There is considerable interest in the association of diet with risk of breast cancer. Because diet is potentially modifiable, it represents an avenue for possible preventive efforts. Most research to date has focused on aspects of diet that increase risk, particularly fat, types of fat, macronutrients, and alcohol. 1 More recently, attention has been directed toward aspects of diet that may lower the risk of disease. For example, recent studies have examined the association of diets high in fruits and vegetables, soy, and antioxidant vitamins with risk of breast cancer. 2,3
The hypothesis that certain B vitamins might be involved in breast cancer pathogenesis is based on several lines of evidence. Biochemical data suggest that deficiencies in vitamin B12 (cyanocobalamin), folic acid, vitamin B6 (pyridoxine), and niacin appear to mimic radiation in damaging deoxyribonucleic acid (DNA) by causing single- and double-strand breaks, oxidative lesions, or both. 4 Vitamin B6 is involved in the biosynthesis of thymidine, a deficiency of which increases DNA replication errors. 5 Folate and vitamin B12 play a role in methylation, and hypomethylation appears to be important in cancer. 6,7 Nicotinamide adenine dinucleotide, the principal metabolic form of niacin, is consumed as a substrate in adenosine diphosphate-ribose transfer reactions, including the repair of DNA strand breaks by adenosine diphosphate-ribosyltransferase. 8 More recently, niacin has been shown to regulate expression of p53 in human breast cells, 9 providing further biological evidence for its importance to DNA repair.
Epidemiologic evidence that low intakes of B vitamins are associated with increased risk of breast cancer is limited. A case-control study of postmenopausal women in western New York found that the odds of high intakes of folate were 30% lower among breast cancer cases than controls. 10 High intakes of fruits and vegetables were less common among premenopausal cases than matched controls, but the association did not appear to be related to folate. 11 Only three prospective studies have appeared in the literature. A nested case-control study using stored sera found that incident breast cancer cases who were postmenopausal at baseline had lower levels of vitamin B12 than controls matched for age, race, and menopause. 12 Neither folate, vitamin B6, nor homocysteine was a strong risk factor. The Nurses’ Health Study 13 examined estimated dietary and supplemental intake of folate on the basis of a food frequency questionnaire. Although the authors reported an interaction with alcohol intake, there was little association of breast cancer with folate alone. There was a stronger association, however, between low dietary folate (lowest 20th percentile) and an increased risk among women who were regular consumers of alcohol. A case-cohort analysis of the Canadian National Breast Cancer Screening Study 14 also revealed that diets high in folate reduced the effect of alcohol consumption on breast cancer risk. None of these prospective studies presented results on niacin.
The current report describes findings from the Iowa Women’s Health Study, a prospective cohort study of cancer occurrence. We performed analyses to estimate the risk of postmenopausal breast cancer associated with specific B vitamins from the usual diet, with and without supplements. Given the wealth of data collected on this cohort and the large number of cases, results were adjusted for age, total energy intake, and known breast cancer risk factors. These results add to the growing body of evidence that low intakes of certain B vitamins may increase risk of breast cancer, especially among women who consume alcohol-containing beverages.
Subjects and Methods
Definition of Cohort
Detailed methods of the Iowa Women’s Health Study have been published elsewhere. 15 Briefly, in January 1986, we mailed a 16-page questionnaire to 98,029 eligible women 55–69 years of age who resided in Iowa. We randomly selected potential participants from the State of Iowa driver’s license list, and the 41,836 respondents (42.7% response rate) form the cohort under study. Rates of breast cancer among responders and nonresponders are virtually identical. 16
Diet and Risk Factor Assessment
The questionnaire solicited information on factors known or suspected to be relevant to breast cancer risk, including family history of breast cancer, pregnancy history, menstrual history, physical activity, smoking history, alcohol use, and anthropometry. It also included a semiquantitative food frequency questionnaire with 127 food items and other questions related to nutrient intake. A section on the intake of vitamin supplements included questions on the use of multivitamins as well as on the use of supplements containing only individual B vitamins. Because there are numerous multivitamin preparations, we asked respondents the brand name of the multivitamin and the frequency of intake. We individually coded these multivitamin brands for estimation of intake of vitamins from supplements and focused the analyses on vitamins B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B12 (cyanocobalamin), niacin, and folate.
The food frequency component was virtually identical to that used in the 1984 dietary assessment in the Nurses’ Health Study 17,18; however, we obtained no information on the duration of vitamin supplement use. The reliability and accuracy of the instrument in this cohort is comparable with that seen in the Nurses’ Health Study. 19
For the analyses presented here, we excluded women at baseline if they were not postmenopausal (N = 569), had had a mastectomy or partial breast removal (N = 1,870), or had any cancer other than skin cancer at baseline (N = 2,293). We also excluded women if 30 or more items on the food frequency questionnaire were left blank or if their responses resulted in extreme energy intake values (<600 or ≥ 5,000 kcal per day) (N = 2,717). These exclusions left a total of 34,387 women eligible for follow-up.
We mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 to establish vital status and change of address. Through linkage with the National Death Index, we identified nonrespondents who were deceased. We ascertained cancer incidence through the State Health Registry of Iowa, a part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. 20 Annually, a computer matched a list of cohort members and the records of Iowans with incident cancer in the Health Registry using combinations of first, last, and maiden name; ZIP code; birth date; and Social Security number. Through December 31, 1997, corresponding to 12 years of follow-up, we identified 1,586 cases of breast cancer (1,398 invasive and 188 in situ) among the cohort at risk.
We calculated the length of follow-up for each individual in the study as the time from completion of the baseline questionnaire until the date of breast cancer diagnosis, estimated date of move from Iowa, or date of death. If none of these events applied, follow-up continued through December 31, 1997.
We used means for continuous variables and percentiles for categorical variables to calculate descriptive statistics and used Spearman rank correlation coefficients to determine the degree of association between the vitamins of interest. Age-adjusted incidence rates, adjusted to the mean age of the cohort, were calculated using Poisson regression models. Because of the narrow age range of the study population, the adjusted and unadjusted rates were similar.
To examine the association of intake of B vitamins with breast cancer, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression. 21 We modeled survival as a function of age instead of time on study, because age is a better predictor of breast cancer risk than is length of follow-up time in this study. 22 The exposures of primary interest were low intakes of B vitamins. In an effort to isolate those at the extreme of low intake, we defined four percentile categories: >50th (referent), 31st–50th, 11th–30th, and ≤10th. We categorized the regular use of alcohol into three levels: never-drinkers, drinkers of ≤4 gm per day, and drinkers of >4 gm per day. The cutpoint among drinkers was approximately the median of use in the entire cohort at risk and is equivalent to one-half drink per day. We first examined only dietary intake of B vitamins. Subsequent models, however, also considered total intake on the basis of both diet and vitamin supplements. For each B vitamin, we fit two sets of regression models: one adjusting only for age and total caloric intake and one adjusting for age, caloric intake, other potential confounding variables, and the remaining set of B vitamins. Although total calorie intake is not associated with breast cancer risk in this cohort, 23 as a covariate it may adjust for over- and underreporting of food intake. 24 The following variables are known factors associated with development of breast cancer and were included in the latter model as potential confounders: education level, family history of breast cancer, age at menarche, age at menopause, oral contraceptive use, hormone replacement therapy, parity, age at first birth, body mass index, waist-to-hip ratio, height, body mass index at age 18, alcohol intake, smoking status, and physical activity level.
As reported elsewhere, 15,25–27 established risk factors were associated with breast cancer incidence as expected. For example, higher values of body mass index, waist-to-hip ratio, alcohol intake, and age at first birth were associated with a higher risk of breast cancer. Older age at menarche, younger age at menopause, and higher weight at age 18 years were associated with lower risk. Use of hormone replacement therapy was a weak risk factor. Table 1 presents the association of these risk factors with total intakes (food plus supplements) of the B vitamins of interest. Few differences in age and reproductive risk factors across intakes of vitamins were evident, suggesting that any observed associations between B-vitamin intake with risk are unlikely to be confounded by these factors. Conversely, higher intakes of B vitamins were associated with lower waist-to-hip ratio, greater use of hormone replacement therapy, and greater alcohol consumption.
Given that the food sources of the individual B vitamins of interest are overlapping, we were interested in the degree of correlation of intakes within an individual. As shown in Table 2, the correlations based on dietary sources alone ranged from a low of 0.46 for thiamine and B12 to a high of 0.84 for thiamine and folate. The nutrient database does not generate levels of niacin from food sources only. Therefore, we repeated analyses using total B-vitamin intake (diet plus supplements); the correlations were greater, with roughly half greater than 0.8. This high degree of correlation should be considered in the interpretation of subsequent analyses when individual B vitamins are examined.
Table 3 presents age-adjusted incidence rates and RRs of breast cancer according to dietary intake of B vitamins (other than niacin) adjusted for (1) age and total energy intake and (2) age, total energy intake, and nondietary risk factors. Note that these results do not reflect intakes based on supplemental vitamin use. We based the multivariate-adjusted RRs on models that include each of the other B vitamins as covariates. In general, low intakes of the B vitamins were unrelated to risk of breast cancer. There were minimal differences between the age-adjusted and multivariate-adjusted results.
The frequency of vitamin supplement use among cohort members was high. Approximately 30% reported regular use of multivitamins, and 8% reported regular use of B-complex vitamins. The percentage of women reporting use of specific supplements of vitamin B6 or folate was 3% and 1%, respectively. After adjustment for age, total energy intake, and potential confounders, women who reported regular intake of a multivitamin or B-complex vitamin supplement were at lower risk of breast cancer than women who did not take supplements (RR = 0.88; 95% CI = 0.79–0.98). Therefore, we performed additional analyses based on categorization of women according to total vitamin intakes. Table 4 presents incidence rates and RRs according to estimated total intakes of specific B vitamins adjusted either for age and total energy intake alone or, after further adjustment, for other risk factors and the other B vitamins. The categories of exposure include vitamin intake from both diet and supplement intake, so the cutpoints differ from Table 3. No striking trends were apparent. There was a weak trend of lower folate being associated with increasing age- and energy-adjusted risk of breast cancer, but evidence for a trend was reduced when there was adjustment for other risk factors and other B vitamins.
Data from the Nurses’ Health Study suggest that low intakes of folate (diet plus supplements) increased risk of breast cancer only among women who consumed at least 15 gm of alcohol per day. 13 Therefore, we conducted analyses to attempt to corroborate this finding. We categorized alcohol consumption into three levels: never, less than the median (approximately 4 gm per day for drinkers), and greater than the median. Nondrinkers with the highest dietary folate intake served as the reference group for all comparisons. As shown in Table 5, low dietary folate (without supplements) was not associated with risk of breast cancer among women who never consumed alcohol-containing beverages. Women who had folate intakes greater than the lowest 10th percentile were not at increased risk of breast cancer if they drank alcohol (Figure 1). There was a modest elevation of risk for women with low dietary folate (lowest 10th percentile) and alcohol intake less than the median (RR = 1.33, 95% CI = 0.86–2.05). We observed, however, that women with low dietary folate and alcohol use above the median had a 59% increased risk of breast cancer (95% CI = 1.05–2.41) compared with cohort members with no alcohol use and folate intake above the median. This finding translates to a rate difference of 205 cases of breast cancer per 100,000 person-years.
We repeated analyses after inclusion of dietary supplements and found that the results were essentially unchanged (Figure 2). Although the same general pattern was evident (Table 6), the RR of breast cancer among women with greater than median alcohol intake and lowest folate intake was decreased to 1.45 (95% CI = 0.95–2.23). We also examined possible interactions between niacin and alcohol in a similar manner but found no evidence for an interaction on the risk of postmenopausal breast cancer (data not shown).
These analyses were all based on a median cutpoint of 4 gm per day among drinkers. To allow for a more direct comparison with results from the Nurses’ Health Study, we repeated the analyses using a cutpoint of 15 gm of alcohol per day; a total of 2,198 women (6.4%) were included in this category. Compared with nondrinkers with the highest dietary folate intake, women with the lowest dietary folate and highest alcohol intakes were at 1.71-fold elevated risk of breast cancer (95% CI = 0.89–3.29), based on 11 cases in the category. The corresponding RR for women with low folate and alcohol intake less than 15 gm per day was 1.45 (95% CI = 1.01–2.08).
For most of the women in the study cohort, low B-vitamin intakes do not represent a major risk factor for the disease. The exception appears to be for low folate intake among the subset of study participants who are regular consumers of alcohol-containing beverages. The incidence rate for women who consume alcohol at or above the median but have the highest intake of folate (440 cases per 100,000 person-years) is virtually identical to the incidence rate among nondrinkers, regardless of folate intake (range = 398–427 cases per 100,000 person-years). Conversely, compared with nondrinkers with dietary folate intake above the 50th percentile, women with folate intake below the 10th percentile and alcohol intake above the median experienced breast cancer at a rate of 624 per 100,000 person-years. This rate translates to a 59% increased risk of breast cancer (RR = 1.59, 95% CI = 1.05–2. 41).
Interpretation of these results should consider the validity of the reported intakes of supplements and foods containing B vitamins. Jacques et al28 compared plasma levels of folate with dietary intake estimated from an earlier version of the Willett semiquantitative food frequency questionnaire (116 items). Whether or not supplement users were included, the age-, sex-, and energy-adjusted correlation between nutrient intake and plasma folate was greater than 0.60. This magnitude of correlation was greater than that observed for any other estimated nutrient. In an earlier publication, we compared estimated intake on the basis of the food frequency questionnaire with an average of five 24-hour recalls in a sample of 44 women. 19 The energy-adjusted correlation for total folate was 0.43 and only 0.26 for folate from diet without supplements. By comparison, the correlations for total intake of other B vitamins were considerably higher: thiamine (0.95), riboflavin (0.93), B6 (0.69), and B12 (0.76). Thus, the relatively poor performance of a food frequency questionnaire to capture usual intake of folate is of some concern. Our analytic approach to focus on the extremes of the distribution of intake should reduce and partially alleviate the likely consequence, namely, misclassification of exposure. Finally, it is difficult for us to imagine that women who reported use of alcohol would differentially report foods high in folate content.
It is also of interest to compare the estimated intake in our cohort with that of the general population. The Second National Health and Nutrition Examination Survey (NHANES II) conducted between 1976 and 1980 estimated dietary folate intakes for white women over the age of 50 years to be 177 μg per day. 29 NHANES III, conducted between 1989 and 1991, estimated median folate levels for white women at approximately 202 μg per day. 30 Both estimates ignored the contributions from vitamin supplements. A more recent analysis of NHANES III data that accounted for supplement use and corrected for the greater bioavailability of synthetic folic acid suggested that the daily dietary folate equivalent level of women over the age of 70 years is closer to 441 μg per day. 31 These estimates are comparable with the estimated median folate intake of 294 μg per day (350 μg per day including supplements) in our study population. Thus, the reported folate intakes in our study population are plausible.
Results of the current study are consistent with findings from the Nurses’ Health Study. 13 That study of 88,818 nurses traced for 16 years found that total folate intake was not associated with overall reduced risk of breast cancer. Nevertheless, among the subset of women who consumed an average of one alcohol-containing beverage per day, folate intake of less than 150 μg per day was associated with a 32% increased risk of breast cancer (RR = 1.32, 95% CI = 1.15–1.50). Although the findings of the two studies are consistent, a direct comparison of the strength of association is difficult because of differences in folate and alcohol cutpoints. In particular, in the current study we used the lowest 10th percentile of folate intake (<186 μg per day). This value is slightly higher than the lowest quintile in the Nurses’ Health Study. Moreover, we defined the reference category as above the median in folate intake, rather than the highest quintile. Results of the current study also agree with the findings of Rohan et al, 14 although from the data they presented, a direct comparison of alcohol intakes across studies is not possible.
The a priori hypothesis examined in this observational study was based on biological plausibility regarding the role of B vitamins in aspects of DNA repair. Given that several B vitamins, especially niacin, are reported to contribute to this process, it was reasonable to expect associations with other B vitamins as well as folate. Multivariate models were constructed that considered folate and niacin simultaneously. We observed that the apparent association of low niacin with breast cancer risk was almost completely attenuated by the addition of folate to the model. Conversely, the association of folate with breast cancer risk was unaffected by niacin or any other B vitamin in the model. Although this association may speak to a true effect of folate, one must also consider the high degree of correlation of the individual B vitamins and the difficulty of isolating the effect of a single nutrient out of complex mixtures of foods in an observational study. Moreover, the strongest observed association in the current study was folate from diet alone, not total folate. This observation tends to weaken the specificity of the association. In addition, if folate is measured with greater accuracy than other B vitamins, then a statistical association may be attributed to folate intake rather than to other vitamins that may also be causally associated with breast cancer risk. Alternatively, one must also acknowledge the possibility that the observed interaction of folate and alcohol on breast cancer risk is simply a chance finding. Arguing against this possibility is the fact that an alcohol-by-folate interaction has been observed in both of the published prospective studies of breast cancer that have examined the hypothesis 13,14 and has also been observed in colon cancer. 32
The biological mechanisms underlying the synergistic effects of alcohol and folate intake on breast cancer are unclear. Under conditions of heavy alcohol consumption, low tissue or circulating folate levels could occur as a result of interference with folate absorption and/or metabolism. 33 As mentioned previously, low folate levels could lead to DNA hypomethylation, which has been linked to several types of cancer. The effect of alcohol intake on folate status in the absence of heavy alcohol intake, however, is not well established. In one study of nonalcoholic elderly subjects, dietary folate intake was inversely related to usual alcohol consumption, but there was little association of serum folate levels with alcohol intake. 34 In a subsample of the Health Professionals Follow-Up Study, reported alcohol intake was inversely correlated with erythrocyte folate level—a marker of negative tissue folate balance 35 —after controlling for folate intake 36; this association was limited to men who consumed at least two drinks per day. In the Nurses’ Health Study, there was little relation between alcohol intake and erythrocyte folate levels. 36 These data suggest that low to moderate alcohol consumption may not result in tissue folate depletion. Alternatively, Giovannucci et al36 hypothesized that alcohol and its primary oxidative metabolite, acetaldehyde, could affect DNA methylation and potentially carcinogenesis through reduced methionine synthesis. It is plausible that these effects might be enhanced under conditions of low dietary folate intake.
Limitations of the current study include those inherent to any study of diet and cancer, including errors in diet assessment. 24 We based all estimates of B-vitamin intake on only a single assessment of diet at baseline. If study participants adopted significant changes in dietary habits during the course of follow-up, then substantial misclassification may have occurred. The likely effect of such misclassification, however, would be to make it more difficult to detect associations of folate intake with breast cancer. Our ability to generalize to other populations may be somewhat compromised given the relatively limited range of intakes in our cohort, the fact that the Iowa cohort is a predominantly white Midwestern population, and the low intake of alcohol. The literature regarding B-vitamin intake and risk of breast cancer is also limited, reducing the ability to examine consistency as a causal criterion. As noted previously, however, our results are congruent with the findings from two other prospective studies. 13,14
Strengths of the current study are several and include the large numbers of cases. Given the low migration from Iowa, the completeness of follow-up through the statewide registry is high. Estimated intake of diet occurred at baseline before diagnosis of breast cancer, thereby eliminating the potential for recall bias inherent in retrospective studies. Fairly extensive data on the use of vitamin supplements likely increased the precision of estimated vitamin intakes. The extensive risk factor questionnaire administered to the cohort permitted adjustment for multiple potential confounding factors.
In summary, the current study suggests that among the subset of women who report regular use of alcohol-containing beverages, breast cancer risk is increased among those with dietary folate intakes in the lowest 10th percentile. We found little evidence that low intakes of other B vitamins are an important determinant of postmenopausal breast cancer. The interaction between alcohol and folate has now been reported in two other large cohort studies, and these findings jointly suggest that folate supplementation may attenuate the risks of breast cancer associated with alcohol-containing beverages. The fact that our food supply is now being supplemented with folate as a means to reduce birth defects may have unintended additional benefits on breast cancer.
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Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
breast neoplasms; folate; alcohol; risk factors; cohort study