Preschool diet and adult risk of breast cancer

Preschool diet and adult risk of breast cancer

Preschool diet and adult risk of breast cancer

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Events before puberty may affect adult risk of breast cancer. We examined whether diet during preschool age may affect a wom- an’s risk of breast cancer later in life. We conducted a case-con- trol study including 582 women with breast cancer and 1,569 con- trols free of breast cancer selected from participants in the Nurses’ Health Study and the Nurses’ Health Study II. Informa- tion concerning childhood diet of the nurses at ages 3–5 years was obtained from the mothers of the participants with a 30-item food- frequency questionnaire. An increased risk of breast cancer was observed among woman who had frequently consumed French fries at preschool age. For one additional serving of French fries per week, the odds ratio (OR) for breast cancer adjusted for adult life breast cancer risk factors was 1.27 (95% confidence interval [CI] 5 1.12–1.44). Consumption of whole milk was associated with a slightly decreased risk of breast cancer (covariate-adjusted OR for every additional glass of milk per day 5 0.90; 95% CI 5 0.82– 0.99). Intake of none of the nutrients calculated was related to the risk of breast cancer risk in this study. These data suggest a possi- ble association between diet before puberty and the subsequent risk of breast cancer. Differential recall of preschool diet by the mothers of cases and controls has to be considered as a possible explanation for the observed associations. Further studies are needed to evaluate whether the association between preschool diet and breast cancer is reproducible in prospective data not subject to recall bias. ‘ 2005 Wiley-Liss, Inc.

Key words: breast cancer; nutrition; epidemiology; early life

Factors during early life may play a role in the etiology of chronic disease. Fetal nutrition and infant growth seem to be pre- dictive of adult risk of cardiovascular disease, hypertension, diabe- tes, and obesity.1–5 In addition, maternal weight and diet during pregnancy, possibly mediated by fetal malnutrition, have been related to coronary heart disease.6,7 Similarly, nutrition in early life is linked to later heart disease.8,9

A high birthweight has been associated with the risk of breast cancer in a number of studies,10–20 but whether this association operates through fetal nutrition, hormonal factors or other mech- anisms has not been resolved. Breast tissue is largely undiffer- entiated until puberty and may be particularly susceptible to carcinogenic influences during that age period.21,22 Migrant studies indicate that rates of breast cancer change after migration primarily affecting the next generation and thus are compatible with modula- tion of risk during early life.23–25 The impact of radiation exposure at a young age on breast cancer risk as an adult lends further support to the existence of a susceptible time period in early life.26–28

DeWaard and Trichopoulos29 and Willett30 have proposed that an energy-rich diet during puberty and adolescence affects the growth of mammary glands and enhances the occurrence of pre- cancerous lesions. The observation that women who experienced the World War II famine in Norway during puberty had a reduced risk of breast cancer later in life supports the importance of diet— whether composition or total energy intake—during early life.31

A number of breast cancer risk factors, such as tallness,32 body size,32,33 rapid growth during childhood34 and early age at menarche,35

are affected, at least in part, by childhood diet. Although taller final height,36 an early age at peak growth34 and an early age at menarche35 are associated with an increase in the risk of breast cancer in adulthood, a high childhood body mass is inversely related to the risk of breast cancer.33,37,38

Our present study explores the role of diet during preschool age on future risk of breast cancer. Information on preschool diet was gathered from the mothers of participants of the Nurses’ Health Study and the Nurses’ Health Study II.

Population and methods

The Nurses’ Mothers’ Study is a case-control study nested in 2 prospective cohort studies, the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHS II). These cohorts consist of 121,700 and 116,678 female registered nurses, respectively, born between 1921–1965. For both cohorts, biennial self-administered questionnaires provide updated information on demographic, anthropometric, and lifestyle factors and on newly diagnosed dis- eases, including breast cancer.

Documentation of breast cancer

On each biennial questionnaire we ask whether breast cancer has been diagnosed and, if so, the date of diagnosis. We also rou- tinely search the National Death Index for deaths among women who did not respond to the questionnaires. We ask women who report breast cancer (or next of kin, for those who have died with- out reporting the incident disease) for permission to review the rel- evant hospital records to confirm the diagnosis. Pathology reports confirmed a breast cancer diagnosis among >99% of participants for whom records could be obtained. The analysis presented in this paper was restricted to cases of invasive breast cancer.

The Nurses’ Mothers’ Study

Details of the Nurses’ Mothers’ Study have been described else- where.9 Briefly, in 1993 participants in the Nurses’ Health Studies who had been diagnosed with incident breast cancer up to 1993 and had not reported the death of their mother on a previous ques- tionnaire were identified, and 2 participants free of breast cancer at that time who belonged to the same cohort were matched to each case by year of birth. Matching occurred before it was known whether the mother was alive and able to participate. Because some mothers had died or were unable to participate, matching was incomplete for a substantial number of cases and controls. Of mothers still living and able to participate, 91% completed and returned our questionnaire. The study population consisted of 582

Grant sponsor: Massachusetts Department of Public Health. *Correspondence to: Obstetrics and Gynecology Epidemiology Center,

Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115. Fax:11-617-732-4899. E-mail: kmichels@rics.bwh.harvard.edu Received 14 March 2005; Accepted after revision 10 June 2005 DOI 10.1002/ijc.21407 Published online 10 August 2005 inWiley InterScience (www.interscience.

wiley.com).

Int. J. Cancer: 118, 749–754 (2006) ‘ 2005 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

nurses with invasive breast cancer and 1,569 nurses free of breast cancer in 1993.

The mothers were asked to complete a mailed, self-adminis- tered questionnaire on perinatal and early life events of their nurse-daughter including information on foods consumed by the daughter during preschool years. The mothers were asked how often their nurse-daughter ate or drank an average serving of any of the 30 food items listed on the questionnaire when she was 3– 5 years old. The dietary part of the questionnaire was structured like a semiquantitative food-frequency questionnaire (FFQ).39

Information on adult breast cancer risk factors was assembled from the large databases already established for each of the two ongoing cohort studies. These variables had been reported by the nurses themselves and included year of birth, age at menarche, parity, age at first birth, height and weight. Data ascertained at baseline before diagnosis of breast cancer among the cases, were used in the analysis (1976 for NHS and 1989 for NHS II). A fam- ily history of breast cancer was available from the nurses’ reports (mother or sisters with breast cancer) as well as from the mothers’ reports (mother herself, grandmothers, or aunts with breast cancer). We created a variable indicating first- or second-degree relative(s) with breast cancer.

Fels Longitudinal Study diet assessment validation

The validity of the dietary information provided by the mothers in the present study could not be directly assessed. To address this problem, we conducted a small validation study in a similar popu- lation, the Fels Longitudinal Study. We sampled 33 female Fels participants born between 1929–195040 for whom 7-day diet records were kept by their mothers when these participants were 3–6 years old.41 In 1997, we mailed the food questionnaire used in the Nurses’ Mothers’ Study to the respective Fels mothers asking them to recall their daughters’ diet during preschool age. The mothers’ ages in Fels ranged from 60–93 years. We obtained 29 completed diet questionnaires from the mothers. Spearman corre- lations of mean daily consumption of foods reported by the moth- ers on the 7-day diet records and on the FFQ were 0.46 (p 5 0.02) for whole milk, 0.37 (p 5 0.07) for broccoli and 0.36 (p 5 0.07) for French fries.

Statistical analysis

Frequencies of intake of the individual foods as specified on the questionnaire were converted into servings/day (e.g., number of glasses of milk per day) or servings/week depending on the food and used as continuous variables.

For 718 nurses, complete data on the frequencies of food intake were available, but for 1,433 participants, data were missing or the mother did not remember the frequency of intake of one or more food items. On average, mothers marked the ‘‘don’t remember’’ option for 8.5% of food items and left 3.8% of food items blank. Overall, the proportion of missingness (blanks and don’t remem- ber) ranged from 4.5% (for milk) to 21% (for cheese).

Multiple imputation was used to account for dietary data not observed.42–44 Multiple imputation replaces each missing value with a number of acceptable values representing a distribution of possibilities. We created 5 imputed data sets by replacing missing values with draws from the conditional distribution of the missing values given the observed values. Each of the 5 imputed data sets was analyzed as if it were complete; the results from the 5 data sets were then combined in a manner that takes account of both the between-imputation and within-imputation variability. The multiple imputation method used in the present analysis does not involve sampling of the parameter values in the imputation model but assumes that the parameter estimates are known without error, and are therefore not changed at each imputation by adding error to them.44

Nutrients were calculated from nutrient composition tables for the year the nurse was 3 years old; using these tables from 1929– 1970 captured changes in the fortification of foods during this time

period when calculating nutrient intake. Nutrient residuals were obtained by regressing nutrient intake on the log scale on mean- centered log values of energy intake and exponentiating the result- ing residuals. The risk of breast cancer among women in the high- est quintile of nutrient intake was compared to that among women in the lowest quintile. Nutrient intake was also considered as a continuous variable, and the risk of breast cancer was estimated per one standard deviation increase in the particular nutrient using continuous residuals divided by their standard deviation.

Odds ratios (OR) were obtained using unconditional logistic regression models. The association between food consumption and breast cancer was estimated for each individual food item, for combinations of foods, and for nutrients. Regression models included adult risk factors for breast cancer obtained from the Nurses’ Health Studies’ questionnaires: year of birth, age at menarche, parity, age at first birth, family history of breast cancer and body mass index (BMI) in 1976 for NHS and in 1989 for NHS II.

Results

Characteristics of the 582 breast cancer cases and 1,569 controls are listed in Table I. Among cases, 63% were premenopausal at diagnosis, 27% were postmenopausal, and 10% were of uncertain menopausal status. Older age at menarche, higher parity, and younger age at first birth were associated with reduced risk of breast cancer in this population. Higher BMI at baseline was asso-

TABLE I – ADULT CHARACTERISTICS OF PARTICIPANTS OF THE NURSES’ HEALTH STUDY AND THE NURSES HEALTH STUDY II WITH BREAST

CANCER (CASES) AND WITHOUT BREAST CANCER (CONTROLS) WHOSE MOTHER PARTICIPATED IN THE NURSES’ MOTHERS STUDY

Characteristic Cases (n 5 582) Controls (n5 1,569)

No. % No. %

NHSI 461 79 1303 83 NHSII 121 21 266 17 Birth year

1921–1925 16 3 93 6 1926–1930 68 12 176 11 1931–1935 105 18 307 20 1936–1940 121 21 347 22 1941–1945 136 23 331 21 1946–1950 70 12 169 11 1951–1955 40 7 86 5 1956–1960 20 3 47 3 1961–1963 6 1 13 1

Age at menarche1

<511 134 23 371 24 12 167 29 427 27 13 179 31 461 30 14 71 12 182 12 151 27 5 117 8

Parity Nulliparous 69 12 174 11 1 59 10 133 8 2 199 34 500 32 3 155 27 405 26 41 100 17 357 23

Age at first birth <524 290 57 859 62 25–29 183 36 437 31 301 40 8 99 7

Body Mass Index1

<521 217 37 437 28 21.1–23 165 28 470 30 23.1–25 99 17 269 17 25.1–29 66 11 232 15 >29 35 6 156 10

Family history of breast cancer No 480 82 1395 89 Yes 102 18 174 11

1Numbers do not always add up to the entire study population because of missing information on some variables.

750 MICHELS ET AL.

ciated with a lower risk of breast cancer among these mostly premenopausal women. Family history of breast cancer was asso- ciated with increased breast cancer risk. The median year of birth of the mothers was 1914 for case mothers and 1913 for control mothers.

The results of the logistic regression analysis for all individual foods are provided in Table II. Regular consumption of French fries was associated with a significantly increased risk of breast cancer, with an OR of 1.27 for one additional serving/week (95% CI 5 1.12–1.44). A slightly decreased risk of breast cancer was apparent for regular consumption of whole milk, although the association was of borderline statistical significance (OR per addi- tional glass of whole milk/day 5 0.90; 95% CI 5 0.82–0.99). Broccoli consumption was associated with an elevated OR for breast cancer of borderline statistical significance in the unad- justed analysis (OR 5 1.24; 95% CI 5 0.98–1.57), but the associ- ation was attenuated after covariate-adjustment (OR 5 1.16; 95% CI 5 0.91–1.47). Among covariates, the most notable correlations with foods

were found for year of birth, possibly reflecting time trends in the availability of certain foods (the consumption of ice cream, orange juice, hot dogs, and French fries became more common over time, consumption of other types of potatoes became less common) or changes in habits (margarine partly replaced butter, and cod liver oil became less popular over time and was increasingly replaced by vitamin supplements). Changes in estimates from the covariate-adjusted analysis compared to the unadjusted regression

model are accounted for mainly by adjustment for year of birth (Table II).

The estimates changed for some foods considerably after adjust- ing for all covariates. After controlling for other covariates, pri- marily year of birth, we found that the association of breast cancer risk with broccoli consumption was attenuated, whereas the esti- mates for consumption of orange juice, cabbage and ground beef where somewhat strengthened. The strongest changes in the odds ratios after covariate adjustment were for broccoli and liver con- sumption; these 2 foods were the least frequently consumed during childhood, and therefore these estimates were the least stable. The estimates for French fries (OR 5 1.27; 95% CI 5 1.12–1.44) and for milk (OR 5 0.90; 95% CI 5 0.82–0.99) did not change appre- ciably after covariate adjustment.

Foods associated with breast cancer risk were considered together in a multiple regression model unadjusted for non-dietary covariates to explore the independent contribution of each food. French fries were paired with ground beef to capture a fast food dietary pattern (French fries: OR 5 1.27; 95% CI 5 1.12–1.43), milk (French fries: OR 5 1.27; 95% CI 5 1.13–1.43), and broc- coli (French fries: OR 5 1.27; 95% CI 5 1.13–1.43). The results indicated that the association between consumption of French fries and risk of breast cancer was not explained by consumption of any of the other 3 foods. The relation of ground beef consumption with breast cancer risk was somewhat diminished by the inclusion of French fries, indicating that the 2 foods might have been custom- arily consumed together (ground beef: OR 5 1.12; 95% CI 5 0.64–1.97). The consumption of milk and French fries was not strongly correlated (whole milk: OR 5 0.91; 95% CI 5 0.83– 1.00) nor was that of broccoli and French fries (broccoli: OR 5 1.22; 95% CI 5 0.97–1.54). The distributions of caloric nutrient intake were within the

range reasonable for girls of preschool age (Table III). No impor- tant relation between intake of any of the calculated nutrients and risk of breast cancer was observed in this study (Table III).

Discussion

In our study, which was embedded in the 2 Nurses’ Health Studies, we found a significant association between frequent con- sumption of French fries during preschool age as reported by the mothers of the study participants and breast cancer risk later in life. For one additional serving of French fries per week during their preschool years, women had a 27% increased risk of breast cancer when they were adults. Although consumption of milk and broccoli were marginally associated with adult breast cancer risk, no other food or nutrient appeared as strongly correlated with adult breast cancer risk as did French fries. As consumption of potatoes themselves was not associated with the risk of breast can- cer, the preparation of French fries, namely the use of frying fat high in saturated fats and trans-fatty acids, may be of relevance. During the period of exposure spanning the years 1924–1970, preparation of French fries changed: solid shortening was used in the earlier years, and hydrogenated oils were used in later years. French fries have also been found to contain acrylamide, an indus- trial chemical that has been classified as a likely human carcino- gen due to its DNA-reactive mechanism but was not related to breast cancer in a Swedish study.45,46

Frequent consumption of French fries did not seem to be a marker of ‘‘fast food’’ habits, because we did not observe a simi- lar association of breast cancer risk with frequent consumption of hot dogs or ground beef. Consumption of French fries, however, could be a marker of a dietary pattern that we might not have been able to detect because we assessed only a limited number of foods with our diet questionnaire.

To our knowledge, no other data on the association between preschool diet and breast cancer risk are available. The role of childhood or adolescent diet recalled by the participants them- selves has been explored in four case-control studies and two

TABLE II – OR AND 95% CI OF ADULT BREAST CANCER AMONG PARTICIPANTS OF THE NURSES’ HEALTH STUDY AND THE NURSES’ HEALTH STUDY II WHOSE MOTHER PARTICIPATED