Context High intakes of fat and specific fatty acids,
including total, animal, saturated, polyunsaturated, and
trans-unsaturated fats, have been postulated to increase
breast cancer risk.
Objective To determine whether intakes of fat and fatty acids are
associated with breast cancer.
Design and Setting Cohort study (Nurses' Health Study) conducted
in the United States beginning in 1976.
Participants A total of 88,795 women free of cancer in
1980 and followed up for 14 years.
Main Outcome Measure Relative risk (RR) of invasive breast cancer
for an incremental increase of fat intake, ascertained by food
frequency questionnaire in 1980, 1984, 1986, and 1990.
Results A total of 2956 women were diagnosed as having breast
cancer. Compared with women obtaining 30.1% to 35% of energy from
fat, women consuming 20% or less had a multivariate RR of breast
cancer of 1.15 (95% confidence interval [CI], 0.73-1.80). In
multivariate models, the RR (95% CI) for a 5%-of-energy increase was
0.97 (0.94-1.00) for total fat, 0.98 (0.96-1.01) for animal fat, 0.97
(0.93-1.02) for vegetable fat, 0.94 (0.88-1.01) for saturated fat, 0.91
(0.79-1.04) for polyunsaturated fat, and 0.94 (0.88-1.00) for
monounsaturated fat. For a 1% increase in energy from
trans-unsaturated fat, the values were 0.92 (0.86-0.98), and
for a 0.1% increase in energy from omega-3 fat from fish, the values
were 1.09 (1.03-1.16). In a model including fat, protein, and energy,
the RR for a 5% increase in total fat, which can be interpreted as the
risk of substituting this amount of fat for an equal amount of energy
from carbohydrate, was 0.96 (95% CI, 0.93-0.99). In similar models, no
significant association of risk was evident with any major types of
fat.
Conclusion We found no evidence that lower intake of total fat or
specific major types of fat was associated with a decreased risk of
breast cancer.
High intake of
total dietary fat has been postulated to increase breast cancer risk on
the basis of animal studies,1,2 international
comparisons,2-4 and a meta-analysis of case-control
studies.5 However, the meta-analysis has been criticized
for ignoring heterogeneity among studies.6 In addition, the
dietary fat hypothesis has not been supported by cohort studies, which
are less prone to bias than case-control studies.7-9 In a
pooled analysis of 7 international cohorts with nearly 5000 cases, the
multivariate relative risk (RR) for the highest compared with the
lowest quintile of total fat intake was 1.05 (95% confidence interval
[CI], 0.94-1.16).9 Some authors have suggested that fat
intake be 20% or less of total energy intake for a protective effect
to be evident and have maintained that such a protective effect has not
been found in cohort studies because they were conducted in Western
populations in whom the level of fat intake is rarely this
low.2
Another possible explanation for the conflicting results of prospective
and retrospective studies of diet and breast cancer is that the intake
of specific fatty acids, rather than that of total fat, may influence
breast cancer risk. In animal studies, certain fatty acids have
modulated mammary tumor growth and metastasis; evidence is strongest
for a promotional effect of polyunsaturated fat1,10-15 and
an inhibitory effect of omega-3 fat from marine
sources.11,16-20 These observations are supported by human
ecological studies.2,21-24
Other epidemiologic studies have been limited in duration and have used
information about dietary intake from only 1 point in time; thus, these
investigations have not taken into account changes in diet over time. A
few case-control studies have used adipose tissue levels of specific
fatty acids as a marker of long-term intake. However, adipose tissue
does not provide an assessment of total fat intake or intake of fatty
acids that can
be endogenously synthesized. Also, because
results are expressed as the percentage of total fatty acids, an
increase in 1 type of fat necessarily means a decrease in another,
making interpretation difficult.
In this analysis we followed up 88,795 women for 14 years,
extending our previous analysis7 by 6 years and more than
1500 cases. This extended study is now large enough and long enough to
assess the effect of very low fat intake (≤20% of energy) even though
intake this low was still not common. We also examined type of fat
consumed and the risk of breast cancer in detail, and we used dietary
intake assessed at 4 different points to calculate a cumulative average
intake that best represented long-term intake.
The Nurses' Health Study Cohort
In 1976, the Nurses' Health Study (NHS) cohort was established when
121,700 female registered nurses from across the United States,
aged 30 to 55 years, answered a mailed questionnaire on risk factors
for cancer and cardiovascular disease. Every 2 years since, we have
sent follow-up questionnaires to NHS participants. In 1980, a 61-item
food-frequency questionnaire designed to assess dietary intake was
added. In 1984, 1986, and 1990, an expanded food-frequency
questionnaire was used. This analysis is based on the 88,795
women who answered the 1980 diet questionnaire, who did not have
implausible scores for total energy intake (<2092 kJ [500 kcal] or
>14,644 kJ [3500 kcal] per day, approximately 2% of
returned diet questionnaires), and who did not have diagnosed cancer
(other than nonmelanoma skin cancer, 3101 cases excluded) prior to
1980.
Semiquantitative Food-Frequency Questionnaires
The food-frequency questionnaires have been described in detail, and
their validity and reproducibility have been documented
elsewhere.25,26 A commonly used portion size was specified
for each food (for example, 1 slice of bread or 1 egg). Participants
were asked to average how frequently over the past year they had
consumed that portion of food. The 9 prespecified responses ranged from
"never" to "6 or more times per day." We also asked about the
types of fat used for cooking and at the table.
We multiplied the frequency of consumption of each food by the nutrient
content of the portion size, taking into account cooking fat, to obtain
nutrient intakes. Nutrient values in foods were obtained from US
Department of Agriculture sources.27 We included all
trans isomers of 18-carbon unsaturated fatty acids in the
calculation of total trans; values for the trans
content of food came primarily from analyses by Enig et
al28 and Slover et al.29 Omega-3 fatty acid
intake from fish represented the summation of eicosapentaenoic and
docosahexaenoic acids. Correlations between intakes from the
questionnaire used in 1986 and onward and intakes from repeated weighed
diet records were 0.67 for total fat, 0.70 for saturated fat, 0.64 for
polyunsaturated fat, and 0.69 for monounsaturated fat.26
Identification
of Breast Cancer Cases
In each biennial questionnaire, participants were asked whether
they had been diagnosed as having breast cancer in the previous 2
years. Deaths were identified by a report from a family member, the
postal service, or the National Death Index; the ascertainment is 98%
complete. Follow-up of the entire cohort through 1994 is 95% complete.
Medical records were obtained for breast cancer cases identified by
either self-report or vital records, and more than 99% of these
records confirmed the self-report. Cases of carcinoma in situ were
excluded.
Each participant accumulated person-time beginning with the
return of the 1980 questionnaire and ending with her cancer diagnosis,
death, or June 1, 1994, whichever came first. In secondary analyses, we
began follow-up at the time of return of the 1984 or 1988
questionnaire. Fat intake from each dietary questionnaire was
classified as a percentage of total energy intake, and total energy
intake was included in each regression model. We used pooled logistic
regression using 2-year time intervals with RR as the measure of
association.30 To take into account dietary changes over
time, we calculated the cumulative average intake of fat from all
available dietary questionnaires up to the start of each 2-year
interval. In this calculation, the 1980 diet was related to breast
cancer incidence between 1980 and 1984; the average of the 1980 and
1984 diets was related to breast cancer incidence between 1984 and
1986; the average of the 1980, 1984, and 1986 diets was related to
breast cancer incidence between 1986 and 1990; and the average of all 4
diets was related to breast cancer incidence between 1990 and 1994. In
alternative analyses, only the 1980 baseline diet was related to
breast cancer incidence. In "substitution" models, fat intake was
simultaneously included as a nutrient density with total energy intake
and protein intake as explanatory variables.26 In these
models, the coefficient for fat can be interpreted as substitution of a
percentage of energy from fat for an equal percentage of energy from
carbohydrates. Intake of dietary factors other than fat, such as total
energy, carbohydrates, protein, alcohol, vitamin A, vitamin E, and
total fiber, was calculated in the same manner as fat intake.
The following nondietary covariates were updated every 2 years:
age, history of benign breast disease, menopausal status, age at
menopause, use and duration of use of postmenopausal hormones, parity,
age at first birth, and weight change since the age of 18 years. Age at
menarche, height, and body mass index (weight in kilograms divided by
the square of height in meters) at the age of 18 years were determined
at baseline, and information on family history of breast cancer was
sought in 1976, 1982, 1988, and 1992. Women of uncertain ovulatory
status (mainly those who had undergone hysterectomy but had intact
ovaries) were excluded from analyses including stratification by
menopausal status. In tests for linear trend across categories of
percentage of energy from fat, ordinal rank was assigned to each
category.
We identified 2956 incident cases of invasive breast cancer among
88,795 women during 1,172,028 person-years of
follow-up between 1980 and 1994. Average intake of total fat as a
percentage of energy intake was 39% in 1980, 36% in 1984, 33% in
1986, and 31% in 1990. Correlations between intakes of particular
types of fat, averaged over the entire period studied, were 0.08 for
saturated fat and polyunsaturated fat; 0.81 for saturated fat and
monounsaturated fat; and 0.41 for polyunsaturated fat and
monounsaturated fat.
Table 1 shows the multivariate RR and
95% confidence interval (CI) of breast cancer incidence according to
the percentage of energy obtained from total fat, cumulatively averaged
from 1980 through 1994. With 30.1% to 35% of energy from fat as the
reference category, women consuming 20% or less of total energy as fat
had a slightly increased risk of breast cancer (RR, 1.15; 95% CI,
0.73-1.80), and the overall linear trend for higher risk with lower fat
intake was statistically significant (P = .03). Results were
similar for both premenopausal and postmenopausal women.
In Table 2,
Table 3,
Table 4, and
Table 5, fat intakes are expressed as continuous
variables. Intervals of intake for total fat and each type of fat were
chosen to represent approximately the interquartile range of intake.
Table 2 shows the multivariate
RR of breast cancer associated with intake of total energy and of
various types of fat, cumulatively averaged for 1980 through 1994 and
stratified by menopausal status at diagnosis. In the whole cohort and
in both the premenopausal and postmenopausal groups there was no
association of breast cancer incidence with intakes of energy, total
fat, animal fat, vegetable fat, polyunsaturated fat, saturated fat, or
cholesterol. Slight inverse associations were seen for monounsaturated
fat among postmenopausal women only and for
trans-unsaturated fat in the whole cohort and among
postmenopausal women. A slight positive association was seen in the
whole cohort and among postmenopausal women for omega-3 fats from fish.
The greater number of food items on the 1984 dietary questionnaire
allowed more extensive calculation of intake of types of fat.
Table 3 provides data on the intake
of an expanded list of types of fat averaged over the 1984, 1986, and
1990 diets, with follow-up from 1984 through 1994. Again, total fat
intake was not associated with breast cancer incidence. Significant
inverse associations with breast cancer incidence were seen for intakes
of vegetable, polyunsaturated, monounsaturated, and
trans-unsaturated fats as well as for oleic and linoleic
acids, with RRs ranging from 0.82 (polyunsaturated fat) to 0.95
(linoleic acid).
Table 4 shows the results of analysis
with "substitution" models: each model included total energy,
percentage of energy from protein, and percentage of energy from total
fat or from types of fat. In this analysis, the coefficient for fat can
be interpreted as substitution of a percentage of energy from fat for
an equal percentage of energy from carbohydrate. For models in which
types of fat are assessed, all major components of fat that contribute
to total fat intake are included. For example, animal and vegetable
fats are included in the same model, as are saturated, polyunsaturated,
monounsaturated, and trans-unsaturated fats. Substitution of
fat for carbohydrate energy was not associated with higher risk of
breast cancer; the RRs for all fats except monounsaturated were
slightly inverse, although not statistically significant. The slight
inverse association previously observed with monounsaturated fat
intake was reversed but remained statistically insignificant after
intakes of other fats and protein were taken into account. Analysis of
these substitution models stratified by menopausal status showed
similar results for premenopausal and postmenopausal breast cancer.
Table 5 shows the results of
alternative assessments of the relationship between total fat intake
and breast cancer incidence. In models A, B, and C, the 1980 baseline
diet was used, and start of follow-up was delayed 0, 4, and 8 years,
respectively. No substantial variation in risk was observed. In model D
we adjusted for cumulatively averaged intakes of folate, fiber, and
vitamin E from foods; again, no substantial difference in results was
seen. In 1994 we asked participants retrospectively about the use of
screening mammography. In model E we limited the analysis to those
women who had had a screening mammogram before 1994. No relation was
observed between fat intake and risk of breast cancer. To address the
possibility that underreporting of total energy intake had biased the
associations, we used models F and G, calculating the ratio of reported
energy intake to expected basal metabolic rate (based on age and
weight) for each woman during each dietary period.31 In the
analysis for each dietary period, we excluded women who fell into the
bottom 20%—and then the bottom 40%—of the distribution of these
ratios. Even after these exclusions, the RR did not change appreciably.
To address the possibility that obesity is an intermediary step between
fat intake and breast cancer, we did not adjust in model H for BMI at
the age of 18 years or weight change since the age of 18 years. The
results remained similar.
We also examined the relation between total fat intake and breast
cancer incidence between 1980 and 1994 within strata of established
breast cancer risk factors. Again, there was no association of fat
intake with breast cancer among women with or without a family history
of breast cancer (in a mother or sister) or among women with or without
a personal history of benign breast disease, or within categories of
BMI. In postmenopausal women, there was no association of fat intake
with breast cancer within categories of current, past, or no use of
postmenopausal hormones.
We also examined associations of fat-containing foods averaged from
1980 through 1994, with breast cancer incidence. The only significant
positive association was with fish intake (RR for 1 84- to 140-g [3- to 5-oz] serving of fish per day, 1.25; 95% CI, 1.05-1.50).
In this large prospective study, we found no evidence that higher
total fat intake was associated with an increased risk of breast
cancer, even though the relationship was assessed many different ways.
Contrary to the prevailing hypothesis, the overall trend was inverse
and statistically significant.
Long-term averaged diet might not be the best way to express the
relationship between diet and breast cancer; a considerable latency
period could exist between fat intake and its effect on disease.
However, beginning follow-up as late as 8 years after the initial
dietary assessment did not change the results. In some studies, breast
cancer risk has been inversely associated with increased intake of
folate, fiber, and vitamin E from foods5,32; correlations
of these nutrients with fat intake could potentially confound the
association between fat intake and breast cancer. However, adjustment
for the intake of these additional nutrients did not change the
results.
Consuming a low-fat diet may be correlated with a whole set of
health-conscious behaviors, such as participation in mammographic
screening, which may detect cancers earlier and thus artificially
increase the incidence of breast cancer among women with low-fat diets.
However, limiting the analysis to women who had undergone screening
mammography did not change the results.
Underreporting of energy and macronutrient intake, particularly
by those persons who are overweight, has been postulated to bias
estimations of the effect of fat on the development of long-term
disease.33-35 We excluded women with the greatest
likelihood of underreporting intake—first the lowest 20% and then the
lowest 40% of the distribution—when comparing reported energy intake
with expected energy intake based on age and weight. The results were
unchanged. Obesity has been postulated as an intermediary between fat
intake and breast cancer. Postmenopausal breast cancer risk has been
positively associated with BMI among women who never used hormone
replacement in this cohort, and risk has been positively associated
with weight gain since the age of 18 years as well.36
However, leaving out of the model BMI at the age of 18 years and weight
change since the age of 18 years did not change the association of
breast cancer risk with fat intake. None of the various modeling
techniques used in Table 5 made any difference in the association of
fat intake with breast cancer risk. In each case the RR was very close
to 1.00, and the 95% CIs all included 1.00. In those models for total
fat, the data are incompatible with more than a 4% increase in risk
per 5% increase in fat intake.
Animal studies have generally supported a promoting effect of
polyunsaturated fats (particularly linoleic acid) as well as an
inhibitory effect of omega-3 fatty acids on breast cancer development
and metastases. The results of observational studies have been mixed. A
case-control study with 128 participants found significantly lower
levels of omega-3 fatty acids in adipose tissue among
cases.37 The European Community Multicenter Study on
Antioxidants, Myocardial Infarction, and Breast Cancer (EURAMIC)
case-control study with 642 participants found the ratio of omega-3 to
omega-6 to be inversely associated with breast cancer.38
However, 2 other case-control studies, with 309 and 999 participants
each, found no association of omega-3 fatty acids with breast
cancer.39,40 These last 2 case-control studies, like the
large pooled prospective study,9 found no association for
linoleic acid39 or polyunsaturated fats.40 A
third case-control study with 140 cases found that polyunsaturated fats
and linoleic acid both had breast cancer risk.41 However, a
large prospective study from Sweden with 674 breast cancer cases
recently reported a positive, if only marginally, significant
association of polyunsaturated fat with breast cancer risk (RR, 1.89;
95% CI, 1.02-2.78 for an intake increment of 8 g/d as assessed by
food-frequency questionnaire); this is the only previous study to
mutually adjust for other types of fat.42
In addition to these fatty acids, animal fats (the major source of
saturated
fat) and trans-unsaturated fats have
been hypothesized to increase the risk of breast cancer, and olive oil
(predominantly composed of monounsaturated fat) to decrease the risk of
breast cancer. The hypothesis that saturated fat, particularly animal
fat, is associated with breast cancer has come primarily from
ecological studies3,4,24 but in general has not been
supported by either case-control studies39-41 or
prospective studies.9,42 The EURAMIC case-control study
found a positive association for trans-unsaturated fat in
adipose tissue, with an odds ratio of 1.40 (95% CI, 1.02-1.93) for the
difference between the 25th and 75th percentiles38;
however, no association was found in a similar study by London et
al.40 Three case-control studies have supported an inverse
association of olive oil intake with breast cancer
risk,43-45 and 1 found an inverse association of
monounsaturated fat and breast cancer risk.41 The Swedish
cohort study documented an inverse association with monounsaturated fat
(RR, 0.45; 95% CI, 0.22-0.95 for an increment of 10 g/d mutually
adjusted for other types of fat),39 whereas the pooled
cohort analysis (not adjusted for other types of fat) found no
association.9
In contrast to the predominant hypotheses, we saw no increased
risk of breast cancer with increased intake of animal fat,
polyunsaturated fat, saturated fat, or trans-unsaturated fat
in models in which fat intake replaced carbohydrate intake. Likewise,
we found no evidence of decreased risk of breast cancer with increased
intake of vegetable fat or monounsaturated fat in similar models. Also
contrary to the predominant hypothesis, we found an increased risk of
breast cancer associated with omega-3 fat from fish.
This study had several strengths: It was prospective, few subjects have
been lost to follow-up, and it was not prone to the biases of
case-control studies.46 It included more cases, longer
follow-up, and more person-time than any previously published
individual prospective study on diet and breast cancer. The assessment
of diet at multiple times during the follow-up period allowed more
accurate quantification of long-term diet.
Our previous inability to find an association between fat intake and
breast cancer in this cohort has been attributed by some to measurement
error.33 However, measurement error is highly unlikely to
account for our findings. Even in the previous analysis with half
the present number of cases and a single baseline measure of dietary
fat, the 95% CI excluded the magnitude of risk predicted by the
international correlations even after taking measurement error into
account.7 In addition, the multiple assessments of diet
over time in this analysis decreased misclassification,26
and the same dietary measurements and methods in this cohort strongly
predict coronary heart disease, even with fewer than one-third the
number of cases.47 These findings strongly suggest that
international correlations between fat consumption and breast cancer
are severely confounded by other factors, including delayed onset of
menses,48 weight gain after the age of 18
years,36 and hormone replacement therapy.36
Our capacity to examine risks of breast cancer at the extremes of fat
intake is limited by the small proportion of women and greater
probability of misclassification of dietary intake in these categories.
However, the fact that the risk of breast cancer tended to be highest
among those with the lowest fat intake makes an important reduction of
risk in this group unlikely.
In conclusion, we found no evidence that lower intake of total fat or
particular types of fat over 14 years of follow-up was associated with
a decreased risk of breast cancer. These findings suggest that
reductions in total fat intake during midlife are unlikely to prevent
breast cancer and should receive less emphasis. Rather, women's
decision about fat intake should be guided primarily by risk of heart
disease, which is strongly influenced by the type but not total amount
of fat.49
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