Multivitamin Supplement Use and Risk of Breast Cancer

Abstract and Introduction

Abstract

Background: The association between consumption of multivitamins and breast cancer is inconsistent in epidemiologic studies.
Objective: To perform a meta-analysis of cohort and case-control
studies to evaluate multivitamin intake and its relationship with breast
cancer risk.
Methods: The published literature was systematically searched and
reviewed using MEDLINE (1950 through July 2010), EMBASE (1980 through
July 2010), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010 issue 1).
Studies that included specific risk estimates were pooled using a
random-effects model. The bias and quality of these studies were
assessed with REVMAN statistical software (version 5.0) and the GRADE
method of the Cochrane Collaboration.
Results: Eight of 27 studies that included 355,080 subjects were
available for analysis. The total duration of multivitamin use in these
trials ranged from 3 to 10 years. The frequency of current use in these
studies ranged from 2 to 6 times/week. In analyses by duration of use 10
years or longer or 3 years or longer and by frequency 7 or more
times/week that were reported in these studies, multivitamin use was not
significantly associated with the risk of breast cancer. Only 1 recent
Swedish cohort study concluded that multivitamin use is associated with
an increased risk of breast cancer. The results of a meta-analysis that
pooled data from 5 cohort studies and 3 case-control studies indicated
that the overall multivariable relative risk and odds ratio were 0.10
(95% CI 0.60 to 1.63; p = 0.98) and 1.00 (95% CI 0.51 to 1.00; p =
1.00), respectively. The association was not statistically significant.
Conclusions: Multivitamin use is likely not associated with a
significant increased or decreased risk of breast cancer, but these
results highlight the need for more case-control studies or randomized
controlled clinical trials to further examine this relationship.

Introduction

Dietary supplements are increasingly used in the US. Multivitamin
formulations with or without minerals are the most common type of
dietary supplements used.^[1]
In the National Health and Nutrition Examination Survey 1999–2000,
about 40% of women in the US reported taking multivitamins and 35% of
adults reported regular use of multivitamin-multimineral supplements.^[1] Many people believe that these supplements will prevent chronic diseases such as cancer and cardiovascular disease.^[2,3]
However, research into whether multivitamin supplements may provide
health benefits or cause adverse effects to consumers has produced
conflicting results. Of concern, some studies showed that the use of
multivitamins with multiminerals may have an adverse impact on health.^[4]
The results of 2 recent epidemiologic studies released during the same
week reported opposing findings. Larsson and colleagues found a 19%
increased risk of breast cancer associated with multivitamin use.^[5]
In contrast, a study in Puerto Rico involving 268 women with recently
diagnosed breast cancer and 457 women without breast cancer found a 33%
decrease in breast cancer risk associated with multivitamin use.^[6] These results are vague and confusing to clinicians and people interested in using multivitamins for preventive purposes.
In the absence of sufficient scientific evidence, many people in
Western and Asian countries choose to use multivitamin supplements to
prevent cancer. Many of these patients are exposed to complementary and
alternative medicine, which comprises a large proportion of
multivitamins and dietary supplements.^[7–9]
However, it is uncertain whether multivitamin supplement use for the
healthy population or patients with cancer is beneficial or harmful.^[10–12]

Results from epidemiologic studies on the relationship between
multivitamin intake and an increased or decreased risk of breast cancer
have been inconsistent. The purpose of this systematic review was to
evaluate the epidemiologic evidence from the cohort and case-control
studies on multivitamins and the risk of breast cancer by summarizing it
quantitatively using a meta-analytic method. We also evaluated whether
the dose and duration of multivitamin intake is associated with an
increased or decreased risk of breast cancer.

Methods

Electronic Searches

We searched MEDLINE (1950 through July 2010), EMBASE (1980 through
July 2010), and the Cochrane Central Register of Controlled Trials (The Cochrane Library
2010, issue 1). Studies in English that described the association
between supplemental multivitamin use and breast cancer risk in women
were identified. The search strategy for MEDLINE and EMBASE was (breast
cancer and multivitamin or vitamin) AND (clinical or cohort
[title/abstract] AND trial [title/abstract] OR clinical trials [MeSH
terms] OR cohort studies [MeSH terms] OR therapeutic use [MeSH terms
subheading]).
Searching other Resources

The authors manually screened the reference lists incorporated in a meta-analysis published by Larsson et al.,^[13] a systematic review of the literature published by Velicer et al.^[14] in 2008, and the references in all identified studies.

Selection and Eligibility Criteria

Publications were retrieved for review if outcomes regarding breast
cancer and women taking multivitamins or vitamins were reported. To
avoid the confounding effects of recurrent disease, studies were
excluded if they were performed in patients with a history of breast
cancer or in those who did not provide information on supplemental
multivitamin use and diet. The characteristics of studies, including
participants, interventions, and relative risk ratios or odds ratios of
the potential risk factors (eg, tumor size, alcohol consumption, smoking
status, body mass, tumor hormone status and postmenopausal hormone
intake, median duration and frequency), were recorded in a standardized
table.

Data Extraction and Management
Two of us (AC, HL) reviewed the studies independently, extracted
pertinent data from the articles selected, and entered the data into the
Review Manager program. Disagreements in the interpretation of study
findings were resolved by consensus.^[12]

Synthesis of Results

A quantitative meta-analytic technique was used to pool data for the
relative risk of breast cancer to explore the differences between women
who took multivitamins and those who did not. The meta-analysis was
performed using the random-effects model. The hypothesis of our study
was that there was no significant association between multivitamin
intake and an increased or decreased risk of breast cancer. The extent
of heterogeneity was quantified using
I²

. The
I²

statistic describes the percentage of variation across studies that is caused by heterogeneity rather than chance.
I²

can be readily calculated from basic results obtained from a typical meta-analysis as
I²

= 100% × (Q – df)/Q, where Q is Cochran's heterogeneity statistic and df is the degrees of freedom. Values of
I²

less than the degrees of freedom are set equal to zero so that
I²

lies between 0% and 100%. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.^[15]

The overall effect was expressed as the relative risk. All analyses
were performed using REVMAN statistical software (version 5.0) by the
Cochrane Collaboration.^[16] We also analyzed the association between breast cancer risk and the frequency and duration of multivitamin intake.

Risk of Bias and Study Quality

The risk of bias in the included studies was assessed by individual
domains such as adequate sequence generation; allocation concealment;
blinding of patients, study personnel, and outcome assessors; incomplete
outcome data; freedom from selective reporting; and freedom from
funding bias. We assessed the overall risk of bias by using the risk of
bias table available in REVMAN according to the judgments on the
relative importance of each domain. We also assessed the quality of
evidence in these studies using GRADE profiler software,^[16]
which allowed us to create a Summary of Findings table. Data from the
systematic review and meta-analyses can be retrieved from a Review
Manager 5 file; these data can be combined with data we entered; a
Summary of Findings table then can be exported, ready for import into
Review Manager 5. The software performs many of the calculations
necessary to present the key results in systematic reviews in a table
format, guiding us through the process of grading the quality of the
evidence using the GRADE approach.^[17]

Results
Study Selection

A total of 27 studies were identified. Only 8 studies (5 were large
cohort studies and 3 were case-control studies) reported the incidence
of breast cancer in women who were taking multivitamin supplements and
were included in our review. No relevant studies were identified
manually (Figure 1).

(Enlarge Image)

Figure 1. Flow diagram of included studies.

<blockquote></blockquote>

Figure 1.


Flow diagram of included studies.

Characteristics of Studies
Table 1
^[5,18–33]
shows the number of participants, interventions, median duration of
exposure, and relative risk of breast cancer. The age of participants
ranged from 50–79 years in 3 cohort studies; 49–83 in 1 cohort study;
and greater than or equal to 45 years in 1 cohort. Participants were
aged 20–70 years and 20–69 years in 2 case-control studies and 1
case-control study, respectively. Five cohort and 3 case-control studies
contributed a total of 355,034 participants. The total number of women
diagnosed with breast cancer during the average follow-up of 3 or 10
years in 4 cohort studies and 3 case-control studies was12,507 and 7283,
respectively.^[5,18–24]
The estimated effects with a confidence interval and the key elements
of the forest plot for all included studies are shown in Figures 2 and

3.

(Enlarge Image)

Figure 2. Overall risk of breast cancer with MV use vs MV nonuse in cohort studies. MV = multivitamin; NA = not available.

<blockquote>
</blockquote>
Figure 2.

Overall risk of breast cancer with MV use vs MV nonuse in cohort studies. MV = multivitamin; NA = not available.

(Enlarge Image)

Figure 3. Overall risk of breast cancer with MV use vs MV nonuse in case-control studies. MV = multivitamin; NA = not available.

<blockquote></blockquote>
Figure 3.

Overall risk of breast cancer with MV use vs MV nonuse in case-control studies. MV = multivitamin; NA = not available.

Results of Individual Studies

When the association between multivitamin use and increased or
decreased risk of breast cancer is considered, the potential prognostic
factors for breast cancer such as tumor size, alcohol consumption,
smoking status, body mass index (BMI), tumor hormone status, and
postmenopausal hormone intake should be included in the analysis.
However, no studies in this meta-analysis reported an association
between multivitamin use and all of these prognostic factors. The
association of multivitamin use with breast tumor size and estrogen
receptors was mentioned only in 1 cohort study.^[17]
The interaction between postmenopausal hormone use or smoking status
with multivitamin use was reported, and no significant association was
found in 5 studies (2 large cohort studies and 3 case-control studies).^{[5,19,22–24]}

In analyses by the frequency of multivitamin use of 7 or more
tablets/week and a duration of current use of 10 years or more or 3
years or more, no significant association between multivitamin intake
and an increased or decreased risk of breast cancer was reported in 3
cohort and 3 case-control studies.^{[18,19,21–24]}

One Swedish study reported a statistically significant relationship
between frequency/duration of multivitamin use and development of breast
cancer.^[5]
In its analysis, women who took 7 or more tablets/week had a 19%
increase in breast cancer risk, and women who had used multivitamins 3
or more years had a 22% increased risk of breast cancer compared with
nonusers.^[5]

Meta-analysis
A meta-analysis of 5 cohort studies and 3 case-control studies showed
no association between multivitamin use and the risk of breast cancer
(RR 0.99 [95% CI 0.60 to 1.60] and OR 1.00 [95% CI 0.51 to 1.97],
respectively) (Figures 4 and 5).

(Enlarge Image)

Figure 4. Overall relative risk of breast cancer in cohort studies. MV = multivitamin.

<blockquote>
</blockquote>
Figure 4.

Overall relative risk of breast cancer in cohort studies. MV = multivitamin.

(Enlarge Image)

Figure 5. Overall odds ratios for risk of breast cancer in case-control studies. MV = multivitamin.

<blockquote>
</blockquote>
Figure 5.

Overall odds ratios for risk of breast cancer in case-control studies. MV = multivitamin.


The overall RR for 10 or more years and 3 or more years showed no
significant association with breast cancer risk in cohort and
case-control studies (Figure 6). The results of the meta-analysis for
the frequency of use 7 or more times/week likewise showed no overall
association with breast cancer risk (Figure 7). One cohort and 1
case-control study were not pooled into the meta-analysis because no
data were available.^[19,23]

(Enlarge Image)

<blockquote>
</blockquote>
Figure 6.

Meta-analysis for intake duration of ≥10 years or ≥3 years. MV = multivitamin.

(Enlarge Image)

Figure 7. Meta-analysis for frequency of use ≥7 times/wk. MV = multivitamin.

<blockquote>
</blockquote>
Figure 7.

Meta-analysis for frequency of use ≥7 times/wk. MV = multivitamin.

Risk of Bias and Study Quality

The results of the assessment on the risk of bias showed that a high
risk of bias is likely to be present in both cohort and case-control
studies. All domains, except incomplete outcome data, in the risk of
bias table were judged to affect the risk of bias across outcomes in
these studies (Figures 8 and 9). In this meta-analysis, we found no
evidence of substantial publication bias caused by funding sponsored by
manufacturers because all retrieved studies had disclosed the sources of
funding. All funding was supported by the National Institutes of Health
or the National Cancer Institute. The results of the quality assessment
of these studies indicated low scores using the GRADE method.

(Enlarge Image)

Figure 8. Risk of bias graph for case-control studies. – = high risk of bias; + = low risk of bias.

<blockquote></blockquote>
Figure 8.

Risk of bias graph for case-control studies. – = high risk of bias; + = low risk of bias.

(Enlarge Image)

Figure 9. Risk of bias graph for cohort studies. – = high risk of bias; + = low risk of bias.

Discussion

In this meta-analysis, we found no clear support for an overall
association between multivitamin intake and breast cancer risk. We also
found no discrepancies between the summary results of 4 cohort studies
and 3 case-control studies for the association between multivitamin use
and increased or decreased risk of breast cancer. In the meta-analyses
of duration of use for 10 years or more or 3 years or more, or frequency
of 7 or more tablets/week, the overall association between multivitamin
intake and the risk of breast cancer was still not significant.
We did not perform a meta-analysis on the nutrient composition of
multivitamins because no relative risk was available in studies
retrieved in this study. However, most multivitamins contain folic acid,
vitamin B, vitamin C, vitamin E, calcium, magnesium, and zinc
supplements; the determination of whether these supplements are
associated with breast cancer is controversial. Two cohort studies
retrieved in this systematic review reported that vitamin C, vitamin E,
vitamin B
₆
, calcium, magnesium, and zinc supplements were not associated with total breast cancer risk,^[5,20]
but 1 case-control study reported that modest risk reduction was
observed among vitamin B supplement users with low dietary intake of
that vitamin.^[22]
However, in this same study, vitamin B supplement use was adversely
associated with breast cancer risk among patients with a high dietary
vitamin B intake, with a significant dose-response effect. Regarding
folic acid in multivitamins, the findings were inconsistent; 1 cohort
study reported that high folate intake for women who consumed 1272 or
more dietary folate equivalents/day of total folate for more than 10
years had a 22% lower risk of breast cancer.^[20]
Furthermore, the Malmö study reported a statistically significant 44%
lower risk among Swedish women who took a median dose of 456 µg/day than
those taking a median dose of 160 µg/day.^[34] In contrast, folic acid and vitamin B
₁₂
supplementation was associated with a
21% increased risk of cancer, a 38% increased risk for dying from the
disease, and an 18% increase in death from all causes.^[35] The concern regarding the adverse effects of folic acid on recurrences and metastases has therefore been raised.^[36]
However, this concern is likely to be resolved by a meta-analysis
conducted by Larsson et al. showing no clear evidence to support the
overall relationship between folate intake or folate blood levels and an
increased or decreased risk of breast cancer.^[13]

Our findings have some limitations. The potential bias may be
inherent in the original studies, as shown in Figures 7 and 8. First,
most of the study designs were based on a self-administered
questionnaire given to patients that solicited information on
multivitamin use; an overestimation or underestimation of breast cancer
risk is inevitable because of recall or interviewer bias. Second, most
studies reported an adjusted variation of duration or frequency of use
(≥10 y or ≥3 y), but no studies retrieved in this review reported the
influence of all other prognostic factors (eg, tumor size, alcohol
consumption, smoking status, BMI, tumor hormone status, postmenopausal
hormone intake) and the composition of multivitamins on increased or
decreased risk of breast cancer. A selective reporting bias is likely to
exist between the studies. Third, inadequate control for confounding
factors that could result from the included studies cannot be solved in a
meta-analysis. This may bias the results, with either an overestimation
or underestimation of risk estimates. Fourth, although the possibility
of publication bias caused by the source of funding sponsored by the
pharmaceutical manufacturer may be ruled out in this meta-analysis
because all retrieved studies did disclose the source of funding and all
funding was granted by the National Institutes of Health, publication
bias that can arise from the tendency for researchers and editors to
handle the reporting of experimental results that are positive (ie, they
show a significant finding) differently from results that are negative
(ie, supporting the null hypothesis) or inconclusive may not be ruled
out.^[37] Based on the GRADE method,^[38]
the quality of individual studies was low, which may influence the
results from meta-analyses in a direction that is difficult to
determine. Until further studies assist in clarifying the association
between multivitamin use and increased or decreased risk of breast
cancer, health-care professionals should open discussions with their
patients regarding multivitamin use and risk of breast cancer.^[38]

In conclusion, the findings from this meta-analysis indicate that
multivitamin use is likely not associated with a significant increased
or decreased risk of breast cancer. These results highlight the need for
more case-control studies or randomized, controlled, clinical trials to
examine whether there is an association between multivitamin
supplements and increased or decreased risk of breast cancer.

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