Nutrition and Cancer, 60(4), 450–460
Copyright © 2008, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
Do Flavonoid Intakes of Postmenopausal Women With
Breast Cancer Vary on Very Low Fat Diets?
Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
and Jean Mayer Human Nutrition Research Center on Aging at Tufts University
and Frances Stern Nutrition Center, Tufts-New England Medical Center, Boston, Massachusetts
Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
Campbell Soup Company, Camden, New Jersey
Biomath Department, University of California at Los Angeles
Diane C. Mitchell
Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania
Department of Science, Bunker Hill Community College, Boston, Massachusetts
In the Women’s Intervention Nutrition Study (WINS), a very
low-fat eating pattern decreased breast cancer recurrence. We
assessed whether the women’s flavonoid intakes varied on the
very low fat diet. A total of 550 randomly selected WINS partic-
ipants who had been treated with conventional therapy (surgery,
chemotherapy, and/or radiation) for primary breast cancer were
randomized to either a very low fat diet (15% of calories from fat,
N = 218) or their usual diets (30% calories from fat, N = 332). We
compared their intakes of total flavonoids and 6 flavonoid classes
(isoflavones, flavones, flavanones, flavonols, flavan-3-ols, and an-
thocyanins) for these 2 groups using the U.S. Department of Agri-
database on three 24-h dietary recalls at baseline and 12 mo after
randomization. At baseline, neither mean fat intakes (31.7% ± 6.8
SD of calories, n = 332 in the usual diet group and 31.6% ± 6.8
SD of calories, n = 218 in the very low fat diet group; P = NS)
nor flavonoid intakes (218 ± 283 SD mg/day, n = 332 in the usual
diet group and 236 ± 393 SD mg/day, n = 218 in the very low fat
diet group; P = NS) differed. Over half of the women’s flavonoid
intakes were from the flavan-3-ols. After 12 months of interven-
tion, with 39 participants lost to follow-up, dietary fat intakes were
30.7 ± 8.4 SD calories (n = 316) among those on their usual diets
Submitted 22 September 2006; accepted in final form 28 October
Address correspondence to Johanna Dwyer, Frances Stern Nutri-
tion Center, Tufts University, 750 Washington St., Tufts-NEMC #738,
Boston, MA 02111. E-mail: email@example.com
but were significantly lower among those on the very low fat diet
intervention: 21.4 ± 8.3 SD calories (n = 195), P = <0.05. How-
ever, flavonoid intakes remained similar in both groups (201 ±
252 SD mg/day, n = 316 in the usual diet group vs. 235 ± 425 SD
mg/day, n = 195 in the very low fat group; P = NS). In this ran-
dom sample of WINS participants, neither total flavonoid intakes
nor intakes of subclasses of flavonoids differed between those who
had dramatically decreased their fat intakes and those who had
not. Flavonoid intakes are therefore unlikely to account for WINS
results on differences between the groups in cancer recurrence.
Breast cancer is the second leading cause of cancer death
among women in the United States, with 178,480 new cases
and 40,460 deaths expected in 2007 (1). Although rates have
decreased slightly in comparison to previous years, there is still
much room for improvement (2) both in early treatment (3,4)
and more effective therapeutic approaches because there is still
a high risk of recurrence 10–15 yr after diagnosis (5,6).
Very low fat diets are one of several dietary manipula-
tions that might decrease long-term risk of breast cancer recur-
rence (7). The WINS (Women’s Intervention Nutrition Study)
study found that the risk of breast cancer recurrence among
postmenopausal women with primary localized breast cancer
who received conventional therapy (surgery, radiation, and/or
chemotherapy) plus a very low fat diet was lower than among
FLAVONOID INTAKE AND VERY LOW FAT DIET ON BREAST CANCER
interval = 0.60–0.98, P = 0.03), especially in estrogen receptor
negative women (8).
In some studies, high intakes of fruits and vegetables re-
duced risk of primary breast cancer (9–11) and its recurrence
(12), whereas in others they did not (13). Flavonoids are high
in fruits and vegetables, and they might account for some of
these differences. Therefore, we wished to determine whether
women who had been randomized to the very low fat diet af-
ter they modified their eating habits to achieve their goals. In
a pilot study of dietary supplement use among WINS partic-
ipants, many used flavonoid-containing dietary supplements,
which might further increase their flavonoid intakes (14).
Our hypothesis was that after randomization to the inter-
ventions, total flavonoids from food and supplements would be
higher in the WINS very low fat diet group than among those
rence observed in WINS might be due not only to fat reduction
but also to increased flavonoid intake, potentially modifying the
interpretation of study results.
The WINS Study
The WINS trial enrolled postmenopausal women with local-
ized breast cancer (48 to 78 yr of age, inclusive) that had un-
dergone standard, defined therapies (15). The demographic and
general characteristics of the WINS population are described in
vival (as the primary study endpoint) and overall survival (16).
By study close, 2,437 postmenopausal women had enrolled in
the trial (8).
Patients were randomized in a 40:60 split assignment to ei-
ther an intervention group with target intakes of 15% calories
from fat or a control group that continued to consume their
usual diets. The low-fat diet group participants received an in-
dividualized educational program targeted to reduce dietary fat
intake, which is described in detail elsewhere (14). The controls
received information on the most recent Dietary Guidelines for
Americans (17) but were provided with minimal ongoing nutri-
tion education beyond that. Participants in both dietary groups
were counseled by dietitians to ensure that nutritional adequacy
Dietary Intake Assessment
A random sample from the very low fat diet and control
groups was drawn by the project statisticians to assess flavonoid
intakes from recalls of diet and supplement intake at baseline
and at 12 mo after randomization.
Dietary intake was assessed with 3 unannounced 24-h tele-
phone recalls at baseline and 12 mo (18,19). The University of
Minnesota’s Nutrient Data System for Research (NDS-R) was
used to collect dietary intake data. NDS-R is a data system con-
the dietary recalls (3 days of baseline dietary data per subject)
were edited so that the recipes were aggregated into whole ana-
lyzable foods (14).Alistoffoods and theircodes wasgenerated
The dietary supplement data was collected in person during
a clinic visit with a dietitian at baseline and annually thereafter.
Participants were asked to bring all supplements with them for
the visit. Supplements were recorded on a WINS supplement
record form and on the WINS supplement ingredient form by
copying or photocopying label information (20).
Food Flavonoid Database
The flavonoid compounds of particular interest were the
compounds included in the U.S. Department of Agricul-
ture (USDA) provisional databases for flavonoids (21) and
isoflavonoids (22) that are the most common monomeric
flavonoids in foods in the United States (23,24). The 26 com-
kaempferol, myricetin, and isorhamnetin; the flavones lute-
olin and apigenin; the flavanones hesperetin, naringenin, and
eriodictyol; the flavan-3-ols (+)-catechin, (+)-gallocatechin,
(-)-epicatechin, (-)-epigallocatechin, (-)-epicatechin-3-gallate,
and (-)-epigallocatechin-3-gallate; the anthocyanidins cyani-
din, delphinidin, malvidin, pelargonidin, peonidin, and petu-
nidin; and the isoflavonoids daidzein, biochanin A, genistein,
coumestrol, and formononetin. Also included were the tea
flavonoid dimers theaflavin, theaflavin-3-gallate, theaflavin-3?-
gallate, theaflavin-3,3?-digallate, and the tea oligomeric flavan-
3-ols, the thearubigins.
The USDA food composition database for flavonoids is pro-
visional and relatively small, with only 225 food items and only
64% of these receiving higher confidence codes of “A” or “B”
in the USDA database, we utilized values based on flavonoid
analytic data for 23 (44%) of 52 items; values were imputed for
20 (39%) from flavonoid data based on the food’s close botani-
cal relative; and for 9 (17%) foods qualitative values were used
for flavonoids, as quantitative values were not available. Impu-
tations were made for an additional 619 foods such as potato
chips from existing flavonoid data and knowledge of processing
techniques and recipes.
Database for Flavonoid-Containing Dietary Supplements
Certain commonly consumed dietary supplements such as
soy isoflavones, citrus complex, green tea extract, and pyc-
nogenol are highly concentrated sources of flavonoids. We
developed a provisional flavonoid supplement database be-
cause none existed that was suitable for our study. The major
flavonoid-containing dietary supplements were identified from
label ingredient declarations and the dietary recalls of women
J. DWYER ET AL.
Characteristics of Participants in the WINSaFull Study and Flavonoid Substudy
CharacteristicsLow Fat (N = 218)
Usual Diet (N = 332)
Substudy (N = 550)
Full Study (N = 2,437)
57.0 Age (median), yr
Marital status (%)
Highest education level (%)
Current alcohol intake (%)
Ever smoked (%)
aAbbreviation is as follows: WINS, Women’s Intervention Nutrition Study.
sis of the botanical classification of their ingredients and their
processing were selected; 17 were plant ingredients (acerola,
alfalfa, black cohosh, dong quai, Echinacea, garlic, ginger,
ginkgo, ginseng, goldenseal, grape seed, green tea, kelp, milk
thistle, parsley, rose hips, and St. John’s wort), 3 were com-
pounds (hesperidin, quercetin, and rutin), and 5 were products
containing one or more flavonoid compounds (bioflavonoids,
pycnogenol, soy isoflavones, bee pollen, and royal jelly).
Taxonomic data on the plant ingredients for the dietary sup-
plement database were obtained from the Germplasm Research
Information Network (25). The Commonwealth Agricultural
Bureau and Medline databases, which contain chemical analyt-
ical data citations, were searched using botanical and common
was used to identify the manufacturer and related information
on specific flavonoid-containing dietary supplements.
were sought for each plant or ingredient. Individual plants were
further researched in the Phytochemical Dictionary (27) and
The Handbook of Natural Flavonoids (28) for references to
flavonoids in their botanical genera and families.
When analytical values were available from the literature,
amounts of individual flavonoid compounds in supplements
were then calculated based on chemically analyzed values pro-
vided in the literature. For missing values, we relied on botani-
cal precedents. Some flavonoid classes and compounds are re-
stricted to 1 or 2 taxa (family, genus, or species), and some are
classification is known along with subsequent processing char-
acteristics that might alter or remove flavonoids. When direct
calculation of flavonoid amounts was not possible because pub-
lished analytic data could not be found even after an extensive
literature search, flavonoids in the ingredients listed were esti-
mated based on published literature for a closely related plant
from the botanical standpoint.
were defined and entered into the database for 1) any ingredient
that comprised less than 1% of the total food supplement or
for less than 0.1% by weight of the ingredient. Exceptions were
made, and the compound was included if it still accounted for
more than 1 mg compound per 100 g of supplement after this
FLAVONOID INTAKE AND VERY LOW FAT DIET ON BREAST CANCER
criterion had been taken into account. “Likely analytical zeros”
were defined as constituents devoid of flavonoid content on the
basis of their botanical classification and processing rather than
being defined as constituents that had not been analyzed. All
reported values below the limits of detection for the assay were
To estimate the amount of each compound per pill, the fol-
lowing formula was used. Flavonoid compound mg/pill = (m)
%/M, where M = 100 mg plant, % = flavonoid amount in plant
(mg/100 mg dry weight), and m = amount (mg) of plant present
in pill. The quality and amount of information were then rated
using the USDA system (23). Flavonoid estimated values were
based on analyzed data for 283 of 609 supplement items and on
items containing flavonoids.
Table 2 shows that for the vast majority of constituents, little
Therefore, dietary supplement values for flavonoids that were
used involved varying degrees of imputation. In most cases,
data were judged inadequate due to gaps in the analytical litera-
ture. Quantitative analytical data were available on 3 flavonoid
compounds in dietary supplements (hesperidin, quercetin, and
flavonoids in 7 plants (alfalfa, garlic, ginkgo, grape seed, green
tea, parsley, St. John’s wort), and bee pollen. For 9 constituents
(acerola, Echinacea, ginger, ginseng, kelp, milk thistle, pyc-
nogenol, rose hips, royal jelly), only the presence or absence
of flavonoids had been noted in chemical analyses or only one
data point in one article was available; and no specific data
was available for the flavonoid content of 3 plants (black co-
hosh, dong quai, goldenseal) that, on the basis of their botanical
classification, should contain flavonoids.
Calculation of Flavonoid Intakes in WINS Participants
The amounts of flavonoid compounds available in each
flavonoid-containing food and supplement used by the WINS
participants were first estimated using published analytical val-
ues for flavonoid compounds in the plant constituents. Then
imputations were made for items without specific flavonoid
data. Next, flavonoid values were assigned to each of the
foods and recipes consumed. The amount of each flavonoid
class (mg/100 g) was entered for each food component. The
flavonoid database was then applied to the WINS participants’
food intakes for flavonoid analysis. Estimates for flavonoid-
containing supplements were developed using the flavonoid
supplement database. Finally, the dietary supplement and food
data from the dietary recalls were merged and estimates of to-
tal intakes calculated. Intakes of the 6 individual classes of
monomeric flavonoids (anthocyanins, flavan-3-ols, flavanones,
computed for each woman’s usual diet from the sets of 24-h
Mean intakes of the 6 individual classes of monomeric
flavonoids and of total flavonoids were computed for the very
low fat and usual diet groups at baseline and 12 mo. The Mann–
Whitney and Kruskal–Wallace analysis of variance for non-
parametric data were performed to assess differences between
groups. For certain comparisons of paired data from baseline
to 12 mo, the Wilcoxon signed ranks tests for paired data were
also performed. Additional comparisons were made between
users of flavonoid-containing dietary supplement and nonusers
in both groups over time. A P value of >0.05 was considered
not statistically significant (NS).
Loss to follow-up over the course of the study was greater in
the very low fat group (n = 23, or 11%) than in the usual diet
group (n = 16, or 5%).
Table 3 shows that there were no statistically significant dif-
ferences between the very low fat and usual diet groups at base-
line for total flavonoid intakes using the Mann–Whitney test on
unpaired data. Neither was there any significant difference in
total flavonoids at 12 mo, although at 12 mo, fat intakes had
decreased significantly in the very low fat group (P < 0.0001).
However, for both groups, there was a significant increase in
intakes of flavanones (P ≤ 0.05 very low fat and usual diet)
and for anthocyanins in the very low fat group (P < 0.05) be-
tween baseline and 12 mo, suggesting more intakes in fruits and
vegetables. The usual diet group had significantly decreased in-
takesofflavones (P<0.05)andisoflavones (P=0.05)between
baseline and 12 mo.
Therefore, the data from women with intakes at both baseline
and 12 mo were compared using the Wilcoxon signed ranks
test. Table 4 shows that total flavonoids decreased significantly
among those in the usual diet group from baseline to 12 mo
(P < 0.05) but did not change in the very low fat group. Intakes
of some classes of flavonoids did change, however. Flavanone
paired data (very low fat group P = 0.0005; usual diet group,
P = 0.05). Isoflavone intake significantly decreased in the very
low fat group (P < 0.05) and the usual diet group’s flavone
intake significantly decreased (P < 0.001).
Flavonoid-Containing Supplement Users and Nonusers
Table 5 shows that at baseline in the very low fat group of
218 women, 45 (21%) were using flavonoid-containing supple-
group, 30 (15%) were using such supplements. In the usual diet
Specific Flavonoid Content of the 25 Most Common Flavonoid-Containing Dietary Supplements in WINSa
St. John’s Wort
Soy isoflavones Glycine
Compounds Hesperidin Quercetin
aAbbreviation is as follows: WINS, Women’s Intervention Nutrition Study. Key: d, quantitative data; p, qualitative data; g, quantitative data available only on genus, or
products of the genus; f, quantitative data available only on family; i, investigated not present; blank, not expected, not investigated.
Intakes of Fat and Flavonoids From Foods and Supplements in WINS Participants, Unpaired Data Using Mann–Whitney Testa
Flavonoid Classes (mg/day)
Total Fat (g/day) Total Fat (% kcal) Total Flavonoids (mg/day) Anthocyanins Flavan-3-ols Flavanones
Visit and Group
Mean SD Mean
Baseline, very low fat 218
Baseline, Usual diet
12 mo, very low fat
12 mo, Usual diet
bP < 0.0001 for comparison of the very low fat group from baseline to 12 mo using 2-tailed t-test of means.
Intakes of Fat and Flavonoids From Foods and Supplements in WINS Participants with Dietary Data at Both Baseline and 12 mo Paired Data Using the
Wilcoxon Signed Ranks Testa
Flavonoid Classes (mg/day)
Total Flavonoids (mg/day)
Visit and Group
Baseline, very low fat
12 mo, very low fat
aAbbreviation is as follows: WINS, Women’s Intervention Nutrition Study. Items with the same subscript are significantly different from each other. Subscripts a, c, and e,
P < 0.05; subscripts b and d, P < 0.001; Wilcoxon signed ranks test.
FLAVONOID INTAKE AND VERY LOW FAT DIET ON BREAST CANCER
Total Flavonoid Intakes of WINS Users and Nonusers of Flavonoid-Containing Supplements at Baseline and 12 moa
Total Flavonoids in Food and Dietary Supplements (mg/day)
Very Low Fat Diet Usual Diet
Total Food and SupplementsTotal Food and Supplements
Group and Flavonoid Supplement Use
12 mo Nonusers
12 mo Users
aAbbreviation is as follows: WINS, Women’s Intervention Nutrition Study. Items with the same subscript are significantly different from
each other. P < 0.01 for subscripts a and b, p ≤ 0.05 for subscripts c and d; Mann–Whitney test.
63 (20%) were using flavonoid-containing supplements. When
flavonoid intakes from food only were compared, the very low
fat group at baseline had slightly but not significantly lower
intakes (P = NS, data not shown).
For the supplement use, subgroups total flavonoid intakes
from food plus flavonoid-containing supplements were exam-
ined using the Mann–Whitney test for independent groups.
Total flavonoid intakes of users of flavonoid-containing sup-
plements were significantly higher at baseline than those of
nonusers of flavonoid-containing supplements between both
those women in the usual diet group and those in the very
low fat diet group. At 12 mo, differences between users and
nonusers of flavonoid-containing supplements were not appar-
ent in either group. Results were similar using paired data (data
There is considerable in vitro (29,30) and some experimen-
tal animal evidence (31) that specific flavonoid classes such as
the flavones, isoflavones, and flavanones inhibit breast cancer
cell proliferation (32). Intakes of some flavonoids are associ-
ated with decreased risk of occurrence and possibly also re-
currence of breast cancer. In some (33–35) but not all (36,37)
studies, diets high in isoflavones, which are thought to be antie-
strogenic, have been associated with decreased breast cancer
risk. Also, in two recent case-control studies (9,11), flavones
were found to be protective, whereas the other flavonoid classes
Mean flavonoid intakes of the WINS women were approxi-
which range from 190–243 mg/day (38–40). In studies us-
ing Western diets (9,11,38–48), mean intakes from the various
classes of flavonoids were about 10 mg/day for anthocyanins,
84 mg/day for flavan-3-ols, 33 mg/d for flavanones, 0.5 mg/d
for flavones, 17 mg/day for flavonols, 6 mg/day for isoflavones,
and 170 mg/day for total flavonoids. The women in the WINS
population tended to have higher mean intakes compared to
these other populations of flavan-3-ols, flavones, flavonols and
lower for flavanones, perhaps because we used more complete
data than were available to these earlier investigators or because
we included flavonoid-containing supplements.
Because only the monomeric flavonoids were assessed,
the actual flavonoid intakes of the WINS women may have
been considerably higher than that reported here. A database
for proanthocyanidins, the oligomeric flavonoids (condensed
in Western diets, was not available at the time of analysis (49).
Because proanthocyanidins are common in foods and are per-
haps the second most abundant natural phenol group after lig-
nans in foods, it is important to include them in future studies
The WINS women’s total flavonoid intakes changed only
slightly from baseline to 12 mo postintervention, nor were
changes in subclasses striking. It was surprising that flavonoid
intakes among women in the very low fat diet group were not
higher. Increases in intakes of flavonoid rich foods such as soy,
the low fat diet group (51), and these probably accounted for the
few small increases in flavonoid intakes that existed at 12 mo.
Similar results were reported in the Women’s Health Initiative
Study in which extensive attempts to increase fruit and veg-
etable intakes and decrease fat intake led to only slightly more
fruit and vegetable intake and decreased fat intake but not to
prescribed target levels (52). Recently, the WHELS study found
that among survivors of early stage breast cancer, adoption of a
diet that was very high in fruits and vegetables and low in fat
did not reduce breast cancer events or mortality during a 7.5-yr
J. DWYER ET AL.
Dietary Supplement Use
Dietary supplement use has increased greatly over the past
cer reported regular use of at least 1 dietary supplement (57,59).
Single vitamin and mineral products are usually consumed at
much higher rates than in the general population. For example,
49% of cancer survivors used a vitamin E supplement (com-
pared to 13% in the general population sample in NHANES
In an earlier analysis of the baseline data from WINS, the
vast majority of women (85%) in the WINS study were taking
dietary supplements of some type, with 41% taking botanical
supplements (including herbals). However, only 14% of the
dietary supplements they took contained flavonoids (60). To our
knowledge, this is the first study to report the total flavonoid
intakes of breast cancer survivors.
The algorithm used to estimate the amounts of flavonoids
in dietary supplements involved many assumptions that require
further validation. The available data on flavonoids in supple-
ments consisted of a few analytical values and many estimates
(see Table 2). Many assumptions had to be made because pub-
lished analytical values were not available, increasing the po-
tential for measurement error (61). Label declarations of the
amounts of nonnutrient compounds are not required by law for
either foods or dietary supplements and are not always sub-
stantiated by chemical analysis. Until analytical data becomes
available or regulations require analytical backup for label dec-
larations, label declarations are the best estimates available.
Therefore, the quantitative estimates we report are only rough
approximations of flavonoid intake.
We included only flavonoids in the USDA food compo-
sition database in the dietary supplement database. Although
the flavonoid compounds in foods and those in botanical sup-
plements are often similar, they are not completely identical.
Botanical supplements may also contain several flavonoids not
that may have health effects. This is another limitation of this
ment groups were found over time. The many adjustments we
made to estimate flavonoid intakes and the variability in exist-
ing data on flavonoids in foods meant that the various sources
of measurement error were several and potentially large. They
may have obscured true differences. For some compounds, such
as total flavonoids, power estimates appeared to be adequate;
whereas for others, they were not. The sample size necessary
to detect differences in intakes between groups at 12 mo for
some of the compounds such as anthocyanins, flavones, and
isoflavones needs to be much larger. Confirmation of differ-
ences between these compounds would require analyzing the
complete population, which was not possible for this study.
The provisional flavonoid database that we developed and
applied included both food and dietary supplements and was
much more complete than those used in previous studies of di-
etary flavonoids and breast cancer recurrence. However, among
women on very low fat as opposed to usual dietary fat intakes,
intakes of total flavonoids and 6 classes of flavonoids differed
only slightly at 12 mo postrandomization. Therefore, flavonoid
intakes were unlikely to account for the association between de-
creased fat intakes and lowered risk of breast cancer recurrence
in postmenopausal women in WINS.
We thank the following institutions for partial support of this
work: American Institute for Cancer Research to Dr. Dwyer,
Massachusetts Department of Public Health’s Breast Cancer
Research Grants Program, and the National Research Initia-
tive of the USDA Cooperative State Research, Education and
Extension Service, Grant 2006-35200-17259 to Dr. Peterson.
This project was also supported in part by the USDA, under
agreement No. 58-1950-4-401 at the Jean Mayer USDA HNRC
on Aging at Tufts University. The contents of this publication
donotnecessarilyreflect theviews orpolicies oftheUSDA,nor
does mention of trade names, commercial products, or organi-
zations imply endorsement by the U.S. government. We also
thank Dr. Ritva Butrum who first stimulated our thinking about
bioactive compounds. Note that information on the supplement
flavonoid dataset is available from the authors.
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