Affiliations of authors: S. M. Zhang, Department of Epidemiology, Harvard School of Public Health, and Division of Preventive Medicine and Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA; W. C. Willett, D. J. Hunter, E. L. Giovannucci, Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School; J. Selhub, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston; M. D. Holmes, Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School; G. A. Colditz, S. E. Hankinson, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston.
Correspondence to: Shumin M. Zhang, M.D., Sc.D., Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (e-mail: Shumin.Zhang{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Several epidemiologic studies, including three large prospective cohort studies, have suggested that adequate folate intake may be important in the prevention of breast cancer (715), particularly among women who consume alcohol (710,14). A direct association between moderate alcohol consumption and breast cancer incidence has consistently been observed in epidemiologic studies (16). Alcohol is a known folate antagonist (17,18) and thus could plausibly increase an individuals requirement for folate intake. For vitamin B12, unlike folate, variation in amount absorbed rather than intake is the main determinant of plasma levels in Western populations (19). In the only published study using prospectively collected blood, in which 195 casecontrol pairs were analyzed, lower plasma levels of vitamin B12 were associated with increased risk of breast cancer among postmenopausal women; however, lower plasma levels of folate, pyridoxal 5'-phosphate, and homocysteine were not associated with breast cancer risk (20). Because folate, vitamin B6, and vitamin B12 could potentially have important effects, we conducted a prospective, nested casecontrol study with a large number of case patients to evaluate these nutrients in relation to breast cancer risk in the Nurses Health Study. We also examined these associations according to alcohol intake.
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PATIENTS AND METHODS |
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The Nurses Health Study was established in 1976, when 121 700 female registered nurses aged 3055 years living in 11 states completed a mailed questionnaire about their medical history and lifestyle. Follow-up questionnaires were sent to the cohort members every 2 years to update health-related information and to ascertain newly diagnosed diseases. In 1989 and 1990, we obtained blood samples from 32 826 participants who were 4369 years of age at the time of blood collection. Details regarding blood collection in the Nurses Health Study have been published previously (21). Briefly, participants were sent a blood collection kit containing all needed information and supplies. Each participant had her blood sample drawn and then mailed it to our laboratory via overnight courier; 97% of the samples arrived within 26 hours of being collected. Approximately 75% of the blood samples were collected at least 8 hours after the participant had last eaten. On arrival at our laboratory, the samples were centrifuged (4 °C at 1530g) and separated into plasma, white blood cells, and red blood cells. Plasma, white blood cell, and red blood cell samples were then stored at 130 °C, or colder, in continuously alarmed and monitored liquid nitrogen freezers. As of May 31, 1996, the follow-up rate among women who provided blood samples was 99%. Written informed consent was obtained from all subjects, and the research protocol was approved by the Use of Human Subjects in Research Committee at the Brigham and Womens Hospital and the Human Subjects Committee at the Harvard School of Public Health.
Identification of Case Patients and Control Subjects
Incident cases of breast cancer that were initially identified by self-report on biennial follow-up questionnaires were confirmed by medical record review. Through May 31, 1996, 735 incident cases of breast cancer (i.e., both carcinoma in situ and invasive) were documented among women who provided blood samples and who did not report a cancer diagnosis prior to the time of blood collection. Time from blood collection to diagnosis of breast cancer ranged from less than 1 month to 82 months (mean = 40 months). For each case patient, one control subject with no history of cancer was individually matched by year of birth (±1 year), time of day that blood was collected (in 2-hour intervals), fasting status (>10 hours since last meal versus 10 hours since last meal), month of blood collection, recent use of postmenopausal hormones (within 3 months prior to blood collection), and menopausal status (premenopausal or postmenopausal). Most control subjects were matched to their case patients exactly; however, when needed, the criteria of matching factors were relaxed.
Semiquantitative Food Frequency Questionnaires
Dietary information was collected using food frequency questionnaires that had been completed by the participants in 1980, 1984, 1986, and 1990. These questionnaires assessed the average consumption of a specific amount of each food (e.g., one orange) during the past year, and it allowed nine frequency responses, ranging from "never" to "six or more times per day." Nutrient intake per day was calculated by multiplying the frequency response by the nutrient content of the specified portion sizes. Total alcohol intake per day was calculated as the sum of the alcohol content contributed from beer, wine, and liquor, assuming 12.8 g of ethanol for 360 mL (12 oz) of beer, 11.0 g for 120 mL (4 oz) of wine, and 14.0 g for 45 mL (1.5 oz) of liquor. Duration, brand, and type of multivitamin supplement use were updated in the biennial questionnaires or the food frequency questionnaires, and a comprehensive database on the folate, vitamin B6, and vitamin B12 content of the multivitamin preparations was developed.
The validity and reliability of the food frequency questionnaires used in the Nurses Health Study have been described previously (19,2224). For example, in a sample of 173 participants, alcohol intake calculated from the 1984 food frequency questionnaire was highly correlated with both alcohol intake calculated from the four 1-week diet records collected from 1980 through 1981 (r = 0.84) and plasma high-density lipoprotein cholesterol levels (r = 0.40), which are known to be sensitive to alcohol (25). Vitamin B6 intake calculated from the 1980, 1984, and 1986 food frequency questionnaires was also correlated with participants diet records, with correlation coefficients ranging from 0.54 to 0.58 (19,22,23). In a sample of 188 participants, the correlation coefficients between folate intake calculated from the 1980 food frequency questionnaire and erythrocyte folate concentrations in 1987 were 0.55 for folate from foods and supplements and 0.38 for folate from foods only (26).
Laboratory Analyses
Plasma levels of folate and vitamin B12 were determined by a radioassay kit (Bio-Rad, Richmond, CA), according to the manufacturers instructions. Plasma levels of homocysteine were measured using high-performance liquid chromatography, with fluorescence detection as described by Araki and Sako (27). Briefly, plasma thiol compounds such as homocysteine were derivatized with a thiol-specific fluorogenic reagent, ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulphonate. The derivatives were then separated by reverse-phase high-performance liquid chromatography (27). Plasma levels of vitamin B6 were determined by an enzymatic procedure using radioactive tyrosine and the apo-enzyme tyrosine decarboxylase as described by Shin-Buehring et al. (28). All assays were conducted at the Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University.
All matched casecontrol blood samples were handled identically and together, shipped in the same batch, and assayed in the same analytical run. The blood samples were labeled by number only and ordered randomly within each casecontrol pair. During the assay process, we interspersed replicate plasma samples, which were labeled to preclude their identification by the laboratory, to assess laboratory precision. The mean coefficients of variation for 75 pairs of replicate plasma samples were 6.5% for folate, 7.2% for vitamin B6, 7.3% for vitamin B12, and 7.9% for homocysteine. All assays were conducted by the investigators and laboratory personnel without knowledge of the casecontrol status of the samples.
Statistical Analysis
A total of 712 casecontrol pairs were included in this study after excluding 23 pairs who had missing information on plasma levels in one member of the pair. We categorized plasma levels of folate, vitamin B6, vitamin B12, and homocysteine into quintiles based on the distribution of plasma levels of these vitamins in the control subjects for the analyses of all women combined, premenopausal women, and postmenopausal women. Mixed-effect regression models were used to test the differences in mean levels of plasma nutrients and other covariates as continuous variables between case patients and control subjects to adjust for the correlation between cases and controls within the matched set (29). The MantelHaenszel test was used to compare the differences in proportions of covariates as categorical variables between case patients and control subjects (30).
Conditional logistic regression, which preserves the matching of case patients and control subjects, was used to calculate the relative risks (RRs) and 95% confidence intervals (CIs) for the analysis of plasma levels of folate, vitamin B6, vitamin B12, and homocysteine and their association with breast cancer risk among all women combined. To increase statistical power, unconditional logistic regression, after controlling for matching factors including year of birth, time of day that blood was collected, month of blood collection, fasting status, recent use of postmenopausal hormones, and menopausal status, was used to further examine these associations by menopausal status and alcohol intake (i.e., <15 g/day versus 15 g/day). A cut point of 15 g/day of alcohol, which is approximately equivalent to one drink per day, was used because it was associated with increased risk of breast cancer in cohort studies (16). Alcohol intake calculated from the 1990 food frequency questionnaire was used for this analysis because that was the questionnaire completed closest to the timing of blood sample collection (i.e., during 1989 and 1990).
To better represent long-term intakes, the average intakes of folate, vitamin B6, and vitamin B12 were calculated from the 1980, 1984, 1986, and 1990 food frequency questionnaires. Unconditional logistic regression was used to evaluate the association between the average intakes of these vitamins and risk of breast cancer. In the multivariable analysis, we further controlled for potential confounders, such as age at menarche, parity, age at first birth, age at menopause, history of breast cancer in mother or a sister, history of benign breast disease, alcohol intake, body mass index (BMI) at age 18 years, BMI at blood collection, and duration of postmenopausal hormone use. To reduce measurement errors resulting from general over- or under-reporting of food items (19), we also adjusted the analysis of the average intakes of these vitamins and their association with risk of breast cancer for total calorie intake. Tests for trend were calculated by using the median values for quintiles of plasma estimates as a continuous variable. All P values were two-sided.
A generalized linear model was used to calculate the Pearson correlation coefficients between the average intakes of folate, vitamin B6, and vitamin B12 and plasma levels of folate, vitamin B6, vitamin B12, and homocysteine, and between alcohol intake and plasma levels of these nutrients after controlling for total calorie intake, matching factors, and the covariates listed above. Only control subjects were included in this correlation analysis because breast cancer itself may affect plasma levels of these vitamins. Multivitamin supplement users were excluded from the correlation analysis of nutrient intakes from foods only. Nutrients measured by the food frequency questionnaires and in plasma were loge-transformed to improve normality.
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RESULTS |
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The inverse association between plasma folate levels and risk of breast cancer was similar among premenopausal and postmenopausal women; the multivariable RRs comparing the highest with the lowest quintile were 0.65 (95% CI = 0.26 to 1.65) and 0.75 (95% CI = 0.49 to 1.15), respectively. In contrast, the inverse association between plasma vitamin B6 levels and breast cancer risk was stronger in postmenopausal women (RR = 0.66, 95% CI = 0.43 to 1.01) than it was in premenopausal women (RR = 0.91, 95% CI = 0.39 to 2.14). Higher plasma vitamin B12 levels were associated with a statistically significantly lower risk of breast cancer among premenopausal women (RR = 0.36, 95% CI = 0.15 to 0.86), but not among postmenopausal women (RR = 1.08, 95% CI = 0.70 to 1.67). Plasma homocysteine was not appreciably associated with risk of breast cancer among either premenopausal women or postmenopausal women.
The inverse association between plasma folate levels and breast cancer risk was particularly strong among women consuming at least 15 g/day of alcohol (i.e., approximately 10% of women) in our study (Table 3). The multivariable RRs of breast cancer comparing women in the highest quintile with those in the lowest were 0.11 (95% CI = 0.02 to 0.59) for women consuming at least 15 g/day of alcohol and 0.72 (95% CI = 0.49 to 1.05) for those consuming less than 15 g/day of alcohol. To address the issue of whether the effect of plasma folate on breast cancer risk among women consuming at least 15 g/day of alcohol was driven by results for women with extremely high alcohol intakes, we excluded women who consumed more than 45 g/day of alcohol (i.e., approximately 0.6% of women) and found that the multivariable RRs for the higher four quintiles versus the lowest quintile among women consuming at least 15 g/day of alcohol did not change appreciably (RRs = 0.31, 0.54, 0.16, and 0.15 [95% CI = 0.03 to 0.84], for highest versus lowest quintile).
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When plasma folate and alcohol intake were examined in combination among all women, higher alcohol intake (i.e., 15 g/day) appeared to increase risk of breast cancer only in women with lower folate levels (Fig. 1
). That is, higher plasma folate levels appeared to reduce the increased risk of breast cancer associated with higher alcohol intake. The inverse association between plasma vitamin B6 levels and breast cancer risk was also greater, although not statistically significantly, among women consuming at least 15 g/day of alcohol (Table 3
). The multivariable RRs of breast cancer comparing women in the highest quintile with those in the lowest were 0.44 (95% CI = 0.10 to 2.04) for women consuming at least 15 g/day of alcohol and 0.64 (95% CI = 0.44 to 0.93) for those consuming less than 15 g/day of alcohol. The associations between plasma levels of vitamin B12 and homocysteine and risk of breast cancer did not differ substantially by level of alcohol intake.
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DISCUSSION |
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The prospective design and high follow-up rates in this study minimize the possibility that our findings are caused by methodologic biases. Because controlling for established risk factors for breast cancer, such as reproductive factors and family history of breast cancer, had minimal effect on the RRs of breast cancer, our results are unlikely to be explained by residual confounding by those factors. The inverse association between plasma folate levels and risk of breast cancer among women consuming at least 15 g/day of alcohol is also unlikely to be explained by plasma levels of vitamin B6, vitamin B12, and homocysteine, because the RRs did not change appreciably after controlling for them, either one-at-a-time or simultaneously. Our results are also unlikely to be explained by the potential bias that breast cancer itself (before it was diagnosed) may have affected plasma levels of these nutrients because the RRs, after excluding both case patients who were diagnosed with breast cancer within the first 2 years after blood collection and their matched control subjects, were similar to those using all case patients and control subjects combined.
Our findings that the inverse association of plasma folate levels or the average folate intake from foods and supplements with risk of breast cancer was modified by alcohol intake are consistent with results from several previous investigations relating folate intake to risk of breast cancer, including the Nurses Health Study cohort (7), the Canadian National Breast Screening Study cohort (8), the Iowa Womens Health Study cohort (9), and casecontrol studies in Italy (10) and in Switzerland (14). In another casecontrol investigation (31), no association between folate intake and risk of breast cancer was observed, but the authors did not report this association stratified by alcohol intake. In the whole cohort of the Nurses Health Study (7), higher total folate intake or use of multivitamin supplements was associated with decreased risk of breast cancer among women consuming at least 15 g/day of alcohol, but total folate intake was not associated with overall risk of breast cancer. These findings support the notion that alcohol increases an individuals requirement for folate. The detrimental effects of alcohol on folate metabolism may be related to reduced intestinal absorption and increased renal excretion (17). Alcohol may also perturb folate metabolism through inhibition of methionine synthase in the liver, which may trap folate as 5-methyltetrahydrofolate, leading to a shortage of tetrahydrofolate and a conditional folate deficiency (32,33). Acetaldehyde, derived from alcohol oxidation, may directly destroy folate through cleavage of 5-methyltetrahydrofolate at the C9-N10 bond (34) or interact with tetrahydrofolate (32,35), thereby interfering with folate coenzyme metabolism.
The only other published study that, to our knowledge, relates plasma levels of folate, vitamin B6, vitamin B12, and homocysteine to breast cancer risk (20) was much smaller than the current study. Because our study contains more than three times the number of case patients, we were able to examine these associations with higher precision. In the previous study (20), which included 195 casecontrol pairs from 1974 through 1993, plasma levels of folate and vitamin B6 were not associated with risk of breast cancer in either the 1974 cohort or the 1989 cohort. The present study, which uses blood samples collected during 1989 and 1990, with approximately 6 years of follow-up, has a shorter follow-up period than the previous studys 1974 cohort had, but a longer follow-up period than the 1989 cohort had (20), suggesting that the difference in findings of these two studies is unlikely to be explained by different lengths of follow-up. In the previous study (20), more than half of the blood samples were from the 1974 cohort and were collected at a time when multivitamin supplements were not a major source of folate intake, primarily because the U.S. Food and Drug Administration limited the maximum folate content in supplements to 100 µg before 1973 (36). This fact may explain the substantially lower concentrations of plasma folate and vitamin B6 in the 1974 cohort than those in the 1989 cohort (20) and in our own study. The results from our study suggest that higher plasma levels of folate and vitamin B6 than those in the 1974 cohort are needed to reduce breast cancer risk. Although plasma levels of folate and vitamin B6 in the 1989 cohort (20) were similar to those in the present study, it is possible that the lack of association between plasma levels of folate and vitamin B6 and the risk of breast cancer observed in that study reflects the small sample size. Because of their potential practical importance for chemoprevention, the inverse associations observed in our study between plasma levels of folate and vitamin B6 and risk of breast cancer need to be confirmed in other well-designed, large prospective studies.
Another interesting finding from this study is that lower plasma vitamin B12 levels were associated with increased risk of breast cancer only among premenopausal women in the highest quintile of plasma vitamin B12. This result has no obvious biologic explanation and requires confirmation by other larger studies. It also contrasts with the observation from the previous study (20) that a statistically significant effect of plasma vitamin B12 on breast cancer risk was seen mostly among postmenopausal women.
The findings from this study suggest that folate and vitamin B6 may have the potential to be chemopreventive against breast cancer and that ensuring adequate circulating levels of folate and vitamin B6 by consuming foods that are rich in these nutrients, such as oranges, orange juice, and fortified breakfast cereals, or vitamin supplements, may contribute to a reduction in the risk of breast cancer. Adequate folate levels may be particularly important for women who are at higher risk of breast cancer because of higher alcohol consumption.
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NOTES |
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We thank Marie Nadeau for conducting all laboratory assays and Todd Reid and David Coppola for their technical help with this research.
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Manuscript received May 9, 2002; revised December 12, 2002; accepted January 13, 2003.
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