Intakes of selected nutrients and food groups and risk of ovarian cancer.

Abstract

In a hospital-based case-control study, we examined dietary intakes of selected nutrients and food groups and ovarian cancer risk among 496 women with primary, histologically confirmed epithelial ovarian cancer and 1,425 women with nonneoplastic diagnoses, ages 20-87 years, admitted to Roswell Park Cancer Institute between 1982 and 1998. Data on diet and other relevant risk factors in the few years before admission were collected with a self-administered questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression adjusting for age, education, region of residence, regularity of menstruation, family history of ovarian cancer, parity, age at menarche, oral contraceptive use, and energy intake. Women in the highest vs. the lowest quartile of total energy had a weak increase in risk (OR = 1.25, 95% CI = 0.90-1.73). Significantly reduced risks were associated with higher intakes of dietary fiber (OR = 0.57, 95% CI = 0.38-0.87), vitamin A (OR = 0.66, 95% CI = 0.45-0.98), carotenoid (OR = 0.64, 95% CI = 0.43-0.93), vitamin E (OR = 0.58, 95% CI = 0.38-0.88), beta-carotene (OR = 0.68, 95% CI = 0.46-0.98), and total fruit and vegetable intake (OR = 0.62, 95% CI = 0.42-0.92). Our findings suggest that a diet high in plant foods may be important in reducing risk of ovarian cancer.

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Intakes of Selected Nutrients and Food
Groups and Risk of Ovarian Cancer
Susan E. McCann, Kirsten B. Moysich, and Curtis Mettlin
Abstract: In a hospital-based case-control study, we exam-
ined dietary intakes of selected nutrients and food groups
and ovarian cancer risk among 496 women with primary,
histologically confirmed epithelial ovarian cancer and
1,425 women with nonneoplastic diagnoses, ages 20–87
years, admitted to Roswell Park Cancer Institute between
1982 and 1998. Data on diet and other relevant risk factors
in the few years before admission were collected with a self-
administered questionnaire. Odds ratios (OR) and 95%
confidence intervals (CI) were estimated by unconditional
logistic regression adjusting for age, education, region of
residence, regularity of menstruation, family history of
ovarian cancer, parity, age at menarche, oral contraceptive
use, and energy intake. Women in the highest vs. the lowest
quartile of total energy had a weak increase in risk (OR =
1.25, 95% CI = 0.90–1.73). Significantly reduced risks were
associated with higher intakes of dietary fiber (OR = 0.57,
95% CI = 0.38–0.87), vitamin A (OR = 0.66, 95% CI =
0.45–0.98), carotenoid (OR = 0.64, 95% CI = 0.43–0.93),
vitamin E (OR = 0.58, 95% CI = 0.38–0.88), ?-carotene
(OR = 0.68, 95% CI = 0.46–0.98), and total fruit and vege-
table intake (OR = 0.62, 95% CI = 0.42–0.92). Our findings
suggest that a diet high in plant foods may be important in
reducing risk of ovarian cancer.
Introduction
Ovarian cancer is an important cause of morbidity and
mortality among women. Over 25,000 new cases were esti-
mated in 1999, with ?14,000 estimated deaths (1). The dis-
ease is difficult to detect and often quite advanced by
diagnosis. The etiology of ovarian cancer has not been
clearly elucidated, but risk factors tend to be related to those
affecting hormonal and reproductive events. Higher parity
and oral contraceptive use have been associated with re-
duced risks (2). Putative mechanisms for ovarian cancer re-
lated to hormonal factors are excessive levels of circulating
gonadotropins associated with lower parity and decreased
number of ovulatory cycles from higher parity, resulting in
reduced mitotic events in the ovary (2).
Diet could contribute to the etiology of ovarian cancer
through modulation of the endogenous hormonal milieu
(3–13) or through antioxidant and anticarcinogenic mecha-
nisms (14). The relationship between nutrient and food in-
take and ovarian cancer has been addressed in case-control
and prospective designs, although the results have been in-
conclusive. In general, somewhat increased risks have been
reported for higher intakes of total fat and animal fat, choles-
terol and lactose intakes (15–17), and higher intakes of meat,
eggs, and whole milk (17–19). Conversely, inverse associa-
tions have been reported for fiber, vitamin A, ?-carotene
(20–22), and fruit and vegetable intakes (15–17).
Beginning in 1982, all individuals admitted to Ros-
well Park Cancer Institute (RPCI), a comprehensive cancer
center in Western New York, were asked to complete a com-
prehensive epidemiological questionnaire that included re-
productive and medical histories, family history of cancer,
occupational and environmental exposures, tobacco and al-
cohol consumption, and diet. Since 1982, ?40,000 patients
with cancer and noncancer diagnoses have completed the
questionnaire. Among these, ?500 women were diagnosed
with ovarian cancer, providing a unique opportunity to in-
vestigate the impact of diet on risk of ovarian cancer.
Methods
Subjects
The study population included women admitted to RPCI
between 1982 and 1998 who agreed to complete a compre-
hensive epidemiological questionnaire. Informed consent
was obtained from all participants. Only women with com-
plete data for the present analyses were included. Cases were
496 women with primary, incident epithelial ovarian cancer,
identified from the RPCI tumor registry and diagnostic in-
dex. Cases were predominantly Caucasian (98%) and ranged
in age between 20 and 87 years. Controls included 1,425
NUTRITION AND CANCER, 39(1), 19–28
Copyright © 2001, Lawrence Erlbaum Associates, Inc.
S. E. McCann is affiliated with the Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY 14214. K. B. Moysich and C. Mettlin
are affiliated with the Department of Cancer Prevention, Epidemiology and Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263.

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women who received medical services at RPCI for non-
neoplastic conditions, randomly selected from a pool of
5,700 eligible women and frequency matched to the cases by
five-year age intervals. The most frequently utilized services
for the control patients included the breast clinic (28%), gy-
necology clinic (17%), surgery (15%), and dermatology
clinic (11%). Among the control women, nonneoplastic di-
agnoses were distributed among the following disease cate-
gories: circulatory system (21%), respiratory system (18%),
digestive system (16%), musculoskeletal system and con-
nective tissue (12%), endocrine disorder (11%), central
nervous system (6%), and other (16%). Similar to cases,
women in the control group were predominantly Caucasian
and ranged in age between 25 and 90 years.
Questionnaire
All participants agreed to complete the Patient Epidemi-
ology Data System (PEDS) questionnaire, which is offered
to all new patients as part of the admission process and is
completed by ~50% of new patients within three months of
diagnosis. The self-administered 16-page instrument covers
information on reproductive and medical histories, family
history of cancer, occupational and environmental expo-
sures, tobacco and alcohol consumption, and diet.
Diet in the few years before diagnosis (or admission for
controls) was queried using a 44-item food frequency ques-
tionnaire (FFQ) and did not include information regarding
portion size. The five response categories range from never
to five to seven times per week. The questionnaire was de-
signed to provide an assessment of intakes of fruits and veg-
etables, cruciferous vegetables, and foods providing good
sources of vitamins A, C, and E, fat, and fiber (23). Foods in-
cluded on the questionnaire were chosen to provide a profile
for each respondent for these nutrients. The foods were se-
lected from data from a detailed diet interview, lasting ~2.5
hours, with each of 282 healthy individuals, participants in
the Western New York (WNY) Diet Study I (1975–86). The
interview included detailed questions regarding frequency
of consumption, portion size, seasonality of intake, and
preparation methods for 140 foods. From the food frequency
data, an index of nutrient intake was calculated. Multiple lin-
ear regression models were then calculated, with nutrient in-
dex as the dependent variable and intake of individual foods
as the independent variables to obtain the list of foods that
explained the largest amount of variance for each nutrient.
Although brief, the resultant 44-item food list constituted
those foods most highly correlated with the nutrient profiles
in question and explained 90% of the total variability in in-
gestion of vitamins A, C, and E, fat, and dietary fiber (23).
Because of the brevity of the FFQ, nutrient intake was
calculated using regression weights derived from the
process used to obtain the food list included on the question-
naire. The gender-specific regression weights were com-
puted using dietary data from 1,475 male and 780 female
controls, participants of the WNY Diet Study I (1975–86).
First, nutrients were computed for the WNY Diet Study us-
ing 140 foods, reported frequency of consumption, portion
size, cooking method, seasonality, and US Department of
Agriculture food composition values. With use of the foods
in the WNY Diet Study that represent the 44 foods included
on the shorter questionnaire, multiple linear regression mod-
els were calculated with each nutrient as the dependent vari-
able and the 44 foods as the independent variables. The
resulting regression coefficient for each food and nutrient
was then multiplied by the frequency of use reported on the
PEDS FFQ summed across foods to obtain an index of each
nutrient. Regression weights were available for calculation
of mean daily intakes of energy, protein, carbohydrates, total
fat, saturated fat, monounsaturated fat, polyunsaturated fat,
animal and vegetable fat, cholesterol, dietary fiber, vitamins
A, C, and E, retinol, total carotenoids, ?-carotene, ?-caro-
tene, cryptoxanthin, lutein + zeaxanthin, and lycopene.
In addition to investigating risk of ovarian cancer with
nutrient intake, risk associated with monthly frequency of
use of several food groups was of interest. Because the FFQ
was limited to 44 food items (predominantly fruits and vege-
tables), we examined the following food groups only: fruits
and fruit juices, vegetables, total fruits and vegetables, and
meats, categorized according to US Department of Agricul-
ture classification definitions. We were unable to examine
frequency of use of dairy products, breads and cereals, or
snacks and sweets, inasmuch as these items were not in-
cluded on the questionnaire.
Statistical Analyses
Descriptive analyses included Student’s t-tests of means
for cases and controls for continuous variables, and ?2tests
for categorical variables. For estimation of risk associated
with each nutrient, daily nutrient intake was divided into
quartiles on the basis of the intake distribution of the con-
trols. Risk of ovarian cancer in each quartile relative to the
lowest (referent) quartile of nutrient intake was estimated by
odds ratios (ORs) and 95% confidence intervals (CIs) calcu-
lated with unconditional logistic regression. ORs were ad-
justed for potential confounders, including age, education,
region of residence, age at menarche, parity, oral contracep-
tive use, presence of irregular menses, family history of
ovarian cancer, and total energy intake. Covariates were in-
cluded in the final regression model only if they were estab-
lished risk factors in these data or changed the observed risk
estimates by ?15%.
Analyses of risk associated with specific food groups
were conducted in a similar manner. Monthly frequency of
use of each group was divided into quartiles on the basis of
the intake distribution of the controls. ORs were adjusted for
the same covariates as for nutrient intake, with the exception
of total energy. To account for differences in diet composi-
tion, each food group was further adjusted for monthly fre-
quency of use of the remaining major food groups. Tests for
trend for each nutrient and food group were computed from
20Nutrition and Cancer 2001

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the P value (2-tailed) of the logistic regression of the contin-
uous nutrient or food group variable within the specified
models.
Results
The descriptive characteristics of the ovarian cancer
cases and controls are shown in Table 1. Consistent with the
literature, women with ovarian cancer tended to have a later
age at first pregnancy, be nulliparous, be less likely to have
breast-fed, be less likely to have used oral contraceptives or
have a tubal ligation, be less likely to have regular menstrual
cycles, and be more likely to have a family history of ovar-
ian cancer than women without ovarian cancer. Cases were
also less likely than controls to reside in Western New York.
Age at menarche did not differ for women with and without
ovarian cancer.
Risk of ovarian cancer associated with mean daily energy
and macronutrient intake is shown in Table 2. Compared
with women in the lowest quartile of intake, women in the
highest quartile of total energy had a weak, but statistically
nonsignificant, increase in risk (OR = 1.25, 95% CI =
0.90–1.73). Risk was not related to daily intakes of protein,
carbohydrates, total fat, or any fat component in these data,
although we observed a borderline statistically significant
trend in increasing risk associated with fat from animal
sources (p = 0.05).
Risk of ovarian cancer associated with mean daily micro-
nutrient intake is shown in Table 3. We observed reductions
in risk of ~30–40% for women in the highest vs. lowest
quartiles of dietary fiber (OR = 0.57, 95% CI = 0.38–0.87),
total vitamin A (OR = 0.66, 95% CI = 0.45–0.98), total ca-
rotenoids (OR = 0.64, 95% CI = 0.43–0.93), vitamin E (OR
= 0.58, 95% CI = 0.38–0.88), and ?-carotene (OR = 0.68,
95% CI = 0.46–0.98). Somewhat weaker reductions in risk
were also observed for vitamin C (OR = 0.69, 95% CI =
0.47–1.03), retinol (OR = 0.71, 95% CI = 0.48–1.04), ?-car-
otene (OR = 0.75, 95% CI = 0.53–1.06), lycopene (OR =
0.81, 95% CI = 0.57–1.15), and lutein + zeaxanthin (OR =
0.76, 95% CI = 0.52–1.10), with vitamin C and lutein +
zeaxanthin exhibiting statistically significant trends for re-
duced risks associated with increasing intake (p = 0.02).
Consistent with the reduced risks observed for the micro-
nutrients, as shown in Table 4, risk of ovarian cancer was re-
duced by ~40% for women in the highest vs. the lowest
quartile of total fruit and vegetable intake (OR = 0.62, 95%
CI = 0.42–0.92). Although risks were reduced for women in
the highest quartiles of fruits (OR = 0.85, 95% CI =
0.59–1.21) and vegetables (OR = 0.76, 95% CI = 0.52–1.10)
examined separately, there did not seem to be a significant
improvement in contribution to risk reduction by either indi-
vidual group. Risk was not related to monthly frequency of
meat consumption (OR = 1.17, 95% CI = 0.80–1.71).
Discussion
Relatively little is known concerning the etiology of ovar-
ian cancer, although hormonal exposures appear to be im-
portant (2). There have been few investigations of the impact
of food and nutrient intake on ovarian cancer risk, but these,
in general, support a protective effect of diets higher in fruits
and vegetables, as well as nutrients commonly associated
with these foods, such as vitamin C, dietary fiber, and ?-car-
otene (15–17,20–22), and a risk-elevating effect for foods
from animal sources, fat, and cholesterol (15–19). Our find-
ings confirm previously reported associations of reduced
ovarian cancer risks with vitamin C, dietary fiber, and ?-car-
otene, although we observed no increases in risk associated
with any nutrient or food group. Several mechanisms could
account for our findings. Vitamins C and E and several of
the carotenoids have been shown to be potent antioxidants
and, therefore, could affect cancer risk. Diet composition
can affect steroid hormone levels, and, therefore, may affect
Vol. 39, No. 1 21
Table 1. Descriptive Characteristics of Ovarian Cancer
Cases and Hospital Controls: Roswell Park Cancer
Institute, Buffalo, NY (1982–96)a
Cases
(n = 496)
Controls
(n = 1,425)
Mean ± SD
Age, yr
Age at menarche, yr
Age at 1st pregnancy, yr
55.1 ± 13.4
13.1 ± 5.7
23.2 ± 4.8*
54.7 ± 13.6
13.2 ± 6.2
22.7 ± 5.1
Number (%)
Education
Up to high school
College
Place of residence
Western New York
Outside Western New York
Tubal ligation
Yes
No
Oral contraceptive use
Ever
Never
Regularity of menses
Regular
Irregular
Parity
Nulliparous
1–2
3–4
?5
Breast feeding
Never
Ever
Family history of ovarian cancer
No
Yes
258 (52.0)
238 (48.0)
781 (54.8)
644 (45.2)
234 (47.2)†
262 (52.8)
1200 (84.2)
225 (15.8)
67 (13.5)†
429 (86.5)
253 (17.8)
1172 (82.2)
158 (31.9)†
338 (68.1)
494 (34.7)
931 (65.3)
432 (87.1)†
64 (12.9)
1154 (81.0)
271 (19.0)
110 (22.2)†
180 (36.3)
168 (33.9)
38 (7.7)
255 (17.9)
503 (53.3)
496 (34.8)
171 (12.0)
311 (64.0)†
175 (36.0)
789 (56.6)
605 (43.4)
460 (92.7)†
36 (7.3)
1377 (96.6)
48 (3.4)
a: Statistical significance is as follows: *, p ? 0.05 (t-test); †, p ? 0.05 (?2
test).

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22Nutrition and Cancer 2001
Table 2. ORs and 95% CIs for Risk of Ovarian Cancer With Daily Macronutrient Intake: Roswell Park Cancer Institute,
Buffalo, NY (1982–96)a
n
OR
(95% CI)
P Value
for TrendCases Controls
Energy
Q1 (?1,346 kcal)
Q2 (1,347–1,754 kcal)
102
140
358
354
1.00
1.26
0.45
(0.92–1.73)
1.17
(0.85–1.62)
1.25
(0.90–1.73)
Q3 (1,755–2,256 kcal) 128361
Q4 (?2,256 kcal)126352
Proteinb
Q1 (?56 g)
Q2 (57–76 g)
109
129
357
359
1.00
1.08
0.16
(0.77–1.51)
1.10
(0.74–1.61)
1.20
(0.69–2.08)
Q3 (77–102 g) 129 361
Q4 (?102 g) 129348
Carbohydratesc
Q1 (?167 g)
Q2 (168–216 g)
108
142
354
354
1.00
1.10
0.81
(0.78–1.57)
0.95
(0.62–1.44)
0.86
(0.47–1.59)
Q3 (217–273 g)124366
Q4 (?273 g) 122 351
Total fatd
Q1 (?49 g)
Q2 (50–67 g)
109
131
355
362
1.00
1.17
0.11
(0.83–1.64)
1.22
(0.82–1.80)
1.48
(0.85–2.60)
1.00
1.16
(0.83–1.62)
1.18
(0.80–1.73)
1.34
(0.78–2.32)
Q3 (68–89 g) 127360
Q4 (?90 g)
Fat from animal sourcese
Q1 (?34 g)
Q2 (35–49 g)
129348
111
132
359
360
0.05
Q3 (50–68 g) 124357
Q4 (?68 g) 129349
Fat from vegetable sourcese
Q1 (?14 g)
Q2 (15–17 g)
117
131
356
352
1.00
1.10
0.68
(0.80–1.52)
1.01
(0.72–1.43)
0.90
(0.60–1.34)
Q3 (18–22 g)123360
Q4 (?22 g) 125 357
Saturated fate
Q1 (?16 g)
Q2 (17–24 g)
112
122
357
361
1.00
1.06
0.70
(0.76–1.49)
1.22
(0.8–1.79)
1.36
(0.79–2.35)
Q3 (25–34 g) 129 359
Q4 (?34 g) 133 348
(Continued)

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Vol. 39, No. 123
Table 2. (Continued)
n
OR
(95% CI)
P Value
for TrendCases Controls
Monounsaturated fate
Q1 (?15 g)
Q2 (16–21 g)
109
128
358
361
1.00
1.18
0.30
(0.84–1.65)
1.22
(0.82–1.80)
1.50
(0.87–2.61)
Q3 (22–28 g) 123 354
Q4 (?28 g) 136352
Polyunsaturated fate
Q1 (?8 g)
Q2 (9–10 g)
115
131
362
351
1.00
1.17
0.40
(0.84–1.61)
1.05
(0.74–1.49)
0.92
(0.60–1.42)
Q3 (11–13 g) 127 360
Q4 (?13 g)123352
a: Q = quartile, adjusted for age, education, region of residence, regularity of menstruation, family history of ovarian cancer, parity, age at menarche, and oral
contraceptive use. OR, odds ratio; CI, confidence interval.
b: Further adjusted for carbohydrates and fat.
c: Further adjusted for protein and fat.
d: Further adjusted for carbohydrates and protein.
e: Further adjusted for total fat.
Table 3. ORs and 95% CIs for Risk of Ovarian Cancer With Daily Micronutrient Intake: Roswell Park Cancer Institute,
Buffalo, NY (1982–96)
n
ORa
(95% CI)
P Value
for Trend CasesControls
Cholesterol
Q1 (? 229 mg)
Q2 (230–323 mg)
120
129
355
364
1.00
0.88
0.51
(0.64–1.22)
0.86
(0.60–1.23)
0.99
(0.63–1.55)
Q3 (324–460 mg)117 356
Q4 (?460 mg) 130350
Dietary fiber
Q1 (?16 g)
Q2 (17–22 g)
117
141
350
359
1.00
1.06
0.03
(0.77–1.45)
0.85
(0.60–1.19)
0.57
(0.38–0.87)
Q3 (23–30 g) 137362
Q4 (?30 g) 101354
Vitamin C
Q1 (?112 mg)
Q2 (113–173 mg)
111
136
351
354
1.00
1.14
0.02
(0.83–1.58)
1.12
(0.80–1.56)
0.69
(0.47–1.03)
Q3 (174–250 mg) 153 360
Q4 (?250 mg)96 360
(Continued)