Published OnlineFirst July 9, 2008; DOI: 10.1158/1940-6207.

CAPR-08-0003

Cancer Prevention Research

Low-Fat Dietary Pattern and Risk of Benign Proliferative Breast Disease:

A Randomized, Controlled Dietary Modification Trial
Thomas E. Rohan,1 Abdissa Negassa,1 Bette Caan,2 Rowan T. Chlebowski,3 J. David Curb,4 Mindy Ginsberg,1
Dorothy S. Lane,5 Marian L. Neuhouser,6 James M. Shikany,7 Sylvia Wassertheil-Smoller1 and David L. Page8

Abstract

Modifiable factors, including diet, might alter breast cancer risk. We used the Women's
Health Initiative Dietary Modification trial to test the effect of the intervention on risk of benign proliferative breast disease, a condition associated with increased risk of, and considered to be on the pathway to, invasive breast cancer. The Women's Health Initiative Dietary
Modification trial was a randomized, controlled, primary prevention trial conducted in 40 U.S.
clinical centers from 1993 to 2005. A total of 48,835 postmenopausal women, ages 50 to
79 years, without prior breast cancer, were enrolled. Participants were randomly assigned to
the dietary modification intervention group or to the comparison group. The intervention was
designed to reduce total dietary fat intake to 20% of total energy intake, and to increase fruit
and vegetable intake to 5 servings/d and intake of grain products to 6 servings/d, but
resulted in smaller, albeit significant, changes in practice. Participants had biennial mammograms and regular clinical breast exams. We identified women who reported breast biopsies
free of cancer, obtained the histologic sections, and subjected them to standardized central
review. During follow-up (average, 7.7 years), 570 incident cases of benign proliferative
breast disease were ascertained in the intervention group and 793 in the comparison group.
The hazard ratio for the association between dietary modification and benign proliferative
breast disease was 1.09 (95% confidence interval, 0.98-1.23). Risk varied by levels of baseline total vitamin D intake but it varied little by levels of other baseline variables. These results
suggest that a modest reduction in fat intake and increase in fruit, vegetable, and grain
intake do not alter the risk of benign proliferative breast disease.

Breast cancer incidence rates vary 4- to 5-fold internationally

and have been observed to change on migration from low-risk
to high-risk countries (1). These observations have led to the
hypothesis that modifiable factors, including diet, might influence breast cancer risk. Most of the focus in epidemiologic
studies of the association between diet and breast cancer has
been on the roles of dietary fat, fiber, and fruit and vegetable

intake. In general, cohort studies have not supported an association between dietary fat intake and breast cancer risk (25),
although several recent cohort studies have reported small
increases in risk in postmenopausal women (68). Additionally, there is little recent evidence from cohort studies that
fruit and vegetable consumption (9, 10) and dietary fiber intake (11) are associated with altered breast cancer risk,
although earlier studies provided some support for inverse
associations (5).
The Women's Health Initiative (WHI) randomized controlled Dietary Modification trial was the first large-scale randomized trial to test the effect of adoption of a low-fat dietary
pattern (decrease in total fat intake, increase in fruit, vegetable,
and grain intake) on breast cancer risk (12). After 8 years of
follow-up, risk in the intervention group was 9% lower than
that in the comparison group, but the effect was not statistically significant. Among the possible explanations for this lack
of effect is that the follow-up period was too short. If that is
the case, it does not preclude the possibility of an effect of the
intervention on earlier stages in the natural history of breast
cancer in the short term, with a subsequent (and consequent)
reduction in breast cancer incidence. Therefore, we used the
WHI Dietary Modification trial to test the effect of adoption
of a low-fat dietary pattern on risk of benign proliferative
breast disease, a condition which is associated with increased

Authors' Affiliations: 1Department of Epidemiology and Population Health,

Albert Einstein College of Medicine, Bronx, New York; 2Division of
Research, Kaiser Permanente Northern California, Oakland, California;
3
Harbor-University of California at Los Angeles Medical Center, Torrance,
California; 4Department of Geriatric Medicine, University of Hawaii, Honolulu,
Hawaii; 5Department of Preventive Medicine, School of Medicine, State
University of New York at Stony Brook, Stony Brook, New York; 6Public Health
Sciences Division, Fred Hutchinson Cancer Research Center, Seattle,
Washington; 7Division of Preventive Medicine, School of Medicine, University
of Alabama, Birmingham, Alabama; and 8Department of Pathology,
Vanderbilt University Medical School, Nashville, Tennessee
Received 01/04/2008; revised 02/25/2008; accepted 03/13/2008.
Grant support: NIH grant RO1 CA077290-07.
Requests for reprints: Thomas E. Rohan, Department of Epidemiology
and Population Health, Albert Einstein College of Medicine, 1300 Morris Park
Avenue, Bronx, NY 10461. Phone: 718-430-3355; Fax: 718-430-8653; E-mail:
rohan@aecom.yu.edu.
2008 American Association for Cancer Research.
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Cancer Prevention Research
Furthermore, 4-d food records were provided by all women before
randomization (12), a 4.6% sample provided further 4-d food records
at 1 y after randomization, as well as 24-h dietary recalls at 3 and 6 y
postrandomization, and 1% samples of women provided a 24-h
dietary recall annually. The dietary data presented here were derived
from the baseline food frequency questionnaire.

risk of, and is considered to be on the pathway to, invasive

breast cancer (1315).

Materials and Methods

Study population

Ascertainment of outcomes

The WHI Dietary Modification trial has been described in detail

elsewhere (12, 16, 17). In brief, 48,835 postmenopausal women, ages
50 to 79 y at initial screening, who were likely to reside in the area
for 3 y, and who provided written informed consent, were enrolled
between 1993 and 1998 at 40 clinical centers throughout the United
States. Major reasons for ineligibility for the trial included a history
of breast or colorectal cancer, a history of other cancer except nonmelanoma skin cancer in the last 10 y, medical conditions with predicted
survival of <3 y, adherence and retention considerations (e.g., alcoholism, dementia), or a diet at baseline with fat intake of <32% of total
energy. All participants had a baseline mammogram and clinical
breast examination; abnormal findings suggestive of breast cancer required clearance before study entry. Eligible women were randomized
either to the dietary modification intervention group (40%; n = 19,541)
or to the comparison group (60%; n = 29,294) using a permuted block
algorithm with stratification by clinic and age. Dietary modification
participants were also eligible to be in the WHI hormone therapy
and calcium/vitamin D supplementation trials (16). The WHI and
the ancillary study reported here (in which all 40 WHI clinical centers
participated) were approved by institutional review boards at all
participating institutions.

The outcome of interest for the present study was histologically

confirmed incident benign proliferative breast disease with or without
atypia (see Histology). Clinical events including breast cancers and
breast biopsies for noncancerous lesions were initially identified from
self-administered questionnaires completed every 6 mo. Breast cancers
were confirmed by local and central adjudicators who reviewed medical records and pathology reports and who were blinded both to
treatment assignment and to symptoms due to study interventions.
For the present study, women who reported breast biopsies that were
free of cancer were identified, and clinical centers were sent lists of
potentially eligible subjects quarterly. Clinic staff contacted participants to obtain written informed consent to solicit the histologic
sections resulting from the biopsies. To investigate the possibility that
breast biopsies were missed by using this approach, the charts of
100 randomly selected participants who did not report a breast
biopsy were reviewed at one center and none was found to have
unreported biopsies.

Histology
H&E-stained histologic sections were reviewed by the study pathologist (D.L.P.), who was blinded to the randomization assignment. The
benign lesions were classified using well-established criteria as nonproliferative lesions, proliferative lesions without atypia (classified
further according to whether they were mild, moderate, or florid in
extent), or atypical (ductal/lobular) hyperplasia (1921).

Dietary intervention and retention

The dietary intervention was designed to promote dietary change
with the goals of reducing intake of total dietary fat to 20% of total
energy intake (as a consequence of which, saturated fat intake was
expected to be reduced to 7% of energy intake), increasing fruit
and vegetable intake to 5 servings/d, and increasing intake of grain
products to at least 6 servings/d (12). Women in the comparison
group were not offered a nutrition intervention program because
the general strategy for this group was minimum interference with
customary diets while collecting nutritional data considered appropriate for comparison with the intervention group. However, they were
provided with a copy of the dietary guidelines for Americans. Neither
the intervention nor the comparison group was asked to modify
health-related behaviors, including use of dietary supplements.
Dietary change was encouraged by providing social support and
positive interactions. To this end, women randomized to the intervention arm were assigned to a permanent group of 8 to 15 members led
by a designated nutritionist. During the first year of follow-up, the
group met weekly for 6 wk, biweekly for 6 wk, and monthly for
9 mo; subsequently, it met quarterly. Each participant had an individual counseling session with her group nutritionist between 12 and
16 wk from the beginning of the intervention sessions.

Statistical analysis
Incidence rates of benign proliferative breast disease in the dietary
modification and comparison groups were compared based on the
intention-to-treat principle using time-to-event analyses. The primary
analysis used a weighted (two-sided) log-rank test with weight
increasing linearly from zero at randomization to a maximum of 1
at 10 y and constant thereafter to enhance statistical power under
the design assumptions (12). The time to benign proliferative breast
disease was defined as the number of days from the date of randomization to the date of the first postrandomization diagnostic biopsy.
Follow-up time was censored at the date of last documented contact,
diagnosis of breast cancer, mastectomy, death, or trial close-out (between October 2004 and March 2005), whichever came first. Women
who developed a nonproliferative benign breast lesion continued to be
followed up because they remained at risk of developing a subsequent
proliferative lesion. Event rates over time were summarized using
cumulative hazard plots. The intervention effect was summarized
using hazard ratios (HR) and 95% confidence intervals (95% CI) estimated from Cox proportional hazards models (22), with stratification
by age, prior breast biopsies, and randomization to the WHI hormone
therapy and calcium/vitamin D supplementation trials. Stratification
was time dependent in the case of the calcium/vitamin D supplementation trial (16). The possibility that the intervention effect differed by
levels of other characteristics of the study population was investigated
by including product terms between treatment assignment and indicator variables for the subsets of interest in Cox proportional hazards
models stratified by age, prior breast biopsies, and randomization to
the hormone therapy and calcium/vitamin D trials (16), and was assessed by testing the equality of the product-term coefficients. Given
that a total of 22 interactions were tested, approximately one significant test at an level of 0.05 was expected by chance alone. The proportional hazards assumption, which was tested both by fitting
models containing a product term between the intervention and

Baseline data collection, follow-up, and assessment of

adherence
Comprehensive information on breast cancer risk factors was
obtained at baseline by interview (for lifetime hormone use) and by
self-report (other covariates) using standardized questionnaires (16).
Study participants were contacted every 6 mo for collection of information on outcomes. Clinic visits were required annually, at which
time height and weight were measured using standardized procedures. Mammograms were required every 2 y, and regular clinical
breast exams were done as well.
Dietary intake for all participants was monitored using the WHI
food frequency questionnaire (12, 18). The food frequency questionnaire was administered to all participants at baseline and 1 y after
randomization. Thereafter, about one third of participants completed
the food frequency questionnaire annually in a rotating sample.

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Diet Modification and Risk of Benign Breast Disease

follow-up time and assessing the coefficient of the product term for
statistical significance, and by fitting piecewise constant intervention
effects on nonoverlapping time intervals and testing for equality of
such terms with the intervals chosen in advance, was shown not to
be violated. Annualized event rates were calculated for comparisons
of absolute disease rates. Results were considered statistically significant when two-sided P 0.05.

the association between dietary modification and benign proliferative breast disease was 1.09 (95% CI, 0.98-1.23; Table 2).
The intervention was associated with a slight, statistically nonsignificant increase in risk of benign proliferative breast disease without atypia (HR, 1.10; 95% CI, 0.97-1.25) and with a
statistically significant increase in risk for either atypical hyperplasia or moderately extensive or florid proliferative disease without atypia (HR, 1.16; 95% CI, 1.02-1.33). Risk of
atypical hyperplasia was essentially unaltered by the intervention (HR, 1.05; 95% CI, 0.79-1.39). The Kaplan-Meier estimate of the cumulative hazard of benign proliferative
breast disease (all types combined) revealed that there was
little difference between the intervention and comparison
groups for the first 4 years of follow-up, after which the hazard for the dietary modification group exceeded slightly
that for the comparison group (Fig. 1).
The overall dietary modification effect was largely unchanged by exclusion of the first year of follow-up (HR,
1.09; 95% CI, 0.97-1.23), exclusion of women with a breast
biopsy before the commencement of the trial (HR, 1.07; 95%
CI, 0.93-1.23), or adjustment for annual measures of height
and weight (HR, 1.09; 95% CI, 0.98-1.23) or use of prior hormone therapy (estrogen alone or estrogen plus progestin; HR,
1.09; 95% CI, 0.97-1.22).
Risk of benign proliferative breast disease in association
with dietary modification varied by levels of baseline total
vitamin D intake (from diet and supplements), albeit not substantially and not monotonically. Risk did not vary by levels of
other dietary variables (Table 3), and it varied little by levels
of most of the other baseline variables examined (Table 4).
Although risk varied significantly by levels of estrogen plus
progestin use as reported at baseline, the magnitude of the
difference in risk between categories of this variable was not
large.
To address the possible effect of nonadherence on the study
results, we used an inverse probability weighting scheme to
estimate a full adherence relative risk function for the intervention as described earlier (12). This yielded a HR of 1.37
(95% CI, 0.95-1.99) for all proliferative breast diseases combined.
The WHI study protocol mandated that participants had
biennial mammograms and regular clinical breast exams.
Compliance with these exams was high, and there was essentially no difference between the intervention and comparison
groups with respect to the frequency with which these were
done (12). Neither adjustment for the frequency of mammograms (HR, 1.10; 95% CI, 0.98-1.23) nor adjustment for the
frequency of clinical breast exams (HR, 1.09; 95% CI, 0.981.23) had much impact on the estimated dietary modification
effect.

Results
The study groups differed little at baseline with respect to
age, ethnicity, breast cancer risk factors, participation in other
WHI trials, or intake of energy or selected nutrients and vitamins (Table 1).
Data on follow-up and adherence, as well as change in
nutrient and food intake and blood biomarker levels, were
reported elsewhere (12). In brief, 4.7% of women in the intervention group and 4.0% of those in the comparison group
withdrew from the study or were lost to follow-up. Estimated
adherence rates were 87% and 75% in the comparison group
and 57% and 31% in the intervention group at years 3 and 6,
respectively. Based on estimates from the food frequency
questionnaires, the intervention and comparison groups were
essentially identical at baseline with respect to intake of fat,
fruit and vegetables, and grains (as well as other dietary
items). One year after randomization, statistically significant,
albeit modest, between-group differences in intake of these
dietary items were evident: For the intervention and comparison group, the mean (SD) percent energy from fat, servings of
fruit and vegetables per day, and servings of grains per day
were 24.3 (7.5) versus 35.1 (6.9), 5.1 (2.3) versus 3.9 (2.0), and
5.1 (2.7) versus 4.2 (2.3), respectively. By year 6, the mean (SD)
difference in change (change in intervention group minus
change in comparison group) in percent energy from fat
between the intervention and comparison groups was 8.1
(7.8), whereas the mean differences in change for servings
per day of fruit and vegetables and of grains were 1.1 (2.1)
and 0.4 (2.6), respectively; all of these differences were
statistically significant. Compared with blood levels in the
comparison group, the intervention group showed a greater
reduction in blood levels of -tocopherol, a greater increase
in -cryptoxanthin, and smaller decreases in - and -carotene.
Estradiol levels decreased more and sex hormone-binding
levels increased more in the intervention group than in
the control group.
During follow-up (average duration, 7.7 years), we identified 3,383 potentially eligible biopsies that had been done
for benign breast disease. The eligibility of 65 biopsies could
not be determined due to lack of consent, hospital refusal, and
other reasons. Of the 3,318 biopsies confirmed to be eligible,
consent was provided for review of 3,314, and 3,254 histologic
sections were obtained. Of the sections reviewed, 172 were
from biopsies that occured outside the trial period and 217
had no breast tissue. The remaining 2,865 sections were from
2,610 women. Of these women, 19 were censored (so that the
corresponding section was excluded from consideration), 7
had no pathological diagnosis, 1,221 had a nonproliferative lesion (and therefore continued to be eligible to develop a proliferative lesion), and 1,363 had a proliferative lesion.
Overall, 570 cases of benign proliferative breast disease
were ascertained in the intervention group and 793 were
ascertained in the comparison group. The estimated HR for

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Discussion
The results of this study suggest that the WHI low-fat dietary intervention, which yielded a statistically significant, albeit modest, decrease in fat intake and increase in intake of
fruit, vegetables, and grains, was not associated with altered
risk of benign proliferative breast disease after almost 8 years
of follow-up. Although there was a small increase in overall
risk (9%) that was even larger (37%) when the extent of adherence to the dietary intervention was taken into account,

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Table 1. Baseline characteristics of participants in the WHI Dietary Modification trial

No. participants (%)

Age, y*
Race/ethnicity, %
White
Black
Hispanic
American Indian
Asian/Pacific Islander
Other
Unknown
Family history of breast cancer, %
Gail model 5-y risk 1.75, %
Body mass index, kg/m2*,
Prior breast disease
No
1 biopsy
2 biopsies
Unknown
Age at menarche, y
10
11-14
15
Unknown
Age at first full-term pregnancy, y
Never had term pregnancy
<20
20-29
30
Unknown
Parity
Never
1
2
3
4+
Unknown
Age at natural menopause, y*
Oral contraceptive use
Ever used, %
Duration of use, y*
Postmenopausal hormone use
Estrogen alone
Ever used, %
Duration of use, y*
Estrogen plus progestin
Ever used, %
Duration of use, y*
Mammography screening
within 2 y, %

Dietary modification (n = 19,541)

Comparison (n = 29,294)

62.26 (6.87)

62.26 (6.86)

15,871 (81.22)
2,135 (10.93)
751 (3.84)
88 (0.45)
431 (2.21)
221 (1.13)
44 (0.23)
3,396 (17.38)
6,510 (33.31)
29.16 (6.05)

23,891 (81.56)
3,127 (10.67)
1,094 (3.73)
114 (0.39)
674 (2.30)
339 (1.16)
55 (0.19)
4,929 (16.83)
9,696 (33.10)
29.17 (6.46)

13,812
2,553
1,014
2,162

20,559
3,914
1,553
3,268

(70.68)
(13.06)
(5.19)
(11.06)

(70.18)
(13.36)
(5.30)
(11.16)

1,311 (6.71)
16,338 (83.61)
1,834 (9.39)
58 (0.30)

1,907 (6.51)
24,520 (83.70)
2,771 (9.46)
96 (0.33)

496 (2.54)
2,709 (13.86)
11,577 (59.24)
1,372 (7.02)
3,387 (17.33)

732 (2.50)
4,183 (14.28)
17,220 (58.78)
2,008 (6.85)
5,151 (17.58)

2,114 (10.82)
1,682 (8.61)
4,766 (24.39)
4,714 (24.12)
6,159 (31.52)
106 (0.54)
48.01 (6.47)

3,214 (10.97)
2,463 (8.41)
7,002 (23.90)
7,183 (24.52)
9,294 (31.73)
138 (0.47)
47.91 (6.51)

8,751 (44.78)
5.32 (5.14)

12,992 (44.35)
5.27 (5.24)

7,279 (37.25)
9.96 (8.9)

10,842 (37.01)
10.02 (8.86)

5,345 (27.35)
5.78 (5.18)
15,729 (80.49)

7,995 (27.29)
5.72 (5.06)
23,708 (80.93)

NOTE: Percentages may not sum to 100% because of rounding error.

*Mean (SD).

First-degree female relative.

Calculated as weight in kilograms divided by the square of height in meters.

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Diet Modification and Risk of Benign Breast Disease

Table 1. Baseline characteristics of participants in the WHI Dietary Modification trial (Cont'd)
No. participants (%)
Dietary modification (n = 19,541)
Enrollment in WHI estrogen alone trial, %
No
16,359 (83.72)
Active
615 (3.15)
Control
670 (3.43)
Enrollment in WHI estrogen plus progestin trial, %
No
16,359 (83.72)
Active
972 (4.97)
Control
925 (4.73)
Enrollment in WHI calcium plus vitamin D supplementation trial, %
No
9,896 (50.64)
Intervention
4,767 (24.39)
Control
4,878 (24.96)
Total daily energy intake, kcal*
1,790 (710)
Total daily fat intake, g*
75.7 (34.1)
Total daily calcium intake (supplements plus diet), mg*
1,123.7 (686.8)
Total daily vitamin D intake (supplements plus diet), IU*
349.0 (262.9)

24,426 (83.38)
1,039 (3.55)
1,068 (3.65)
24,426 (83.38)
1,457 (4.97)
1,304 (4.45)
13,729 (46.87)
7,827 (26.72)
7,738 (26.41)
1,789 (703)
75.7 (33.6)
1,117.5 (662.9)
348.5 (265.1)

three (2931) measured diet in adulthood and showed that

intakes of dietary fat, carotenoid, fiber (29, 30), and folate
(31) were not related to risk of subsequent benign proliferative
breast disease, whereas one study (28) showed that vitamin E
and fiber intakes during adolescence had inverse associations
with risk that were of borderline statistical significance.
Although the dietary intervention was not associated with
altered risk of benign proliferative breast disease overall, it
was associated with an increase in risk in some subgroup analyses. It is conceivable that the latter represent chance findings
due to the many subgroup analyses that were done. However,
the dietary intervention was complex, and although it seems
unlikely that detrimental changes might have been introduced
as a result of the intervention, an alteration in the balance
between nutrients that mitigate the risk of cancer and those
that increase risk might have occurred.
The mammary gland is particularly susceptible to environmental influences early in life (34, 35). Indeed, early life events
are considered to play a role in the etiology of breast cancer, as
evidenced by the positive associations of breast cancer risk
with birthweight and height (a marker of the adequacy of
nutritional status in childhood; ref. 36). Hence, it is conceivable that the essentially null results of this trial (and those of the
parent trial; ref. 12) reflect the fact that the intervention was
administered well after the critical exposure period.
Limitations of the parent trial were discussed elsewhere
(12). In brief, recruitment took longer than expected so that
the average follow-up duration was less than had been
planned and perhaps insufficiently long to show an effect
(in this regard, follow-up of the Dietary Modification trial participants is continuing and an updated report is expected
soon); the between-group (intervention versus comparison)
difference in percent energy from fat was only 70% of the
target; relatively few women managed to reduce their fat
intake to 20% of energy; self-report methods were used to assess between-group differences in dietary intake, although the

neither of these effect estimates was statistically significant.

Furthermore, although the intervention was associated with
a statistically significant increase in the risk of the combined
outcome category consisting of either atypical hyperplasia or
moderately extensive or florid proliferative disease without
atypia, the magnitude of this effect was small (16% increase
in risk). Similarly, although there were statistically significant
interactions between the intervention and baseline total vitamin D intake, postmenopausal hormone use before entry into
the trial, and enrollment in the WHI estrogen plus progestin
trial, the magnitude of the variations in risk by categories of
these variables was not large.
It seems that there have not been any previous randomized
trials of the effect of dietary modification on the risk of benign
proliferative breast disease. However, the role of diet in the
etiology of benign proliferative breast disease has been examined in several case-control (2327) and cohort studies (2831).
Of the case-control studies, two (24, 25) showed positive associations between saturated fat intake (or indices thereof) and
risk of atypical (24) or proliferative forms (25) of benign breast
disease, whereas the other studies (23, 26, 27) provided little
support for a role for dietary fat. With respect to other nutrients, one case-control study provided some evidence for
inverse associations between retinol and -carotene intake
and risk (26) and also showed strong inverse associations for
dietary fiber and its components (soluble and insoluble nonstarch polysaccharides and cellulose; ref. 32). These findings
were supported to some extent by those of another study
(23) in which risk of benign epithelial hyperplasia was reduced in association with consumption of fruit and leafy
and orange-red vegetables, both of which contain fiber and
micronutrients such as -carotene. However, in another study
(33), carotene and retinol intakes were not associated with risk
of atypical or nonatypical forms of benign proliferative breast
disease. Findings from cohort studies have been less supportive of associations. Of the four cohort studies to date (2831),

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Comparison (n = 29,294)

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Table 2. Risk of benign proliferative breast disease in association with dietary modification, overall and by the
presence/absence of atypia
No. cases (annualized %)

HR (95% CI)*

Unweighted* Weighted

Dietary modification Comparison

(n = 19,541)
(n = 29,294)
Benign proliferative breast disease, all
Benign proliferative breast disease without atypia
Benign proliferative breast disease without atypia
(moderately extensive or florid) or with atypia
Atypical hyperplasia

570 (0.38)
477 (0.32)
429 (0.29)

793 (0.35)
660 (0.29)
565 (0.25)

1.09 (0.98-1.23)
1.10 (0.97-1.25)
1.16 (1.02-1.33)

0.13
0.12
0.03

0.18
0.22
0.05

93 (0.06)

133 (0.06)

1.05 (0.79-1.39)

0.76

0.59

*Proportional hazards model stratified by age, prior breast disease, and treatment assignment in the hormone therapy and calcium plus
vitamin D supplementation trials.

Weighted log-rank test stratified by age, prior breast disease, and treatment assignment in the hormone therapy trial and adjusted for
calcium plus vitamin D supplementation trial randomization as a time-dependent covariate. Weights increase linearly from zero at randomization to a maximum of 1 at 10 y.

observed relative changes in blood levels of -tocopherol and

carotenoids are consistent with reported differences between
the randomization groups with respect to consumption of fats,
oils, and fruits and vegetables; and the complexity of the intervention (reduction in fat intake and increase in fruit, vegetable, and grain intake) limits the ability to attribute effects to
any specific component of the dietary changes. With respect
to the present study, there are two additional potential limita-

tions. First, differential ascertainment of the outcome in the

two randomization groups may have occurred, although this
seems unlikely given that compliance with the biennial mammograms and regular clinical breast exams was high and essentially the same in both groups, and that adjustment for the
frequency of these exams had minimal effect on the estimate
of the dietary modification effect (underascertainment in both
groups is a possibility given that breast biopsies were not

Fig. 1. Kaplan-Meier estimates of the cumulative hazard of benign proliferative breast disease in the dietary modification and comparison groups.

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Diet Modification and Risk of Benign Breast Disease

Table 3. Risk of benign proliferative breast disease in association with dietary modification, by intake of
selected dietary variables at baseline
No. cases of BPBD (annualized %)*

HR (95% CI)

Pinteraction

Dietary modification (n = 19,541) Comparison (n = 29,294)

Energy intake, kcal
<1,392
169 (0.37)
1,392-<1,664
112 (0.40)
1,664-<1,959
97 (0.38)
1,959
190 (0.38)
Percentage of energy from fat
<32.3
76 (0.42)
32.3-<36.8
248 (0.44)
36.8
244 (0.32)
Total fat intake, g/d
<46.2
100 (0.40)
46.2-<59.8
112 (0.38)
59.8-<76.0
137 (0.40)
76.0
219 (0.36)
Vegetable and fruit, servings/d
<2.3
130 (0.34)
2.3-<3.3
146 (0.40)
3.3-<4.6
141 (0.38)
4.6
151 (0.40)
Grains, servings/d
<3
133 (0.36)
3-<4.3
161 (0.41)
4.3-<5.9
136 (0.37)
5.9
140 (0.38)
Total daily calcium intake (supplements plus diet), mg
<635.6
135 (0.37)
635.6-<979.4
152 (0.41)
979.4-<1,459.6
134 (0.36)
1,459.6
147 (0.39)
Total daily vitamin D intake (supplements plus diet), IU
<133.2
125 (0.34)
133.2-<262.6
174 (0.46)
262.6-<533.8
145 (0.39)
533.8
124 (0.33)
Caffeine intake, mg/d
0-<76.8
153 (0.41)
76.8-<177.4
138 (0.39)
177.4-<196.7
139 (0.37)
196.7
138 (0.36)
Alcohol intake, g/d
0
236 (0.38)
0-<5
191 (0.39)
5-15
99 (0.39)
>15
42 (0.31)

232
153
135
272

(0.33)
(0.38)
(0.35)
(0.36)

1.05
1.08
1.19
1.09

(0.85-1.29)
(0.83-1.39)
(0.90-1.57)
(0.90-1.32)

0.91

104 (0.40)
322 (0.38)
366 (0.32)

1.14 (0.83,1.56)
1.16 (0.97-1.38)
1.02 (0.86-1.21)

0.56

126
152
207
307

(0.34)
(0.35)
(0.40)
(0.34)

1.10
1.15
1.01
1.12

(0.83-1.45)
(0.89-1.49)
(0.80-1.26)
(0.93-1.34)

0.87

183
204
187
218

(0.32)
(0.37)
(0.34)
(0.38)

1.07
1.05
1.18
1.07

(0.84-1.36)
(0.84-1.32)
(0.94-1.48)
(0.86-1.33)

0.90

187
188
210
208

(0.33)
(0.33)
(0.39)
(0.36)

1.05 (0.83-1.33)
1.26 (1.00-1.57)
0.99 (0.79-1.24)
1.09 (0.87,1.37)

0.50

164
216
215
197

(0.29)
(0.38)
(0.38)
(0.36)

1.28
1.06
0.94
1.14

(1.00-1.63)
(0.86-1.32)
(0.75-1.18)
(0.91-1.42)

0.33

169
192
210
221

(0.30)
(0.33)
(0.38)
(0.39)

1.12
1.41
1.04
0.85

(0.87-1.43)
(1.13-1.75)
(0.83-1.30)
(0.68-1.08)

0.02

200
188
208
196

(0.36)
(0.33)
(0.37)
(0.34)

1.12
1.12
1.06
1.07

(0.93-1.34)
(0.93-1.36)
(0.87-1.28)
(0.88-1.29)

0.95

315 (0.34)
263 (0.36)
141 (0.37)
73 (0.36)

1.07
1.14
1.12
0.92

(0.92-1.23)
(0.97-1.35)
(0.90-1.40)
(0.67-1.27)

0.65

Abbreviation: BPBD, benign proliferative breast disease.

*For some variables, the number of events does not equal the total number shown in Table 2 due to missing values.

Unweighted proportional hazards model stratified by age, prior disease, and randomization group.

In conclusion, the results of the trial reported here suggest that

a modest reduction in fat intake and a modest increase in fruit,
vegetable, and grain intake in postmenopausal women do not
alter their risk of subsequent benign proliferative breast disease.

done on all study subjects). Second, it is possible that there was

some misclassification of the outcome, although this is likely to
have been nondifferential, with consequent biasing of the effect
estimate for dietary intervention toward the null (37).

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Cancer Prevention Research

Table 4. Risk of benign proliferative breast disease in association with dietary modification, by selected baseline
characteristics
No. cases of BPBD (annualized %)*
Dietary modification (n = 19,541)

Pinteraction

HR (95% CI)

Comparison (n = 29,294)

Age, y
50-59
249 (0.43)
60-69
257 (0.38)
70-79
64 (0.27)
Race/ethnicity
White
474 (0.39)
Black
52 (0.32)
Hispanic
18 (0.32)
Other
25 (0.46)
Family history of breast cancer in first-degree relative
No
434 (0.37)
Yes
105 (0.40)
Gail model 5-y risk, %
<1.25
190 (0.35)
1.25-1.74
174 (0.36)
1.75
206 (0.42)

311 (0.36)
371 (0.36)
111 (0.31)

1.24 (1.04-1.48)
1.04 (0.88,1.23)
0.88 (0.63-1.21)

0.13

688 (0.37)
51 (0.21)
18 (0.22)
33 (0.39)

1.03
1.65
1.92
1.20

(0.91-1.17)
(1.10-2.48)
(0.96-3.85)
(0.71-2.03)

0.06

591 (0.33)
161 (0.43)

1.13 (0.99-1.29)
0.95 (0.74-1.23)

0.23

231 (0.29)
256 (0.35)
306 (0.42)

1.24 (1.01-1.53)
1.09 (0.89-1.33)
1.00 (0.83-1.20)

0.31

1.08
1.09
1.09
1.13

(0.88-1.33)
(0.90-1.31)
(0.85-1.41)
(0.83-1.54)

0.99

Body mass index, kg/m2

<25
25-29
30-34
35

171 (0.43)
206 (0.39)
116 (0.34)
77 (0.34)

234
292
163
104

Age at menarche, y
10
11-14
15

32 (0.32)
483 (0.38)
54 (0.39)

46 (0.31)
669 (0.35)
74 (0.34)

0.94 (0.58-1.52)
1.11 (0.98-1.26)
1.07 (0.74-1.56)

0.79

15 (0.40)
94 (0.46)
345 (0.39)
47 (0.45)

23 (0.41)
105 (0.33)
496 (0.37)
54 (0.35)

0.91
1.44
1.03
1.27

(0.46-1.83)
(1.07-1.94)
(0.89-1.20)
(0.84-1.92)

0.19

54 (0.33)
56 (0.44)
154 (0.42)
136 (0.38)
169 (0.36)

79 (0.32)
61 (0.32)
218 (0.40)
192 (0.35)
242 (0.34)

1.13
1.46
0.99
1.07
1.10

(0.79-1.62)
(1.00-2.14)
(0.79-1.24)
(0.85-1.35)
(0.89-1.35)

0.55

236 (0.43)
55 (0.40)
154 (0.39)
104 (0.34)

312 (0.37)
70 (0.35)
221 (0.38)
149 (0.33)

1.11
1.16
1.09
1.10

(0.93-1.32)
(0.80-1.67)
(0.88-1.35)
(0.85-1.44)

0.99

(0.33)
(0.41)
(0.47)

396 (0.32)
225 (0.40)
172 (0.38)

1.04 (0.88-1.22)
1.04 (0.84-1.30)
1.28 (1.01-1.61)

0.32

(0.35)

420 (0.29)

1.23 (1.06-1.43)

0.08

Age at first full-term pregnancy, y

Never had term
<20
20-29
30
Parity
0
1
2
3
4
Age at natural menopause, y
<48
48-<50
50-<53
53

Oral contraceptive use, y

None
271
<5
151
5
148
Baseline postmenopausal hormone use, y
Estrogen alone, y
None
329

(0.39)
(0.36)
(0.32)
(0.31)

*For some variables, the number of events does not equal the total number shown in Table 2 due to missing values.
Unweighted proportional hazards model stratified by age, prior disease, and randomization group.

Calculated as weight in kilograms divided by the square of height in meters.

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Published OnlineFirst July 9, 2008; DOI: 10.1158/1940-6207.CAPR-08-0003

Diet Modification and Risk of Benign Breast Disease

Table 4. Risk of benign proliferative breast disease in association with dietary modification, by selected baseline
characteristics (Cont'd)
No. cases of BPBD (annualized %)*
Dietary modification (n = 19,541)
<5
5
Estrogen plus progestin, y
None
<5
5
Enrollment in WHI hormone trials
Estrogen alone
Active
Placebo
Estrogen plus progestin
Active
Placebo
Enrollment in WHI calcium plus vitamin
Intervention
Placebo

HR (95% CI)

Pinteraction

Comparison (n = 29,294)

83 (0.39)
158 (0.46)

117 (0.38)
256 (0.49)

0.96 (0.71-1.30)
0.93 (0.76-1.15)

341 (0.31)
97 (0.45)
132 (0.69)

531 (0.32)
117 (0.36)
145 (0.50)

0.97 (0.84-1.12)
1.30 (0.97-1.73)
1.38 (1.08-1.76)

0.02

19 (0.40)
13 (0.26)

32 (0.40)
18 (0.22)

0.81 (0.43-1.51)
1.26 (0.63-2.53)

0.35

20 (0.27)
11 (0.15)
D trial
149 (0.40)
166 (0.44)

49 (0.44)
28 (0.28)

0.60 (0.34-1.04)
0.63 (0.30-1.32)

0.90

239 (0.39)
214 (0.35)

1.09 (0.88-1.34)
1.21 (0.98-1.49)

0.48

Restricted to those who were randomized.

Bette Caan; Medical College of Wisconsin (Milwaukee, WI)Jane Morley

Kotchen; MedStar Research Institute/Howard University (Washington, DC)
Barbara V. Howard; Northwestern University (Chicago/Evanston, IL)Linda
Van Horn; Rush Medical Center (Chicago, IL)Henry Black; Stanford Prevention Research Center (Stanford, CA)Marcia L. Stefanick; State University of
New York at Stony Brook (Stony Brook, NY)Dorothy Lane; The Ohio State
University (Columbus, OH)Rebecca Jackson; University of Alabama at Birmingham (Birmingham, AL)Cora E. Lewis; University of Arizona (Tucson/
Phoenix, AZ)Tamsen Bassford; University at Buffalo (Buffalo, NY)Jean
Wactawski-Wende; University of California at Davis (Sacramento, CA)John
Robbins; University of California at Irvine (Irvine, CA)F. Allan Hubbell; University of California at Los Angeles (Los Angeles, CA)Howard Judd; University of
California at San Diego (LaJolla/Chula Vista, CA)Robert D. Langer; University
of Cincinnati (Cincinnati, OH)Margery Gass; University of Florida (Gainesville/
Jacksonville, FL)Marian Limacher; University of Hawaii (Honolulu, HI)David
Curb; University of Iowa (Iowa City/Davenport, IA)Robert Wallace; University
of Massachusetts/Fallon Clinic (Worcester, MA)Judith Ockene; University of
Medicine and Dentistry of New Jersey (Newark, NJ)Norman Lasser; University
of Miami (Miami, FL)Mary Jo O'Sullivan; University of Minnesota (Minneapolis,
MN)Karen Margolis; University of Nevada (Reno, NV)Robert Brunner; University of North Carolina (Chapel Hill, NC)Gerardo Heiss; University of Pittsburgh (Pittsburgh, PA)Lewis Kuller; University of Tennessee (Memphis, TN)
Karen C. Johnson; University of Texas Health Science Center (San Antonio,
TX)Robert Brzyski; University of Wisconsin (Madison, WI)Gloria E. Sarto;
Wake Forest University School of Medicine (Winston-Salem, NC)Denise
Bonds; Wayne State University School of Medicine/Hutzel Hospital (Detroit,
MI)Susan Hendrix.
The WHI program is funded by the National Heart, Lung and Blood Institute,
U.S. Department of Health and Human Services.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments
We thank the WHI investigators and staff for their outstanding dedication and
commitment. A list of key investigators involved in this research follows. A full
listing of WHI investigators can be found at the following website: http://www.
whi.org.
Program Office: National Heart, Lung, and Blood Institute (Bethesda, MD)
Elizabeth Nabel, Jacques Rossouw, Shari Ludlam, Linda Pottern, Joan McGowan, Leslie Ford, and Nancy Geller.
Clinical Coordinating Centers: Fred Hutchinson Cancer Research Center
(Seattle, WA)Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L.
Kooperberg, Ruth E. Patterson, and Anne McTiernan; Wake Forest University
School of Medicine (Winston-Salem, NC)Sally Shumaker; Medical Research
Labs (Highland Heights, KY)Evan Stein; University of California at San Francisco (San Francisco, CA)Steven Cummings.
Clinical Centers: Albert Einstein College of Medicine (Bronx, NY)Sylvia
Wassertheil-Smoller; Baylor College of Medicine (Houston, TX)Jennifer Hays;
Brigham and Women's Hospital, Harvard Medical School (Boston, MA)JoAnn
Manson; Brown University (Providence, RI)Annlouise R. Assaf; Emory University (Atlanta, GA)Lawrence Phillips; Fred Hutchinson Cancer Research Center
(Seattle, WA)Shirley Beresford; George Washington University Medical Center (Washington, DC)Judith Hsia; Los Angeles Biomedical Research Institute
at Harbor-University of California at Los Angeles Medical Center (Torrance, CA)
Rowan Chlebowski; Kaiser Permanente Center for Health Research (Portland,
OR)Evelyn Whitlock; Kaiser Permanente Division of Research (Oakland, CA)

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Published OnlineFirst July 9, 2008; DOI: 10.1158/1940-6207.CAPR-08-0003

Low-Fat Dietary Pattern and Risk of Benign Proliferative

Breast Disease: A Randomized, Controlled Dietary
Modification Trial
Thomas E. Rohan, Abdissa Negassa, Bette Caan, et al.
Cancer Prev Res 2008;1:275-284. Published OnlineFirst July 9, 2008.

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