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American Journal of Epidemiology Advance Access originally published online on March 15, 2008
American Journal of Epidemiology 2008 167(10):1197-1206; doi:10.1093/aje/kwn027
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

A Prospective Study of Multivitamin Supplement Use and Risk of Breast Cancer

Ken Ishitani1,2, Jennifer Lin1, JoAnn E. Manson1,3,4, Julie E. Buring1,3,5 and Shumin M. Zhang1

1 Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
2 Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA
4 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
5 Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA

Correspondence to Dr. Shumin M. Zhang, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215 (e-mail: shumin.zhang{at}channing.harvard.edu).

Received for publication September 20, 2007. Accepted for publication January 28, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors evaluated the association between multivitamin supplement use and breast cancer risk in a completed trial. At baseline (1992–1995), 37,920 US women aged ≥45 years and free of cancer provided detailed information on multivitamin supplement use. During an average of 10 years of follow-up, 1,171 cases of invasive breast cancer were documented. Multivitamin use was not significantly associated with overall risk of breast cancer. Compared with the risk for never users, the multivariable relative risks were 0.97 (95% confidence interval: 0.81, 1.16) for past users and 0.99 (95% confidence interval: 0.82, 1.19) for current users. Current multivitamin use for ≥20 years or ≥6 times/week was also not significantly associated with risk. Multivitamin use was nonsignificantly inversely associated with risk of breast cancer among women consuming ≥10 g/day of alcohol and with risk of estrogen receptor negative–progesterone receptor negative breast cancer. Multivitamin use was nonsignificantly associated with a reduced risk of developing ≤2-cm breast tumors but an increased risk of >2-cm tumors. The authors' data indicate no overall association between multivitamin use and breast cancer risk but suggest that multivitamin use might reduce risk for women consuming alcohol or decrease risk of estrogen receptor negative–progesterone receptor negative breast cancer.

alcohol drinking; breast neoplasms; receptors, estrogen; receptors, progesterone; vitamins

Abbreviations: CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; RR, relative risk


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Multivitamin supplements are the most commonly used dietary supplements in the United States. According to the 1999–2000 National Health and Nutrition Examination Survey, 35 percent of adults reported recent use of multivitamin supplements (1). Numerous experimental studies have suggested some favorable effects of several individual vitamins contained in multivitamin supplements on DNA synthesis and repair, DNA methylation, oxidative damage, inflammation, angiogenesis, immunity, cell differentiation, cell proliferation, and apoptosis (2–6).

Most epidemiologic studies on vitamins and breast cancer risk to date have focused on individual vitamins (7–9). Three previous prospective cohort studies have evaluated the association between multivitamin supplement use and risk of breast cancer; one reported an inverse association among those who regularly consumed alcohol (10), but two others found no overall association (11, 12). Because of limited data on multivitamin supplement use and breast cancer risk, we conducted a detailed analysis in the Women's Health Study, a large prospective cohort.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study cohort
The Women's Health Study was established in 1992 when 39,876 female US health professionals (registered nurses, 75 percent) aged 45 years or older and free of cancer and cardiovascular disease at baseline were enrolled in a randomized trial evaluating the benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease (13–16). Upon enrollment in the study, all participants completed a baseline questionnaire inquiring about their medical history and lifestyle factors, including potential risk factors for breast cancer. As of the end of the trial (March 31, 2004), the average duration of follow-up was 10 years, and follow-up rates for morbidity and mortality were 97.2 percent and 99.4 percent, respectively (13, 14, 16). The current analysis was restricted to 37,920 women after we excluded those who did not provide information on multivitamin supplement use and diet, had implausible total energy intakes (<600 kcal/day or >3,500 kcal/day), or had prerandomization cancers that were reported and confirmed after randomization.

Assessment of multivitamin supplement use
Information about the status (never, past, or current) and duration (0–1, 2–4, 5–9, 10–14, 15–19, or ≥20 years) of multivitamin supplement use was asked on the enrollment questionnaire at baseline. At baseline, 39,345 (98.7 percent) women in the Women's Health Study also completed a 131-item food frequency questionnaire, a format that has been used in the Nurses' Health Study. The questionnaire assessed average consumption over the past year of a specific amount of each food and allowed nine responses, ranging from "never" to "six or more times per day." The food frequency questionnaire also included a section on current use of multivitamin supplements. For current users, women were asked about the exact brand and type of multivitamins they used (write-in format) and how many times they took multivitamins per week (≤2, 3–5, 6–9, or ≥10). These categories of multivitamin supplement use were included in a previous study of colorectal cancer in this cohort (17). The validity and reliability of the food frequency questionnaire have been assessed in the Nurses' Health Study, which has demographic characteristics similar to those of the Women's Health Study (18–20).

Ascertainment of breast cancer cases
Every 6 months during the first year of follow-up and then annually thereafter, participants were sent questionnaires asking about newly diagnosed diseases, including breast cancer. Deaths of participants were identified through reports from family members, postal authorities, and a search of the National Death Index. We sought medical records and other relevant information, which were reviewed by an endpoints committee consisting of physicians to confirm medical diagnoses. Medical record review confirmed 98 percent of self-reported breast cancer cases in the Women's Health Study (21). Detailed information on tumor characteristics at diagnosis, including hormone receptor status, tumor size, lymph node metastasis, histology, and histologic grading and differentiation, was also extracted from medical records. Laboratories affiliated with hospitals where breast cancer cases were diagnosed determined hormone receptor status.

During an average of 10 years of follow-up, we ascertained 1,171 confirmed cases of invasive breast cancer, which were included in this analysis. Of the 1,171 invasive cancers, 790 (67.5 percent) were positive for both estrogen receptor (ER) and progesterone receptor (PR) (ER+PR+), 123 (10.5 percent) were positive for ER but negative for PR (ER+PR–), 23 (2.0 percent) were ER–PR+, 165 (14.1 percent) were ER–PR–, and, for 70 (6.0 percent), ER or PR status was unknown. Tumors classified as borderline positive for ER (n = 5) or PR (n = 8) were considered ER+ or PR+ in the analyses. In addition, 848 of the tumors (72.4 percent) were ≤2 cm, 273 (23.3 percent) were >2 cm, five (0.4 percent) were of any size with direct extension to the chest wall or skin, and, for 50 (4.3 percent), tumor size was unknown. Moreover, 828 (70.7 percent) were negative for lymph node metastasis, 279 (23.8 percent) were positive for lymph node metastasis, and 64 (5.5 percent) were unknown for lymph node metastasis. Furthermore, 261 cases (22.3 percent) had well-differentiated tumors, 480 (41.0 percent) had moderately differentiated tumors, 275 (23.5 percent) had poorly differentiated tumors, and 155 (13.2 percent) had tumors whose histologic grading and differentiation were unknown.

Statistical analysis
We first compared mean values or proportions of baseline risk factors for breast cancer according to status of multivitamin supplement use to evaluate potential confounding by these variables.

Person-years were calculated for each participant, ranging from the date of randomization to the date of confirmed cancer diagnosis, death, or March 31, 2004, whichever occurred first. Cox proportional hazards regression models were used to calculate relative risks and 95 percent confidence intervals (22). We initially estimated the relative risks according to categories of multivitamin supplement use, with adjustment for age (in years) and randomized treatment assignment (aspirin vs. placebo, vitamin E vs. placebo). We further performed a multivariable analysis that additionally adjusted for known or potential risk factors for breast cancer at baseline, including alcohol intake (none, >0–<10, ≥10–<15, ≥15–<30, or ≥30 g/day), body mass index (<23, ≥23–<25, ≥25–<27, ≥27–<30, or ≥30 kg/m2), family history of breast cancer in a first-degree relative (yes or no), history of hysterectomy (yes or no), bilateral oophorectomy (yes or no), smoking status (never, past, or current), benign breast disease (yes or no), age at menarche (≤11, 12, 13, 14, or ≥15 years), parity (0, 1–2, 3–4, 5, or ≥6), age at first birth (≤24, 25–29, or ≥30 years), physical activity (kcal/week, in quartiles), total energy intake (kcal/day, in quintiles), menopausal status (premenopausal, postmenopausal, or uncertain/unknown), and postmenopausal hormone use (never, past, or current and duration). We conducted an additional multivariable analysis by excluding incident cases of breast cancer diagnosed within the first 2 years of follow-up, with additional adjustments for mammography screening in the past year, which was asked on the 12-month questionnaire.

We also performed an analysis according to combined ER and PR status (ER+PR+, ER+PR–, ER–PR–, and unknown), tumor size (≤2 and >2 cm), lymph node metastasis (with metastasis and without metastasis), and histologic grading and differentiation (well, moderately, and poorly differentiated). Because of limited numbers, ER–PR+ breast cancer cases (n = 23), or cases whose tumors were any size with direct extension to the chest wall or skin (n = 5) or whose tumor size was unknown (n = 50), or cases with unknown lymph node metastasis (n = 64), or cases with unknown histologic grading and differentiation (n = 155) were excluded from the analysis of tumor characteristics. All p values were two sided. Tests for interaction were conducted according to categories of alcohol intake (0, >0–<10, or ≥10 g/day), menopausal status (premenopausal or postmenopausal), randomized vitamin E treatment assignment (vitamin E vs. placebo), and postmenopausal hormone use (never, past, or current) and were performed by log likelihood ratio tests comparing the models with or without interaction terms.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
At baseline, 5,033 (13.3 percent) women had never taken multivitamin supplements, 21,784 (57.4 percent) had taken multivitamin supplements in the past, and 11,103 (29.3 percent) were taking multivitamin supplements currently.

Table 1 presents the distribution of baseline risk factors for breast cancer according to status of multivitamin supplement use. Women who were taking multivitamin supplements currently tended to be younger, leaner, or more physically active. They were also more likely to consume more calories, experience late age at menarche, experience late age at menopause, have a larger number of births, take postmenopausal hormones currently, have mammography screening, or have a personal history of hysterectomy, bilateral oophorectomy, or benign breast disease. However, they were less likely to consume alcohol or smoke cigarettes currently. Age at first birth, menopausal status, and history of a mother or a sister with breast cancer did not differ substantially according to multivitamin supplement use. Age-adjusted percentages of women who had mammography screening at 12 months were 56.2 percent, 60.0 percent, and 63.9 percent among never, past, and currents users of multivitamin supplements, respectively.


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  		TABLE 1. Age-adjusted baseline characteristics* according to use of multivitamin supplements, Women's Health Study, United States, 1992–2004

 
Status of multivitamin supplement use was not significantly associated with risk of breast cancer among all women in the model adjusted for age and randomized treatment assignment (table 2). Additional adjustment for risk factors for breast cancer did not materially change the results; the multivariable relative risks were 0.97 (95 percent confidence interval (CI): 0.81, 1.16) for past users and 0.99 (95 percent CI: 0.82, 1.19) for current users. The results were also not appreciably changed after excluding breast cancer cases diagnosed within the first 2 years of follow-up and additionally controlling for mammographic screening, which was asked on the 12-month questionnaire; the multivariable relative risks were 1.00 (95 percent CI: 0.81, 1.22) for past users and 1.01 (95 percent CI: 0.82, 1.25) for current users. There were also no significant associations between duration or frequency of current use of multivitamin supplements and risk of breast cancer, even for those who used them currently at baseline for 20 or more years (multivariable relative risk (RR) = 1.00, 95 percent CI: 0.74, 1.35) or had taken them six or more times per week (multivariable RR = 1.00, 95 percent CI: 0.86, 1.16). The multivariable relative risk was 0.81 (95 percent CI: 0.59, 1.10) for current use of Centrum (including Centrum Silver; Wyeth Consumer Healthcare, Richmond, Virginia), the most frequently consumed multivitamin supplements among current users (18 percent). Other brands were used too infrequently to be analyzed individually.


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  		TABLE 2. Relative risk of invasive breast cancer according to use of multivitamin supplements, Women's Health Study, United States, 1992–2004

 
Although the test for interaction between multivitamin supplement use and breast cancer risk according to levels of alcohol intake was not significant (p for interaction = 0.69), use of multivitamin supplements was nonsignificantly inversely associated with risk of breast cancer among women who consumed ≥10 g/day of alcohol (multivariable RR = 0.81, 95 percent CI: 0.54, 1.21 for past users; multivariable RR = 0.78, 95 percent CI: 0.50, 1.20 for current users) (table 3). There was no association between multivitamin use and breast cancer risk among women consuming <10 g/day of alcohol (table 3). When multivitamin supplement use and alcohol intake were evaluated in combination, multivitamin use appeared to reduce the increased risk of breast cancer associated with higher alcohol intake (figure 1). The association between multivitamin supplement use and breast cancer risk did not differ by randomized vitamin E treatment assignment (p for interaction = 0.94) or by postmenopausal hormone use (p for interaction = 0.71). Analyses according to menopausal status suggested a nonsignificant interaction between multivitamin supplement use and menopausal status in relation to the risk of invasive breast cancer (p for interaction = 0.20). The multivariable relative risks were 1.31 (95 percent CI: 0.83, 2.05) for past users and 1.36 (95 percent CI: 0.85, 2.18) for current users among premenopausal women, and they were 0.89 (95 percent CI: 0.72, 1.09) for past users and 0.82 (95 percent CI: 0.66, 1.03) for current users among postmenopausal women (table 4).


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  		TABLE 3. Relative risk of invasive breast cancer according to use of multivitamin supplements, by alcohol intake, Women's Health Study, United States, 1992–2004

 

Figure 1
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  		FIGURE 1. Multivariable relative risks (RRs; values given above the bars) of breast cancer by multivitamin use and alcohol intake in the Women's Health Study, United States, 1992–2004. The reference group for all comparisons was women who were never users of multivitamins and nondrinkers of alcohol.

 

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  		TABLE 4. Relative risk of invasive breast cancer according to use of multivitamin supplements, by menopausal status, Women's Health Study, United States, 1992–2004

 
Separate analyses according to various hormone receptor statuses revealed a nonsignificant inverse association between status of multivitamin supplement use and risk of developing ER–PR– breast cancer; the multivariable relative risks were 0.67 (95 percent CI: 0.42, 1.06) for past users and 0.73 (95 percent CI: 0.45, 1.20) for current users (table 5). Such an association was significant for past users who took multivitamin supplements for 5 or more years (multivariable RR = 0.46, 95 percent CI: 0.22, 0.96). Past use for 5 or more years was also significantly associated with reduced risk of developing breast tumors with no lymph node metastasis (multivariable RR = 0.68, 95 percent CI: 0.49, 0.94), but no significant association was observed for tumors metastasized to lymph nodes (table 6). In addition, multivitamin use was nonsignificantly associated with a reduced risk of developing ≤2-cm breast tumors but an increased risk for >2-cm tumors. No significant associations for multivitamin supplement use and breast cancer risk were found according to histologic grading and differentiation (data not shown).


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  		TABLE 5. Relative risk of invasive breast cancer according to use of multivitamin supplements, by tumor hormone receptors status, Women's Health Study, United States, 1992–2004

 

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  		TABLE 6. Relative risk of invasive breast cancer according to use of multivitamin supplements, by tumor size and lymph node metastasis, Women's Health Study, United States, 1992–2004

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this large cohort of women, we found that multivitamin supplement use was not significantly associated with overall risk of breast cancer. Current use of multivitamin supplements for 20 or more years or six or more times per week was also not significantly associated with breast cancer risk. There was also no significant association between multivitamin supplement use and risk of breast cancer according to menopausal status and randomized vitamin E treatment assignment. However, we observed a nonsignificant inverse association between multivitamin supplement use and breast cancer risk for past or current users who consumed ≥10 g/day of alcohol. We also found a nonsignificant inverse association between multivitamin supplement use and risk of developing ER–PR– breast cancer. In addition, past use for 5 or more years was significantly associated with risk of developing ER–PR– breast cancer and breast tumors without lymph node metastasis. The associations between multivitamin use and breast cancer risk differed according to tumor size; a reduced risk was observed for ≤2-cm tumors but an increased risk for >2-cm tumors.

The prospective design and high follow-up rates in this study minimize the possibility that our findings are a result of methodological biases. Confounding by other factors is unlikely to explain our findings because we comprehensively controlled for established risk factors for breast cancer, which had minimal effect on the relative risks. Our results are also unlikely to be explained by the potential bias that breast cancer itself (before it was diagnosed) may have affected multivitamin supplement use because the relative risks, after excluding patients who were diagnosed with breast cancer within the first 2 years after randomization, were similar to those when we considered all cases. However, we used the information on multivitamin supplement use at baseline only, so measurement error due to random within-person variation may have been inevitable, which would tend to weaken any true associations. Finally, because the number of events in some exposure categories was relatively modest, we had limited statistical power in some subgroup analyses.

Lack of an overall association between multivitamin supplement use and risk of breast cancer observed in the Women's Health Study is consistent with the findings from previous studies. In the French Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) trial, randomized daily use of combined antioxidant vitamin and mineral supplements (120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta-carotene, 100 µg of selenium, and 20 mg of zinc) for 7.5 years did not significantly affect the risk of breast cancer in women; the incidence rates of breast cancer were 95 per 100,000 person-years in the intervention group and 100 per 100,000 person-years in the placebo group (23). In the American Cancer Society Cancer Prevention Study II Nutrition Cohort, multivitamin use was not significantly associated with risk of breast cancer (11). In that study, there was no assessment of risk according to duration and dosage of multivitamin supplement use or by level of alcohol intake (11). Similarly, in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort, no significant association was found between multivitamin use and breast cancer risk, with the multivariable relative risk of 1.11 (95 percent CI: 0.89, 1.38) when ever users were compared with never users (12). In the Nurses' Health Study, a reduced risk of breast cancer associated with multivitamin supplement use was seen mostly among those women who regularly consumed alcohol (10). In the present investigation, we also observed that multivitamin supplement use nonsignificantly reduced the risk of breast cancer among women who consumed ≥10 g/day of alcohol. Thus, it is possible that multivitamin supplement use may be associated with reduced risk of breast cancer primarily among those whose vitamin status is suboptimal because of alcohol intake.

One multivitamin tablet, which contains 400 µg of folate and ≥2 mg of vitamin B6 (equivalent to or greater than daily Dietary Reference Intakes for adults in the United States for folate and vitamin B6, respectively (24)), is a major source of folate and vitamin B6. In several large, prospective cohort and case-control studies (25), high intakes or blood levels of folate have been associated with reduced risk of breast cancer, especially among women who regularly consume alcohol. In the Nurses' Health Study, plasma vitamin B6 levels were also inversely associated with risk of breast cancer (9). In epidemiologic studies, including the Women's Health Study (26), alcohol intake has been consistently associated with increased risk of breast cancer. Alcohol is known to antagonize folate and increases an individual's requirement for folate (27). Alcohol is also suggested to be associated with an increased requirement for vitamin B6 (24).

It has been suggested that folate may have a dual effect on carcinogenesis: folate may prevent tumor initiation when administrated early in carcinogenesis but promote tumor development when administrated later in carcinogenesis (28–30). This suggestion is consistent with our findings of multivitamin use by breast tumor size (a reduced risk for ≤2-cm tumors but an increased risk for >2-cm tumors), but it is not supported by our null results between multivitamin use and risk of developing breast tumors metastasized to lymph nodes. Alternatively, the association between multivitamin use and breast cancer risk among those consuming ≥10 g/day of alcohol or by tumor size was due to chance given that many subgroups were evaluated.

It is increasingly recognized that human breast cancer consists of diverse subtypes with different risk factors and clinical responsiveness to treatments (31, 32). In the Nurses' Health Study, an inverse association between intake of total folate, which includes folate from multivitamin supplements, and risk of breast cancer was present for mainly ER– breast cancer; such findings are consistent with the biologic data that folate plays an important role in the maintenance of normal DNA methylation, and aberrant methylation of the ER gene may be associated with the loss of ER expression in breast tumors (33). In the present investigation, we also observed an inverse association between use of multivitamin supplements (a major source of folate), especially for past users who took them for 5 or more years, and risk of developing ER–PR– breast cancer in the Women's Health Study. Because status of hormone receptors was decided by laboratories affiliated with hospitals where breast cancer cases were diagnosed, we cannot completely exclude the possibility that cutoff points might be different among laboratories. However, measurement of hormone receptor status has been standardized, and the distribution of hormone receptors in the Women's Health Study is comparable to those reported in other studies of postmenopausal women (34, 35).

Besides folate and vitamin B6, multivitamins also contain other vitamins and minerals. There is a possibility that component(s) other than folate or vitamin B6 may account for the observed inverse associations of multivitamins with risk of breast cancer among women consuming ≥10 g/day of alcohol or with risk of ER–PR– breast cancer. However, epidemiologic evidence on the role of individual vitamins, including vitamin A, carotenoids, vitamin E, and vitamin C, in the risk of breast cancer has been inconsistent (8). In addition, randomized vitamin E supplementation had no significant effect on risk of breast cancer in the Women's Health Study (13, 14, 16). Total vitamin D intake and vitamin D supplements were associated with reduced risk of breast cancer, but primarily among premenopausal women in the Women's Health Study and the Nurses' Health Study (36, 37). In addition, the inverse association for total vitamin D intake was present for mainly ER+ or PR+ breast tumors in premenopausal women in the Women's Health Study (36, 37). Therefore, the observed inverse associations in subgroups may not be explained by vitamins A, C, E, and D contained in multivitamins.

In conclusion, the findings from this prospective study indicate that multivitamin supplement use is not related to overall risk of breast cancer. Our data suggest that multivitamin supplement use might reduce risk of breast cancer among women consuming alcohol or decrease the risk of developing ER–PR– breast cancer.


   ACKNOWLEDGMENTS
 
This study was supported by research grants CA096619, CA-47988, and HL-43851 from the National Institutes of Health (Bethesda, Maryland).

The authors thank Eduardo Pereira for his statistical analytic support. They acknowledge the contributions of the entire staff of the Women's Health Study under the leadership of David Gordon, as well as Marilyn Chown, and Harriet Samuelson. The authors also acknowledge the Endpoints Committee of the Women's Health Study (Dr. Wendy Y. Chen and Dr. I-Min Lee), Anna Klevak, and Natalya Gomelskaya for their assistance with the manuscript.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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