiology, Harvard School of Public Health; G. A. Colditz, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, Department of Epidemiology, Harvard School of Public Health, and Harvard Center for Cancer Prevention.
Correspondence to: Eunyoung Cho, Sc.D., Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: eunyoung.cho{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Previous prospective studies on fat intake and breast cancer risk have included relatively few premenopausal women with breast cancer (57). Because some risk factors for breast cancer vary greatly according to age or menopausal status, the association between fat intake and breast cancer risk among premenopausal and postmenopausal women may be different. Moreover, the associations between fat intake during early adulthood and breast cancer risk have not been investigated extensively. In this study, we evaluated the association of fat intake and risk of breast cancer in premenopausal women enrolled in the Nurses Health Study (NHS) II.
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SUBJECTS AND METHODS |
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The NHS II is a prospective cohort study of 116 671 female registered nurses aged 25 to 42 years and living in one of 14 states within the United States when they responded in 1989 to a questionnaire about their medical histories and lifestyles. Follow-up questionnaires have been sent biennially to update information on risk factors and medical events.
For the current analysis, we started follow-up at 1991, when diet was first measured. From the 97 807 women who returned the 1991 dietary questionnaire, we excluded women (n = 2361) who had an implausible total energy intake (<800 or >4200 kcal/day) or who left more than 70 food items blank in the 1991 food-frequency questionnaire (FFQ). We also excluded women who reported a diagnosis of cancer, except non-melanoma skin cancer, before returning the 1991 questionnaire (n = 1325). Because the number of postmenopausal women at baseline was small (n = 3466), we excluded them from this analysis, leaving a total of 90 655 premenopausal women. Among those who answered the FFQ in 1991, the follow-up rate was 93% by May 31, 1999. The study was approved by the Human Research Committees at the Harvard School of Public Health and the Brigham and Womens Hospital.
Dietary Assessment
A semiquantitative FFQ with 133 and 142 food items was sent to women in 1991 and 1995, respectively, to assess usual dietary intake during the past year. Participants were asked how often, on average, they had consumed each type of food or beverage during the past year. The FFQ had nine possible responses, ranging from never or less than once per month to six or more times per day. Fat intake per individual was calculated as the sum of the contributions from all foods on the basis of U.S. Department of Agriculture food composition data (8), taking into account types of margarine and fats used in cooking and baking. To calculate the percentage of energy contributed by each type of fat, we divided energy intake from each fat by total energy intake. We also examined food groups contributing to intake of animal fat, such as red meat, chicken, fish, and low- and high-fat dairy foods.
Because fat intake has been hypothesized to promote breast carcinogenesis over an extended period of time, we calculated cumulative averaged intakes of fat and food groups using the 1991 and 1995 dietary data to best represent long-term intake for our primary analysis (9). Specifically, the 1991 intake was used for the 19911995 follow-up period, and the average of the 1991 and 1995 intake was used for 19951999 follow-up to maintain a strictly prospective analysis.
The reproducibility and validity of fat intake determined with a similar FFQ have been assessed in cohorts of older women (1012). For specific types of fat, Pearson correlation coefficients between energy-adjusted intakes from the average of two 1-week diet records and from the FFQ ranged from 0.48 to 0.73 (0.57 for total fat and 0.68 for saturated fat), with a correction for attenuation resulting from random error in diet records (11). Total fat intake has been validated using changes in blood lipid levels (12). Spearman correlation coefficients between the percentage of fat intake calculated from the FFQ and the fatty acid composition of subcutaneous fat aspirates has confirmed that the FFQ measured specific fatty acids from exogenous sources reasonably well (r = .51 for trans-unsaturated fat; r = .48 for long-chain omega-3 fatty acids) (10). The reproducibility and validity of individual fat-contributing foods have been evaluated elsewhere (13). Most of the correlation coefficients between diet records and FFQ for intake of meat and dairy foods were greater than .50, after a correction for attenuation resulting from random error in diet records.
Documentation of Breast Cancer
Biennial questionnaires mailed between 1993 and 1999 were used to identify newly diagnosed breast cancers. Most of the deaths in this cohort were reported by family members or by the postal service in response to the follow-up questionnaires. In addition, the National Death Index was searched for nonresponders. When a breast cancer was reported, we asked the participant (or next of kin for those who had died) for confirmation of the diagnosis and for permission to obtain relevant hospital records and pathology reports. Pathology reports confirmed 98% of the self-reported breast cancers. Because the degree of self-reporting accuracy was high, we included the few self-reported breast cancers for whom records could not be obtained. Cases of carcinoma in situ were not included in the analyses. Information on estrogen and progesterone receptor status of the breast cancers was obtained from pathology reports.
Statistical Analysis
Participants contributed person-years from the date of return of the 1991 questionnaire until the date of breast cancer diagnosis, death, or June 1999, whichever came first. Participants were divided into quintiles according to their fat or food group intake. Relative risk (RR) of breast cancer was calculated as the incidence rate for women in a given quintile of fat or food group relative to the rate for those in the lowest quintile. We used Cox proportional hazards regression to account for potential effects of other risk factors for breast cancer (14). The assumptions of proportionality were satisfied. To control for confounding by age or calendar time, or any possible two-way interactions between these two time scales, we stratified the analysis jointly by age in months at start of follow-up and calendar year of the current questionnaire cycle. Multivariable models also simultaneously adjusted for smoking status, body mass index, height, age at menarche, oral contraceptive use, family history of breast cancer, history of benign breast disease, parity and age at first birth, menopausal status, and intakes of calories, protein, and alcohol. All covariates except height, age at menarche, and family history of breast cancer were updated in each questionnaire cycle. SAS PROC PHREG (15) with SAS version 8.2 was used for all analyses. The AndersonGill data structure (16) was used to handle time-varying covariates efficiently, with a new data record created for every questionnaire cycle at which a participant was at risk and covariates set to their values at the time the questionnaire was returned. For all RRs, 95% confidence intervals (CIs) were calculated. Tests for trend were conducted using the median value for each category of fat or food group as a continuous variable. To examine whether the association between animal fat and breast cancer risk was modified by other measures of breast cancer risk factors, a cross-product term of the ordinal score for the level of each factor and intake of animal fat expressed as a continuous variable was included in the multivariable model. P values for tests for interactions were obtained from a likelihood ratio test with one degree of freedom. All P values were two-sided. Spearman correlation coefficients were calculated to examine correlations between different fat intake variables.
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RESULTS |
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Breast tumors differ clinically and biologically by estrogen and/or progesterone receptor status and may have different underlying etiologies. We had information on estrogen receptor status for 80% (n = 570) of breast cancers and progesterone receptor status for 78% (n = 558) of breast cancers. When we divided cancers according to estrogen and progesterone receptor status, the positive association between animal fat intake and breast cancer risk was stronger among women with estrogen receptor-positive or progesterone receptor-positive cancers than among women with hormone receptor-negative cancers (Table 3). However, the
2 test for the difference in associations between receptor-positive and -negative cancers was not statistically significant (data not shown).
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To examine whether the positive association between animal fat intake and breast cancer risk was attributable to animal fat per se or to specific foods contributing to animal fat, we examined animal-based food groups (Table 5). Red meat and high-fat dairy foods (i.e., whole milk, cream, ice cream, butter, cream cheese, and cheese, not including cottage or ricotta cheese), the major contributors of animal fat in this cohort, were both positively associated with breast cancer risk. Intake of dairy fat per se was not statistically significantly positively associated with breast cancer risk: the RR for women in the highest quintile compared with those in the lowest was 1.14 (95% CI = 0.90 to 1.45).
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We further examined the individual food items included in the red meat and high-fat dairy food groups. Although none of the individual foods appeared to be strongly associated with breast cancer risk, the majority of the associations were weakly positive (data not shown).
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DISCUSSION |
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National rates of breast cancer are strongly correlated with per capita total fat consumption (17,18), but this relationship is primarily associated with intake of animal fat, rather than vegetable fat, and intake of meat and milk (19). Results from casecontrol studies regarding associations between total fat intake and breast cancer risk have been inconsistent, but a pooled analysis has suggested a positive association (3,17,18). By contrast, prospective studies have not supported an association with total fat intake (2). The fatty acid composition in fat from animal and vegetable sources differs greatly and may therefore have different associations with breast cancer risk. In the United States, animal fat is composed largely of saturated and monounsaturated fatty acids, whereas vegetable fat consists primarily of polyunsaturated, monounsaturated, and trans-fatty acids. Although animal studies have most strongly supported an adverse effect of polyunsaturated fats in mammary tumorigenesis (4,20), casecontrol studies have implicated saturated fat rather than polyunsaturated fat (3). A pooled analysis of prospective studies reported a weakly positive association between breast cancer risk and saturated fat among both premenopausal and postmenopausal women; there was no statistically significant association for other fats (5). Results from the other prospective studies that were not included in the pooled analysis (5) reported divergent findings. A Norwegian study of 248 women with breast cancer found a positive association with intake of monounsaturated fat (6), and a study among U.S. postmenopausal women that included 996 women with breast cancer found a positive association with intake of unsaturated fat only among women with no history of benign breast disease (n = 255) (7).
Because the etiologies of pre- and postmenopausal breast cancer are different in many respects, the relation between dietary fat intake and breast cancer risk in premenopausal women could be different from that in postmenopausal women. For some risk factors, such as adiposity, the direction of the association is reversed (21). For several other known risk factors, effects may be predominately associated with younger age. For example, reproductive factors act on breast tissue largely during the early adult years, and the breast becomes minimally sensitive to radiation-induced carcinogenesis after age 35 (22). It is also possible that diet in early adult life may have a stronger impact on breast cancer risk than diet later in life because exposures during the years before the first birth of a child appear to be most relevant to future risk of breast cancer (23).
Our study provided a unique opportunity to evaluate fat intake relatively early in adult life in relation to breast cancer risk. The mean age of the women with breast cancer was 43 years, substantially lower than in previous prospective studies (5). The finding that the association between animal fat intake and breast cancer risk was weaker when we restricted analysis to women who remained premenopausal during follow-up than when using results from the entire cohort suggests that the timing of dietary assessment may be more important for detecting an association than menopausal status at diagnosis. However, further data with additional cases of both premenopausal and postmenopausal breast cancers are needed to address this issue.
We are not aware of any compelling biologic mechanism relating intake of animal fat (or saturated fat or monounsaturated fat), but not vegetable fat, to breast cancer risk. Fat in general has been postulated to increase breast cancer risk by elevating levels of circulating estrogen. Although, in a meta-analysis of 13 intervention studies, it was reported that reduction of fat intake decreased serum estradiol levels among both premenopausal and postmenopausal women (especially among postmenopausal women) (24), some of the studies had no control groups and participants that were not comparable regarding total energy intake (25). Furthermore, in one recent cross-sectional study among postmenopausal women, neither total fat nor animal fat intake was positively related to estrogen levels (26). Thus, it is not likely that animal fat intake affects breast cancer risk by modulating estrogen levels.
The positive association we observed between animal fat intake and breast cancer risk could be attributable to other components in foods containing animal fat (e.g., red meat and high-fat dairy foods). For example, cooked red meat is a source of carcinogens such as heterocyclic amines, N-nitroso compounds, and polycyclic aromatic hydrocarbons that are related to induction of mammary tumors in animals (27). We have limited information on the preparation of red meat and are not able to examine these hypotheses further. High-fat dairy foods contain fat-soluble hormones or growth factors, which may be related to breast cancer risk (28).
Our results are not in accord with the pooled analysis of eight prospective studies in which no association was found between intake of red meat and breast cancer risk (29), but there was little overlap between the pooled analysis and our study in the age range of women with breast cancer. In two other relatively small prospective studies, a positive association was found between consumption of meat or fried meat and breast cancer risk (30, 31). Researchers in one casecontrol study reported a positive association between breast cancer and doneness of red meat (32), and the results of another casecontrol study among relatively young women suggested a positive association between intake of high-fat meat during adolescence and breast cancer (33). Our findings on high-fat dairy foods among younger women are also not consistent with the pooled analysis of prospective studies in which little relationship was seen (29). The findings of the few other prospective studies that examined dairy foods and breast cancer risk have also not been consistent (30, 34).
Breast cancer subtypes defined by hormone receptor status may have different etiologies, and associations between breast cancers and some risk factors, such as body mass index, have differed by hormone receptor status (35). In one previous study among postmenopausal women, a positive association between dietary fat intake and breast cancer was suggested only among women with cancers that were positive for estrogen and progesterone receptors (36). We also found that the association between animal fat intake and breast cancer was stronger for women with estrogen receptor-positive cancers than for women with estrogen receptor-negative cancers.
Our study had several strengths. First, the prospective nature of the study avoided some of the biases associated with casecontrol studies, and few participants have been lost to follow-up. Second, because we had repeated measures of dietary intake, we were able to examine long-term averaged diet, as well as baseline diet and most recent intake. Third, we had information on a wide range of potential confounders and adjusted for them.
Our study also had several limitations. First, although our dietary assessment method has been shown to be informative by a variety of methods for intakes of total and specific types of fat (1012), some error is inevitable and would tend to underestimate the magnitude of associations. However, error is reduced by the use of repeated measures, and this error would not account for the positive association we observed with animal fat. Second, the duration of follow-up time and number of cases were limited, especially in analyses stratified by hormone receptor status and other breast cancer risk factors.
In conclusion, in this population of relatively young women, premenopausal animal fat intake was associated with a higher risk of breast cancer, which was largely related to intake of red meat and high-fat dairy foods. Prevention of coronary heart disease already provides a good reason for choosing a diet low in red meat and dairy fat. Because prevention of heart disease is likely to be a low priority for young women, these findings have substantial potential implications in encouraging women to adopt healthy diets and should be evaluated further.
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NOTES |
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We are indebted to Karen Corsano for computer support.
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Manuscript received November 16, 2002; revised May 6, 2003; accepted May 27, 2003.
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