Intake of Carrots, Spinach, and Supplements Containing...

Vol. 6, 887-892. Nm’e,nher 1997 Cancer Epidemiology, Biomarkers & Prevention 887

Intake of Carrots, Spinach, and Supplements Containing Vitamin A in

Relation to Risk of Breast Cancer1

Matthew P. Longnecker,2 Polly A. Newcomb,Robert Mittendorf, E. Robert Greenberg, andWalter C. Willett

Epidemiology Branch. National Institute of Environmental Health Sciences.

Research Triangle Park. North Carolina 27709 IM. P. LI: Fred HutchinsonCancer Research Center, Seattle, Washington 98104 lP. A. N.]; Department of

Obstetrics and Gynecology, Pritzker School of Medicine, The University of

Chicago. Chicago, Illinois (R. M.]: Norris Cotton Cancer Center, Dartmouth

Hitchcock Medical Center, Lebanon, New Hampshire 03756 [E. R. G.l; and

Departments of Nutrition and Epidemiology, Harvard School of Public Health.

Channing Laboratory. Harvard Medical School. and Department of Medicine.

Brigham and V/omens’ Hospital. Boston. Massachusetts t)2l 15 [W. C. W.]

Abstract

Intake of fruits, vegetables, vitamin A, and related

compounds are associated with a decreased risk of breastcancer in some studies, but additional data are needed.To estimate intake of �3-carotene and vitamin A, theauthors included nine questions on food and supplementuse in a population-based case-control study of breastcancer risk conducted in Maine, Massachusetts, NewHampshire, and Wisconsin in 1988-1991. Multivariate-adjusted models were fit to data for 3543 cases and 9406

controls. Eating carrots or spinach more than twiceweekly, compared with no intake, was associated with anodds ratio of 0.56 (95% confidence interval 0.34-0.91).Estimated intake of preformed vitamin A from all

evaluated foods and supplements showed no trend ormonotonic decrease in risk across categories of intake.These data do not allow us to distinguish among severalpotential explanations for the protective associationobserved between intake of carrots and spinach and riskof breast cancer. The findings are, however, consistentwith a diet rich in these foods having a modest protectiveeffect.

Introduction

Epidemiological data suggest that intake of fruits, vegetables,carotenoid vitamin A, or total vitamin A is associated with alower risk of breast cancer ( 1-3), although not all evidence

supports this (4-6). [Some carotenoids can be converted tovitamin A (retinol) in t’ivo; total vitamin A refers to the com-

bined vitamin A activity of vitamin A precursors and preformedretinol.] Selected vegetables and carotenoids appear to preventcancer in some laboratory studies (7, 8), and vitamin A plays a

Received 2119/97: revised 6/I 1/97: accepted 6/27/97.

The costs of publication of this article were defrayed in part by the payment of

page charges. This article must therefore be hereby marked advertisemeiti in

accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

� Supported by USPHS Grants CA 47147 and CA 47305 from the National

Cancer Institute, NIH. Department of Health and Human Services.2 To whom requests for reprints should be addressed.

role in regulating cell differentiation (9): thus, it is biologically

plausible that these may prevent breast cancer in humans.Recent trials in men ( 10. 1 1 ), however, show supplementationwith n-carotene or preformed vitamin A increasing risk of lungcancer in high-risk populations. and other data ( 12) indicate thatassociations with breast cancer attributed to n-carotene may bedue to other aspects of a diet high in vegetables. These obser-vations highlight the need for additional study of the relation

between fruits, vegetables. carotenoids, vitamin A, and breast

cancer.When designing the questionnaire for a large population-

based case-control study of breast cancer ( I 3). we selected abrief set of questions on intake of foods and supplements thatcould efficiently be used to classify subjects according to intake

of f3-carotene and vitamin A. Here we present our resultsregarding risk of breast cancer in relation to intake of selected

foods and supplements and estimated intakes of a-carotene and

vitamin A.

Materials and Methods

Selection of Cases and Controls. Eligible subjects (cases andcontrols) met the following criteria: (a) female: (h) age less than

75 years; (c) resident of Maine, Massachusetts (outside of the

Boston area), New Hampshire, or Wisconsin; (d� telephonenumber listed in a telephone book or available through direc-tory assistance at the time of contact: (e) fluent in English: and

(I) for subjects less than 65 years old, self-reported possessionof a driver’s license. Detailed descriptions of the methods ofthis study are available elsewhere (13, 14).

Cases were eligible if the diagnosis of invasive breastcancer was first reported to one of the four state-wide cancerregistries during I 988 -1 99 1 . During the accrual period. 1 1,879potentially eligible cases were reported to the four cancerregistries. Of these, 28% were not eligible (14), leaving 8579

eligible cases, of whom 6888 (80%) were interviewed. The

cancer registry record indicated histological confirmation ofbreast cancer in 98% of the interviewed cases.

We selected controls less than 65 years old from state

driver’s license lists and controls 65-74 years old from theHealth Care Financing Administration’s list of Medicare ben-

eficiaries. The driver’s license lists and the Health Care Financ-ing Administration lists were updated yearly. We excludedcontrols who reported a previous diagnosis of breast cancer. Weidentified 16,217 potential controls of whom 3 1% were noteligible (14). leaving 1 1,238 eligible controls. of whom 9.428

(84%) were interviewed.

Data Collection. Trained study staff interviewed subjects for

(on average) less than 25 mm by telephone using an identicalprotocol in all states. All interviewers collected data from both

cases and controls. We did not tell the interviewers whether thesubjects were cases or controls. and the interview began with arequest that subjects not discuss their medical history until the

end of the interview. The interviewers reported that they were

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888 Carrots, Spinach, and Breast Cancer Risk

3 The abbreviations used are: OR, odds ratio; Cl, confidence interval; RR, relative

risk; FFQ. food frequency questionnaire.

unaware of case or control status until the end of the interview

for 74% of cases and 90% of controls.Foods and supplements were selected for inclusion on the

questionnaire based on the proportion of between-subject var-iation in intake of (3-carotene or vitamin A they accounted for(15-17) and on their nutrient content. The first version of the

questionnaire asked, “How often, on average, did you eat

____________ two years ago?” The foods ascertained were:“half a raw carrot or carrot sticks,” “a serving of cooked

carrots,” “raw spinach, as in salad,” “a serving of cookedspinach,” “a serving of liver,” and “cold breakfast cereal.” The

type (brand name) of breakfast cereal eaten most often was alsoascertained. For supplements, we asked about ever use ofmultiple vitamins, vitamin A capsules, and cod liver oil. Foreach supplement, we ascertained whether the subject was tak-ing the preparation 2 years ago, and, if so, how often they tookthe preparation at that time. Total duration of use of each

preparation was also obtained, and for vitamin A supplements,we asked the amount contained in each dose.

After data collection began, we found that the median time

between case diagnosis and interview was 14 months. Thus,with a reference date for the dietary questions of “two years

ago,” for most cases, the interval between the reference dateand diagnosis date was less than 1 year. To address the possi-bility that breast cancer might affect diet, the reference date waschanged in 1990 from “two years ago” to “three years ago.”

Standard nutrient databases provided the vitamin A con-tent of cereals, liver, and cod liver oil (Ref. 18; nutrient data-base 2 1 ) and the /3-carotene content of carrots and spinach ( 19).The portion sizes assumed were identical to those for the

Willett questionnaire (20), i.e., raw carrots, #{189}carrot; cooked

carrots, #{189}cup; raw spinach, #{189}cup; cooked spinach, #{189}cup;cold breakfast cereal, I cup; and liver, 3.5 oz. We assumed that

multiple vitamins contained 5000 IU of preformed vitamin A

per pill; although �3-carotene now provides part of the vitaminA activity in multiple vitamins, this is a recent change.

Analysis. For the present analysis, we included cases if theirreference date was I year or more before their diagnosis (n

3543). Of these cases, 2396 (68%) had a reference date 2 yearsbefore interview, and 1 147 (32%) had a reference date 3 yearsbefore interview. Controls were included (n = 9406) unlesstheir reference date was unknown (n = 22). The average age atinterview was 58.6 years (SD, 1 1.9), and 74% of subjects were

aged 50 years or more. The average body mass index was 24.9kg/m2 (SD, 4.7), and 40.9% ofthe women had more than a highschool education. The vast majority (98.5%) were white. Their

average daily lifetime alcohol consumption (14) was 5.7 g/day(SD, 15.1).

For our statistical analysis, we defined categories of intake

of foods and nutrients based on distributions of intake among

cases and controls combined. in genera], we aimed to have thehighest intake category be extreme, yet not too sparse, and todefine categories in round numbers.

Menopausal status was assessed based on reported history

of menopause or bilateral oophorectomy, or, in the case ofhysterectomy, was imputed as described elsewhere (14).

ORs3 and their 95% CIs were estimated from multivariate

unconditional logistic regression models (21). The ORs ad-justed for age (5-year age groups) and state in logistic regres-sion models were virtually identical to those obtained after

stratifying on the same factors with the Mantel-Haenzel ap-

proach (results not shown). The factors (and number of cate-gories for each) included in the fully adjusted models were: age(10), state (4), age at first full-term pregnancy (5), parity (4),

body mass index (6), age at menarche (4), education (4), benign

breast disease (2), family history (2), menopausal status (2), age

at menopause (5), and lifetime alcohol intake (7). Additional

adjustment for use of oral contraceptives (as never used, used

<5 years ago, or used S + years ago), replacement estrogens (asduration of use), or for date of interview had no effect onresults, and therefore these variables were not included in the

fully adjusted models. Except as noted, subjects had to havecomplete data to be included in the analyses. For menopausal

status, family history, and benign breast disease, missing datawere represented as a category. All trend Ps presented are fortwo-sided tests with exposure represented as an ordinal van-

able; exposure was similarly represented when we evaluated

effect modification, which was considered noteworthy if the P

associated with the interaction term was less than 0.10.

Reliability Substudy. Seven hundred controls in Wisconsin

completed a mailed FFQ as part of another study (22). Of these,

642 were included in a reliability substudy; each had an energyintake within a plausible range (500-4000 kcal/day) and had

sufficiently complete FFQ data. The FFQ (20) was modified toassess diet 2 years before the interview. Spearman correlation

coefficients between frequency of consumption measured bythe interview questionnaire and the FFQ were: raw and cooked

carrots and spinach (combined), 0.58; cold breakfast cereal,0.71; liver, 0.58; multiple vitamins, 0.74; vitamin A supple-ments, 0.69; and cod liver oil, 0.37. The correlation between

estimates of intake from the interview and those based on theFFQ were a-carotene, 0.49; preformed vitamin A, 0.61 ; and

total vitamin A, 0.47. We also calculated the Spearman coef-

ficient between the combined frequency of intake of raw andcooked carrots and spinach from the interview and the com-bined frequency of intake of 28 vegetables on the FFQ; the r

was 0.40.

Results

Subjects who ate carrots or raw spinach once weekly or more

(52+ servings/year) had a decreased risk of breast cancer(Table 1), and in general, the OR decreased with more frequent

consumption of these foods. Intake of cooked spinach showeda similar pattern, but the associations were not as strong.

Subjects who ate raw or cooked carrots and spinach more thantwice a week (105 + servings/year) had a 44% lower risk of

breast cancer (95% CI 9-66%). When subjects consuming 105or more servings/year were considered according to more finelydivided categories, the categories of intake (in servings/year)

and fully adjusted ORs (and 95% CIs) were: 105-156, 0.60

(0.37-0.98); 157-208, 0.64 (0.39-1.05); and 209+, 0.50(0.30-0.81). Repeating the analysis shown in Table 1 forcarrots and spinach combined after excluding subjects with nointake still showed a significant trend (P = 0.0007), with an ORfor the 105+ servings/day category of 0.82 (95% CI, 0.61-1 . 1 1). Further adjustment of the results for carrots and spinach

for intake of vitamin A supplements had essentially no effect on

results (data not shown). The reduction in risk associated withcarrots and spinach were independent (data not shown). We

also examined the relation of breast cancer risk with estimatedintake of $-carotene, based on use of carrots and spinach; theresults were similar to those for carrots and spinach (data notshown). The results in Table I from the fully-adjusted model



Table I ORs for breast cancer according to intake of carrots, spinach, breakfast cereal, and liver

Servings per yearTrend P

52-<105 105+None >0-<l2 12-<52

Carrots, raw

Cases 681 294 825 1028 615

Controls 1890 787 2044 2776 1727

OR” 1.00 1.03 1.04 0.91 0.85 0.004

CI” 0.88-1.22 0.92-1.18 0.81-1.02 0.75-0.97

MV-OR’ 1.00 1.02 0.99 0.87 0.81 0.0004

CI 0.85-1.21 0.87-1.14 0.76-0.99 0.70-0.93

Carrots, cooked

Cases 174 285 1197 1549 281

Controls 384 787 2968 4287 867

OR 1.00 0.74 0.78 0.71 0.63 0.0003

CI 0.58-0.93 0.64-0.95 0.59-0.87 0.50-0.80

MV-OR 1.00 0.71 0.76 0.70 0.62 0.0006

Cl 0.56-0.91 0.62-0.94 0.57-0.86 0.48-0.79

Spinach, raw

Cases 1804 732 728 177 39

Controls 4559 1909 1896 761 163

OR 1.00 0.94 0.95 0.59 0.65 0.0001

Cl 0.85-1.05 0.86-1.05 0.49-0.70 0.46-0.94

MV-OR 1.00 0.93 0.90 0.55 0.64 0.0001

CI 0.83-1.04 0.80-1.01 0.45-0.66 0.43-0.94

Spinach, cooked

Cases 1295 569 1092 498 35

Controls 3024 1550 2976 1625 117

OR 1.00 0.91 0.96 0.83 0.79 0.02

CI 0.81-1.03 0.87-1.06 0.73-0.95 0.53-1.17

MV-OR 1.00 0.93 0.97 0.85 0.88 0.07

CI 0.82-1.06 0.87-1.08 0.74-0.97 0.62-1.42

Carrots and spinach. raw and cooked

Cases 43 73 610 1002 1803

Controls 81 197 1486 2547 5078

OR 1.00 0.74 0.76 0.71 0.63 0.0001

CI 0.47-1.19 0.51-1.13 0.48-1.05 0.43-0.93

MV-OR 1.00 0.68 0.66 0.65 0.56 0.0001

CI 0.39-1.19 0.40-1.08 0.40-1.06 0.34-0.91

Breakfast cereal

Cases 728 146 357 710 1567

Controls 2097 447 1031 1888 3854

OR 1 .00 0.94 0.96 1 .00 1 .06 0.20

CI 0.76-1.16 0.83-1.12 0.88-1.13 0.95-1.18

MV-OR 1 .00 0.95 0.94 0.96 1 .02 0.60

CI 0.76-1.18 0.80-1.11 0.84-1.10 0.91-1.15

Liver x x”

Cases 1478 1223 659 162

Controls 4250 2821 1770 505

OR 1 .00 1 . I 2 0.94 0.85 0.17

CI 1.02-1.23 0.85-1.06 0.70-1.03

MV-OR 1.00 1.14 0.97 0.81 0.24

CI 1.03-1.26 0.86-1.09 0.66-1.00

‘, OR. OR adjusted for age and state.

b CI, 95% CI for OR immediately above.

‘ MV-OR, multivariate OR adjusted for age. state, age at the first full-term pregnancy, parity, body mass index, age at menarche, education, benign breast disease, age

at menopause, menopausal status, family history, and average lifetime alcohol intake. Number of cases and controls applies to age and state adjusted results.d A bar over results for adjacent categories means these categories were collapsed due to sparse data.

Cancer Epidemiology, Biomarkers & Prevention 889

differed little from those from the age- and state-adjusted mod-

els, a finding also true for all subsequent analyses.

Eating breakfast cereal was unrelated to relative risk; withsubjects consuming 105 or more servings per year furthersubdivided, ORs remained near one (Table I). Eating liver wasnot clearly associated with risk.

For multiple vitamins, cod liver oil, and especially vitaminA supplements, subjects in the highest category of intake had a

decreased risk of breast cancer, but relatively few people took

large doses, and the CIs were wide (Table 2). When the results

for vitamin A supplements were further adjusted for intake of

a-carotene, the findings were essentially unaltered. A protec-tive association of vitamin A supplement use was suggested,

regardless of duration of use. For multiple vitamins or cod liveroil, duration of use was unrelated to risk. Among ever users ofmultiple vitamins or vitamin A supplements who were not usersat the reference date, risk was increased. This was likely an

artifact due to study design (see “Discussion”).




Table 2 ORs for breast c ancer according to intake of vitamin A from dietary supplements”

Never

users

Ever users

0

Daily intake of preformed vitamin A (lU) at reference date

>0-<3000 3000-<6000 6000-< I 2000 12000+

Trend pI,

Multiple vitamins

Cases 1091 1160

x

172 1011 17

Controls 3 198 2565 474 2864 64

OR 1(X) 1.39 1.01 1.03 0.77 0.75

Cl 1.25-1.54 0.84-1.23 0.93-1.14 0.45-1.33

MV-OR l.()0 1.39 1.04 1.01 0.84 0.95

Cl 1.25-1.56 0.85-1.28 0.90-1.13 0.48-1.48

Vitamin A’

Cases 3285 166 10 13 33 6

Controls 8736 352 69 34 117 31

OR 1.0’) 1.21 0.36 0.93 0.78 0.47 0.01

Cl I .00- 1 .47 0. I 8-0.70 0.49-1 .78 0.53- 1 . I 6 0. 19- 1 . I 3

MV-OR l.()0 1.28 0.34 0.94 0.82 0.40 0.02

Cl

Cod liver oil

Cases 2437

1.05-1.57

992

0.17-0.69 0.48-1.83 0.54-1.24

x

0.15-1.05

51 8

Controls 6436 2660 147 31

OR I .00 1 .00 0.89 0.67 0.24

CI 0.91-1.09 0.64-1.23 0.30-1.49

MV-OR 1(X) 1.02 0.85 0.59 0.14

CI 0.93-I . I 2 0.60-1 .22 0.24-1.48

“ Abbreviations and adjustment factors are as noted in footnotes for Table I.I, Trend tests were calculated after excluding ever users with no intake at the reference date.

‘ One hundred sixty-eight of 3 13 vitamin A supplement users did not specify an amount or unit of vitamin A. For these people. the median of the distribution among those

with known amount and units was assigned ( 10,000 lU).

Intake of preformed vitamin A from all measured supple-ments and from all measured sources showed no overall asso-

ciation with risk (Table 3). In the highest category of intake,however, there was a suggestion of a decreased risk, but the CIwas wide. We divided subjects according to whether their

intake of vitamin A from foods was less than 2000 lU/day andagain examined the relation of vitamin A from supplements of

all types to risk; in both groups, evidence of a trend in risk withincreasing supplement use was not strong (data not shown).

The estimated intake of total vitamin A from all sourceswas associated with a monotonically decreasing risk of breast

cancer, although for any given category of intake the CIs

included one (Table 3). The findings for estimated total vitaminA from foods were similar, except for the highest category of

intake.For intakes of carrots and spinach, a-carotene, preformed

vitamin A, and total vitamin A, we examined the associations

with risk separately according to family history of breast cancer(23), alcohol consumption (3 categories; Ref. 24), and meno-pausal status (25); support for interaction was not present.

We repeated the analysis in Table 1 for carrots and spinach

(combined) after including all cases regardless of the timebetween the reference date in their interview and their diagnosis

(3342 more cases were included). The results were similar tothose shown, although the odds ratios were slightly larger. For

example, for 105 or more servings/day, the OR was 0.64 (95%CI, 0.43-0.96); the trend P was 0.0001. A similar analysis wasdone for the results for total vitamin A from all sources in Table3. For the 18,000 or more lU/day category, the OR with

inclusion of all cases was 0.44 (95% CI, 0.20-0.98). We alsoexamined the results with all cases included for carrots andspinach (combined) after stratifying according to length ofinterval between the case’s reference date and diagnosis. TheOR for the 105 or more servings/day category were: reference

date after diagnosis (10% ofcases), 0.57 (95% CI, 0.25-1.32);

0-<6 months (12%), 0.82 (95% CI, 0.32-2.12); 6-<12months (26.5%), 0.90 (95% CI, 0.44-1.82); l2-<18 months(26.5%), 0.41 (95% CI, 0.41-0.71); and 18+ months (25%),0.97 (95% CI, 0.46-2.04). With all cases included in the

analysis except those with a reference date after diagnosis, theOR for the 105+ servings/day category was 0.66 (95% CI,0.43-1.01), with a trend P across intake categories of 0.0001.

Discussion

In these data, frequent consumption of carrots or spinach was

associated with a decreased risk of breast cancer. The contri-bution of carrots and spinach accounted for most of the asso-

ciation of intake of total vitamin A with decreased risk. Theprotective association between risk and intake of carrots and

spinach could be due to constituents of carrots and spinach, todietary correlates of carrot and spinach intake, to other unmea-sured attributes of subjects who frequently consumed thesefoods, or to recall bias.

Although our carrot-spinach measure was a reasonablyreliable measure of carrot-spinach intake (in the reliabilitysubstudy, r = 0.58), it also reflected, although less precisely,intake of (3-carotene (r = 0.49) and of vegetables (r 0.40). In

four studies, carrot intake was examined in relation to breast

cancer risk; in three studies, the association was protective, andin one study, it was null (1). Case-control data generally supportf3-carotene as protective against breast cancer, but prospectivedata on the whole identify total vitamin A as protective, re-gardless of source (2, 3). Frequent intake of vegetables has beenassociated with decreased risk of breast cancer in numerousstudies (25-29), although these data also are not entirely con-

sistent (reviewed in Ref. 12). Carrots are also a good source ofa-carotene, spinach is a good source of lutein, and both provide



Cancer Epidemiology, Biomarkers & Prevention 891

Table 3 ORs for bre ast cancer a ccording to intake o f vitamin A, for preformed vitamin A. and for total vitamin A, ac cording to source””

Daily Intake in IUTrend P

0 >0-<3000 3000-<6000 6000-< I 2000

Preformed vitamin A

12000-< I 8000 I 800()+

All measured supplements”

Cases

Controls

OR

CI

MV-OR

All measured sources

Cases

Controls

OR

Cl

MV-OR

CI

2169

5547

1.00

1.00

385

1144

1.00

1.00

187

528

0.98

0.81-1.18

1.04

0.85-1.26

1856

4580

1.07

0.94-1.22

1.09

0.94-I .26

964 56

2710 161

1.02 0.97

0.91-1.14 0.70-1.34

1.01 0.88

0.90-1.13 0.63-1.25

813 431

2260 1233

0.95 0.88

0.82-1.09 0.75-1.04

1.06 0.97

0.90-1 .25 0.8 1-1 . I 7

27

105

0.75

0.49-1.17

0.71

0.45-1.14

41

126

0.86

0.59-1.26

0.96

0.64-I .44

6

36

0.46

0.19-1.11

0.40

0.15-1.06

14

59

0.61

0.33-1.11

0.64

0.33-I .23

0.48

0.28

0.001

0.21

Total vitamin A

All measured foods

Cases

Controls

OR

CI

MV-OR

Cl

All measured sources

Cases

Controls

OR

Cl

MV-OR

CI

21

40

1.00

1.00

18

34

1.00

1.00

2735

7154

0.75

0.43-1.30

0.65

0.29-1.46

1873

4766

0.77

0.42-1.42

0.76

0.31-1.87

593 176

1625 545

0.67 0.60

0.38-1.16 0.34-1.06

0.56 0.48

0.25-1.28 0.21-1.1 1

717 835

1862 2420

0.72 0.64

0.39-1.33 0.35-1.18

0.74 0.68

0.30-1.83 0.27-1.67

x

14

35

0.80

0.35-1.86

0.73

0.26-2.07

80

230

0.64

0.33-1.23

0.64

0.25-1.63

x

7

90

0.36

0.16-0.80

0.37

0.13-1.07

0.002

0.0(X)7

0(5)01

0.0049

“ Abbreviations and adjustment factors are as noted in footnotes for Table 1.b For the exposure variables that include intake from supplements, the results are also adjusted for past use of multiple vitamins and vitamin A supplements.

fiber (18, 19). Freudenheim et a!. (12) used a complete diet

assessment in a case-control study and found lower risk ofbreast cancer with greater intake of /3-carotene and lutein,independent of total vegetable intake. Disentangling the effects

of specific vegetables or nutrients with a short food list likeours, however, is not possible.

On the whole, our measure of preformed vitamin A intakewas not strongly related to risk. Supplement users taking larger

doses, however, had lower risk, albeit with wide CIs. In threeprospective studies (5, 25, 30), subjects in the highest dose

category of vitamin A supplements had a reduced risk of breastcancer. Supplement users, however, differ from nonusers innumerous ways (3 1 ); therefore, whether use of vitamin A

supplements accounts for the inverse association is not clear.Furthermore, other constituents of the vitamin A-containingsupplements could affect risk.

Comparisons of intake of n-carotene and vitamin A re-ported prospectively and retrospectively among breast cancer

cases and controls (32, 33) suggest that recall bias probablydoes not account for the associations observed in the present

study. The response rates in the present study (>80% for cases

and for controls) indicate that selection bias, if any, was un-likely to have greatly affected the findings. We used our reli-ability substudy data to examine the relation of energy intake

assessed by FFQ to items assessed by interview. Energy intakewas neither strongly related to intake of carrots and spinach

combined (Spearman r = 0.12) nor to intake of supplementalvitamin A (Spearman r < 0.01). These correlations suggest that

energy intake was unlikely to have substantially confounded

our results. Women who used multiple vitamins or vitamin Asupplements but who were not users at the reference dateappeared to be at increased risk of breast cancer. Use of theseagents in response to a diagnosis of breast cancer may explain

the finding.

The results of our reliability substudy are consistent with

other data (16, 17) that show a large portion of variation inintake of carotenoids and vitamin A is accounted for with a

short list of foods. In a study based on use of diet records for4 weeks (17), intake of carrots accounted for 58% of among-

subject variation in intake of carotene, intake of liver accountedfor 74% of variation in intake of preformed vitamin A from

foods, and use of supplements accounted for 88% of variationin intake of total vitamin A. Nevertheless, our brief dietary

assessment allowed only imprecise measures of nutrient intake,and thus true underlying associations, if any, would have been

underestimated.Many substances in vegetables have anticarcinogenic ac-

tivity in animal models (7, 34). Although high-dose supple-

mentation with �3-carotene has been associated with an in-creased risk of lung cancer ( 10, 1 1 ), diets rich in fruits,vegetables, and carotenoids are consistently associated with

reduced risk of lung and other cancers (29, 35). Animal and

epidemiological evidence is mounting that several specific flu-trients thought to be protective against cancer do not fullyaccount for the protective effect of vegetables (7, 12. 36).

In summary, these data show a protective associationbetween intake of carrots and spinach and risk of breast cancer

although they do not allow us to distinguish among several




potential explanations for the relation. The findings are, how-ever, consistent with a diet rich in these foods having a modestprotective effect against breast cancer.

Acknowledgments

The authors are grateful to Miao-Jung Chen, Donna Li, and Rebecca Darden for

computer programming.

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