![Combined estimate of relative risk (RR) and 95 % confidence intervals (CIs) of breast cancer associated with statin use based on 24 studies {in figure, studies like Lovastatin study groups [12] (RR = 1.15, 95 % CI = 0.37, 3.55), Blais et al. [10] (RR = 0.67, 95 % CI = 0.33, 1.38) and Eaton et al. [27] (RR = 1.30, 95 % CI = 0.70, 2.50) were excluded due to their large CIs and no effect on the final combined estimated RR} comprising 265,482 statin users and 76,759 incident breast cancer cases. Squares indicate RR in each study. The square size is proportional to the weight of the corresponding study in the meta-analysis; the length of horizontal lines represents the 95 % CI. The unshaded diamond indicates the combined RR and 95 % CI (random-effects model)](https://www.researchgate.net/profile/Krishna-Undela/publication/236894684/figure/fig2/AS:393206186430471@1470759068674/Combined-estimate-of-relative-risk-RR-and-95-confidence-intervals-CIs-of-breast_Q320.jpg)
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EPIDEMIOLOGY
Statin use and risk of breast cancer: a meta-analysis
of observational studies
Krishna Undela •Vallakatla Srikanth •
Dipika Bansal
Received: 13 February 2012 / Accepted: 25 June 2012 / Published online: 18 July 2012
ÓSpringer Science+Business Media, LLC. 2012
Abstract Emerging evidence suggests that statins’ may
decrease the risk of cancers. However, available evidence
on breast cancer is conflicting. We, therefore, examined the
association between statin use and risk of breast cancer by
conducting a detailed meta-analysis of all observational
studies published regarding this subject. PubMed database
and bibliographies of retrieved articles were searched for
epidemiological studies published up to January 2012,
investigating the relationship between statin use and breast
cancer. Before meta-analysis, the studies were evaluated
for publication bias and heterogeneity. Combined relative
risk (RR) and 95 % confidence interval (CI) were calcu-
lated using a random-effects model (DerSimonian and
Laird method). Subgroup analyses, sensitivity analysis, and
cumulative meta-analysis were also performed. A total of
24 (13 cohort and 11 case–control) studies involving more
than 2.4 million participants, including 76,759 breast can-
cer cases contributed to this analysis. We found no evi-
dence of publication bias and evidence of heterogeneity
among the studies. Statin use and long-term statin use did
not significantly affect breast cancer risk (RR =0.99,
95 % CI =0.94, 1.04 and RR =1.03, 95 % CI =0.96,
1.11, respectively). When the analysis was stratified into
subgroups, there was no evidence that study design sub-
stantially influenced the effect estimate. Sensitivity analy-
sis confirmed the stability of our results. Cumulative meta-
analysis showed a change in trend of reporting risk of
breast cancer from positive to negative in statin users
between 1993 and 2011. Our meta-analysis findings do not
support the hypothesis that statins’ have a protective effect
against breast cancer. More randomized clinical trials and
observational studies are needed to confirm this association
with underlying biological mechanisms in the future.
Keywords Statin Breast cancer Meta-analysis
Introduction
Breast cancer is by far the most common cancer diagnosed in
women (ranking second in both sexes combined) and the
most common cause of death in women (ranking fifth in both
sexes combined) worldwide [1]. An estimated 1.38 million
women across the world were diagnosed with breast cancer
in 2008, accounting for nearly 23 % of the total cancer cases
and 14 % of the cancer deaths in women [2]. Breast cancer is
now also the leading cause of cancer death among females in
economically developing countries, a shift from the previous
decade during which the most common cause of cancer
death was cervical cancer [2].
Statins’ (3-hydroxy-3-methyl glutaryl-coenzyme A
reductase inhibitors), a therapeutic class of drugs that
reduce plasma cholesterol levels, are used to manage and
prevent coronary heart disease. As such, statins’ are among
the most commonly prescribed drugs worldwide [3].
Recent experimental [4,5] and clinical evidence [6,7]
suggests an additional chemopreventive potential of stat-
ins’. However, there is an inconsistency in the reporting
risk of breast cancer in statin users. Some randomized
clinical trials (RCTs) of statin use in coronary heart dis-
ease, [8,9] report some levels of incidence of breast can-
cer, but most results were ambiguous because of
inadequate power. Moreover, the results from observa-
tional studies published on the association between statin
K. Undela (&)V. Srikanth D. Bansal
Department of Pharmacy Practice, National Institute
of Pharmaceutical Education and Research, SAS Nagar,
Punjab, India
e-mail: krishna.niperian10@gmail.com
123
Breast Cancer Res Treat (2012) 135:261–269
DOI 10.1007/s10549-012-2154-x
use and risk of breast cancer were conflicting, while some
studies reported reduced risk [10,11], others described an
increased risk [12–16] and one study have not identified
any effect [17].
This issue was discussed in a meta-analysis done by
Bonovas et al. [18] using seven RCTs and nine observa-
tional studies published between 1993 and 2005, and
concluded, for no association between statin use and breast
cancer. Recently published observational studies after 2005
have shown contrasting results, including decreased risk
[19–23], increased risk [24–28], and some also reported no
probable association [29–34], which raised the interest of
adding new evidence to the previous analysis. In this meta-
analysis, we examined statin use in relation to breast can-
cer, using epidemiological studies published until January
2012. The strength of the present analysis lies in the
inclusion of 24 observational studies that reported data of
more than 2.4 million participants, including 76,759 breast
cancer cases. Inclusion of additional studies to the previous
analysis has enabled us to perform subgroup analyses,
analyzing various risk factors involved in breast cancer and
statin use. In this meta-analysis, we also analyzed the risk
of breast cancer in long-term statin users and the risk of
breast cancer recurrence in statin users, which are not
discussed in the previous meta-analysis.
Materials and methods
Search strategy
A comprehensive literature search was carried out in
PubMed database. Search terms included: ‘‘HMG-CoA
reductase inhibitor(s)’’ or ‘‘statin(s)’’ or ‘‘lipid-lowering
agent(s)’’ and ‘‘cancer(s)’’ or ‘‘neoplasm(s)’’ or ‘‘malig-
nancy(ies)’’ with limits; Date (January 1966 through Jan-
uary 2012), Humans and English. The title and abstract of
studies were reviewed to exclude irrelevant studies. The
full texts of remaining articles were read to extract infor-
mation on the topic of interest. Bibliographies and citation
sections of retrieved articles were also reviewed for addi-
tional pertinent studies. Abstracts of research presented at
related conferences [American Society of Clinical Oncol-
ogy (ASCO) and American Association for Cancer
Research (AACR)] were also searched.
Selection criteria
The studies considered in this meta-analysis were all
observational (cohort or case–control) studies that evalu-
ated exposure to statins’ and risk of breast cancer. We
included all articles irrespective of publication length; that
is we did not exclude articles published as short reports or
conference abstracts, even though the critical appraisal of
such publications is limited. Articles were excluded from
the analysis if they had insufficient published data for
determining an estimate of relative risk (RR) and confi-
dence interval (CI). When there were multiple publications
from the same population, only data from the most-recent
report were included in the meta-analysis and remaining
were excluded [35,36]. Studies reporting different mea-
sures of RR like risk ratio, rate ratio, hazard ratio (HR), and
odds ratio (OR) were included in the meta-analysis. In
practice, these measures of effect yield a similar estimate
of RR, since the absolute risk of breast cancer is low.
Data extraction and quality assessment
Two investigators (K.U. and V.S.) independently reviewed
the primary studies to assess the appropriateness for
inclusion in the present meta-analysis and data were
extracted. The following information was assayed from
each study: (i) first author’s last name, year of publication,
and country of the population studied; (ii) study design;
(iii) number of female subjects and number of breast cancer
cases; (iv) RR estimates and 95 % CIs; (v) definition of
statin exposure and breast cancer assessment; (vi) control
for potential confounding factors by matching or adjust-
ments, if applicable. We extracted the RR estimates that
reflected the greatest degree of control for potential con-
founding factors.
Statistical analysis
Publication bias was assessed using Begg and Mazumdar
adjusted rank correlation test and the Egger regression
asymmetry test [37,38]. To assess heterogeneity among
the studies, we used the Cochran Qand I
2
statistics; for the
Qstatistic, a Pvalue \0.10 was considered statistically
significant for heterogeneity; for I
2
, a value [50 % is
considered a measure of severe heterogeneity [39]. The
primary measure was combined RR of breast cancer from
individual studies, calculated using the random-effects
model (DerSimonian and Laird method), which accounts
for heterogeneity among the studies. Test for interaction
using summary estimates were performed using the method
described by Altman and Bland [40]. All analyses were
performed using STATA version 11.0 (StataCorp, College
Station, TX). All statistical tests were two-sided and
P\0.05 was considered statistically significant, unless
otherwise specified.
We first estimated the risk of breast cancer in statin
users compared to the non-users. To assess any link
between the (i) long-term statin use and breast cancer risk
and (ii) statin use and breast cancer recurrence risk, we
used the available data from previously collected studies
262 Breast Cancer Res Treat (2012) 135:261–269
123
and some new studies, which reported RR estimates for
these particular associations.
Prespecified subgroup analyses were performed accord-
ing to (i) study design (cohort and case–control), (ii) control
for confounding factors (nC8, nB7), and (iii) studies
before and after Bonovas et al. [18], to examine the impact of
these factors on the association. To test the robustness of
association, we performed a sensitivity analysis by exclud-
ing one study at a time. Cumulative meta-analysis was also
performed to identify the change in trend of reporting risk
over time. The present study was performed according to the
guidelines proposed by the Meta-analysis of Observational
Studies in Epidemiology group [41].
Results
Search results
A total of 1,547,148 citations were identified during the
initial search (Fig. 1). After review of the citations,
1,547,113 citations were found ineligible. Two studies [20,
22] published in an abstract form in ASCO were added
later to the remaining 35 studies. After detailed evaluation
of 37 potential studies, 13 studies were excluded for rea-
sons described in Fig. 1.
Study characteristics
Twenty four relevant studies (13 cohort and 11 case–con-
trol) published between 1993 and 2011were identified. A
total of 2,440,988 female subjects, including 76,759 breast
cancer cases were involved in these studies and followed
for 2–15 years.
Thirteen cohort studies of statin use and risk of breast
cancer were published between 1993 and 2011 which
included 2,042,439 participants and followed for
6–15 years. A total of 1,845 and 17,405 incidents of breast
cancer cases were reported among 251,860 statin users and
1,700,938 non-statin users, respectively. Of them, eight
studies were conducted in United States of America, four in
Europe and remaining one in USA, and Europe. Eight
studies reported RR and 5 reported HR.
Eleven case–control studies were published between
2000 and 2011. These studies included 398,549 partici-
pants and followed for 2–14 years. A total of 1,904 statin
users among 46,575 breast cancer cases, and 6,947 statin
users among 351,974 controls were reported. Of them,
eight studies were conducted in USA and three in Europe.
All case–control studies reported OR.
Of the total 24 studies, 14 are population based and 10
are hospital-based. All studies evaluated exposure to stat-
ins’ and the risk of breast cancer except for three studies
-2 studies reported on similar population
-9 outcome was not breast cancer incidence
-2 exposure was not statin use
13 studies excluded
2 abstract retrieved from ASCO
35 full text studies retrieved for detailed
evaluation
-147 not relevant based on abstract
-838,309 not relevant based on title reading
-24,409 editorials
-81,496 letters
-303,248 case reports
-88,014 clinical trials
-211,490 review articles
1,547,113 citations excluded
1,547,148 citations identified from PubMed
and reviewed
24 studies included in the meta-analysis
Fig. 1 Flowchart representing
the selection process ASCO
American society of clinical
oncology
Breast Cancer Res Treat (2012) 135:261–269 263
123
[11,19,23] that examined the use of all cholesterol-low-
ering drugs and one study [33] examined the use of only
lipophilic statins’ as a surrogate measure for statin use. All
studies were controlled for potential confounding factors
(at least for age) by matching or adjustments. The char-
acteristics of the selected studies are presented in Table 1.
Further, ten studies [17,19,21,23–25,29–31,34] were
reported RR estimates of the association between long-
term statin use and risk of breast cancer (Table 2), and two
studies [42,43] presented an examination of statin use in
relation to breast cancer recurrence (Table 3).
Main analysis
No publication bias was observed among studies using
Begg’s Pvalue (P=0.71); Egger’s (P=0.32) test and
the funnel plot had an expected funnel shape (Fig. 2).
Because of significant heterogeneity (P
heterogeneity
\0.001,
Table 1 Studies included in the meta-analysis
Author, year
a
(country)
b
Study period
(years)
All female
subjects
BC cases Description
of exposure/
reference
e
Study quality
Definition of
statin use
Number of variables
adjusted
f
Lovastatin study groups, 1993
(US, Canada & Finland) [12]
c
NR 241 3 a Self-reported 1
Blais et al. 2000 (Canada) [10]
d
6 (1988–1994) 715 NR b NR 1, 9, 10, 13, 22
Beck et al. 2003 (Canada) [13]
c
8 (1989–1997) 67,472 879 e Database 1
Cauley et al. 2003 (US) [11]
c
15 (1986–2001) 7,528 240 d Medical records 1–4
Graaf et al. 2004 (Netherlands) [14]
d
3 (1995–1998) 9,182 NR c NR 1–3,6–9,11–13
Kaye and Jick 2004 (UK) [15]
d
12 (1990–2002) 8,091 236 d Medical records 1, 14, 15
Boudreau et al. 2004 (US) [17]
d
2 (1997–1999) 1,982 231 g Medical records 1, 5
Friis et al. 2005 (Denmark) [16]
c
13 (1989–2002) 171,937 3,141 e Database 1, 5, 28, 29
Eliassen et al. 2005 (US) [19]
c
12 (1988–2000) 75,828 1,624 d Self-reported 1, 3, 14, 17, 21, 23–25
Kochhar et al. 2005 (US) [20]
d
6 (1998–2004) 40,421 4,771 d Database 1, 11, 15, 21
Cauley et al. 2006 (US) [21]
c
11 (1993–2004) 156,351 4,383 d Medical records 1, 2, 14, 15, 17, 21, 24, 26–28
Dumasia et al 2006 (US) [22]
d
10 (1995–2005) 1,042 NR d Self-reported NR
Boudreau et al. 2007 (US) [24]
c
14 (1990–2004) 92,888 2,707 g Database 1, 3, 9, 11, 14
Setoguchi et al. 2007 (US) [29]
c
9 (1994–2003) 19991 227 d Medical records 1–3, 11, 20, 17, 29, 30
Coogan et al. 2007 (US) [25]
d
14 (1991–2005) 2,355 69 c Self-reported 1, 3, 14, 18–21
Friedman et al. 2008 (US) [30]
c
9 (1994–2003) NR 1,706 e Medical records 35
Smeeth et al. 2008 (UK) [26]
c
11 (1995–2006) 364,854 3,204 d Medical records 1–11, 22, 31, 32, 37–40
Pocobelli et al. 2008 (US) [31]
d
6 (1995–2001) 8,620 607 g Self-reported 1, 3, 14, 17, 18, 25, 27, 31, 35
Eaton et al. 2009 (US) [27]
d
3 (2005–2008) 189 NR d Self-reported 1
Haukka et al. 2010 (Finland) [32]
c
9 (1996–2005) 6,046 583 d Database 1, 33
Hippisley et al. 2010
(England & Wales) [28]
c
6 (2002–2008) 1,014,197 9,823 d Medical records NR
Woditschka et al. 2010 (US) [33]
d
10 (1997–2007) 247,348 NR d Medical records 3, 36
Jacobs et al. 2011 (US) [23]
c
10 (1997–2007) 65,106 2,489 f Self-reported 1–3, 13–15, 20, 24, 27, 34
Vinogradova et al. 2011 (UK) [34]
d
10 (1998–2008) 78,604 7,708 e Medical records 1, 2, 14, 15, 30, 37–40
NR not reported, BC breast cancer
a
Publication year,
b
country of study conducted,
c
cohort studies,
d
case–control studies
e
a, systematic use of lovastatin versus SEER data; b, any use of statins versus use of bile acid-binding resins; c, regular use of statins versus no use of
statins; d, current use of statins versus no current use of statins; e, any use of statins versus no use of statins; f, current use of cholesterol-lowering
drugs versus never use of cholesterol-lowering drugs; g, ever use of statins versus no use of statins
f
1 age, 2 use of nonsteroidal anti-inflammatory drugs, 3 use of hormones, 4 use of cardiovascular drugs, 5 use of antihypertensive drugs, 6 use of
diuretics, 7 use of angiotensin-converting enzyme inhibitors, 8 use of calcium channel blockers, 9 use of other lipid-lowering therapy, 10 use of fibric
acids, 11 diabetes mellitus, 12 prior hospitalization, 13 comorbidity score, 14 body mass index, 15 smoking, 16 body weight, 17 family history of
breast cancer, 18 education, 19 religion, 20 race, 21 alcohol consumption, 22 previous neoplasms, 23 height, 24 physical activity, 25 menopausal
status, 26 hysterectomy, 27 mammogram, 28 percentage of calories from fat, 29 health service utilization, 30 arthritis, 31 calendar year, 32 propensity
score, 33 follow-up period, 34 history of elevated cholesterol, 35 state of residence, 36 use of oral contraceptives, 37 cardiovascular disease, 38
hypertension, 39 use of Cox2-inhibitors, 40 use of aspirin
264 Breast Cancer Res Treat (2012) 135:261–269
123
I
2
=57 %) was observed, a random-effects model was
chosen over a fixed-effects model and we found that statin
use did not significantly affect the risk breast cancer
(RR =0.99, 95 % CI =0.94, 1.04). Both multivariable
adjusted RR estimates with 95 % CIs of each study and
combined RR is shown in Fig. 3.
Subgroup analyses, sensitivity analysis, and cumulative
meta-analysis
We found no association between statin use and risk of
breast cancer among cohort studies (RR =1.01, 95 %
CI =0.98, 1.04) as well as case–control studies
(RR =0.95, 95 % CI =0.84, 1.08), presented in Table 4.
When we examined if thorough adjustment of potential
confounders could affect the combined RR and degree of
heterogeneity, it was observed that studies with higher
control for potential confounders (nC8) as well as studies
with lower control (nB7) presented no association
(RR =0.99, 95 % CI =0.94, 1.04 and RR =0.99, 95 %
CI =0.92, 1.06, respectively). The combined RR for the
studies published in the same time frame included in Bo-
novas et al. [18] was 1.06 (95 % CI =0.95, 1.18) and
studies published after Bonovas et al. was 0.98 (95 %
CI =0.93, 1.03) presented no association between statin
use and breast cancer. Test for interaction showed non-
significant results for subgroups of study design, adjust-
ment for confounders and time frame of Bonovas et al.
analysis; (P
interaction
=0.35, 1.00 and 0.20, respectively)
(Table 4).
To test the robustness of our findings, we also carried
out a sensitivity analysis. To do this, the overall homoge-
neity and effect size were calculated by removing one
study at a time. This analysis showed no significant vari-
ation in combined RR by excluding any of the study (RR
lies between 0.98 and 1.01), confirming the stability of
present results.
A cumulative meta-analysis of total 24 studies was
carried out to evaluate the cumulative effect estimate over
time. In 1993, Lovastatin study groups reported a signifi-
cant effect estimate of 1.15. By adding an effect estimate
from one study published in 2000 [10] to the earlier, RR
Table 2 Studies evaluating the association between long-term statin
use and risk of breast cancer
Study RR 95 % CI Breast
cancer
cases
Definition of
‘‘long-term’’
statin use
Boudreau et al. [17]
a
0.70 0.40–1.00 84 [5 years
Eliassen et al. [19]
b
0.93 0.60–1.44 21 [4 years
Cauley et al. [21]
b
0.94 0.75–1.18 108 C3 years
Boudreau et al. [24]
b
1.27 0.89–1.81 57 C5 years
Setoguchi et al. [29]
b
1.28 0.90–1.84 156 C3 years
Coogan et al. [25]
a
1.5 0.7–3.2 20 C5 years
Friedman et al. [30]
b
1.02 0.86–1.21 NR [5 years
Pocobelli et al. [31]
a
0.8 0.5–1.4 62 C10 years
Jacobs et al. [23]
b
1.11 0.98–1.25 429 C5 years
Vinogradova et al. [34]
a
0.85 0.67–1.08 1768 C6 years
RR Relative risk, CI confidence interval, NR not reported
a
Case–control studies
b
Cohort studies
Table 3 Studies evaluating the association between statin use and risk of breast cancer recurrence
Author, Year
a
(Country)
b
Study period
(years)
All female
subjects
BC recurrence
cases
RR (95 % CI)
Kwan et al., 2008 (Oakland) [42]
c
6 (2000–2006) 1811 210 0.67 (0.39, 1.13)
Chae et al. 2011 (US) [43]
c
9 (1999–2008) 703 149 0.43 (0.26, 0.70)
BC Breast cancer, RR relative risk, CI confidence interval
a
Publication year
b
Country of study conducted
c
Cohort studies
Standard error
0.0
0.2
0.4
0.6
2-2
0.8
-1 0 1
Relative risk (lo
g
arithmic scale)
Fig. 2 Funnel plot (publication bias assessment plot) of the relative
risk of developing breast cancer, by the standard error, for all studies.
Circles studies included in the meta-analysis. Relative risks are
displayed on a logarithmic scale. P=0.71 for the Begg’s test, and
P=0.32 for the Egger’s test
Breast Cancer Res Treat (2012) 135:261–269 265
123
reached to 0.78. By adding another effect estimate from the
study published in 2003 [13] to the previous cumulative
estimate, RR reached to 1.07. By adding another 21 studies
published between 2003 and 2011, the overall effect esti-
mate of 0.99 was obtained.
Results for long-term statin use
The calculated combined RR for breast cancer in long-term
statin use was found to be 1.03 (95 % CI =0.96, 1.11)
(Table 4). However, there was high evidence of no heter-
ogeneity among these studies (P
heterogeneity
=0.21,
I
2
=26 %). Stratification by study design showed that the
association was neutral in cohort studies (RR =1.07, 95 %
CI =0.99, 1.17) and non-significant inverse association in
case–control studies (RR =0.84, 95 % CI =0.70, 1.02)
with P
interaction
being 0.02.
Results for recurrence of breast cancer in statin users
The calculated combined RR of two studies for breast
cancer recurrence in statin users was found to be 0.53
(95 % CI =0.37, 0.76) with no heterogeneity among the
studies (P
heterogeneity
=0.23) (Table 4).
Discussion
In the past decade, the role of statins’ in the development of
breast cancer has been increasingly understood. With the
present updated combined analysis of 24 observational
studies currently available, it is obvious that there is no
reduction in breast cancer risk among statin users as
compared to non-users and this association remained stable
even after the sensitivity analysis. Our results do not sup-
port the hypothesis that long-term statin use may reduce the
risk of breast cancer incidence. Overall, when compared to
non-users of statins’, we found no significant difference in
breast cancer risk among ever users, current users and even
in those taking hydrophobic statins’. However, an inverse
association was observed that is a 47 % reduction in risk of
breast cancer recurrence in statin users compared to non-
users. There was significant heterogeneity among studies in
the overall analysis except among the studies adjusted for
Study, Year RR (95% CI)
0.01
Combined estimate (n = 21)
Vinogradova et al., 2011
0.1 0.2 0.5 1
Relative risk (95% confidence interval)
2
0.99 (0.94, 1.04)
1.00 (0.93, 1.08)
0.98 (0.88, 1.10)
1.02 (0.97, 1.08)
1.04 (0.98, 1.11)
1.01 (0.96, 1.06)
1.00 (0.80, 1.20)
1.17 (0.95, 1.43)
0.99 (0.92, 1.06)
1.20 (0.80, 1.80)
0.99 (0.74, 1.33)
1.07 (0.88, 1.29)
Beck et al., 2003 1.09 (0.93, 1.28)
Cauley et al., 2003 0.28 (0.09, 0.86)
1.07 (0.65, 1.74)Graaf et al., 2004
1.30 (1.00, 1.90)Kaye and Jick, 2004
1.00 (0.70, 1.20)Boudreau et al., 2004
1.02 (0.76, 1.36)Friis et al., 2005
Eliassen et al., 2005 0.91 (0.76, 1.08)
0.49 (0.38, 0.62)Kochher et al., 2005
Cauley et al., 2006 0.91 (0.80, 1.05)
0.78 (0.47, 1.31)Dumasia et al., 2006
Boudreau et al., 2007
Setoguchi et al., 2007
Coogan et al., 2007
Friedman et al., 2008
Smeeth et al., 2008
Pocobelli et al., 2008
Haukka et al., 2010
Hippisley et al., 2010
Woditschka et al., 2010
Jacobs et al., 2011
Fig. 3 Combined estimate of
relative risk (RR) and 95 %
confidence intervals (CIs) of
breast cancer associated with
statin use based on 24 studies
{in figure, studies like
Lovastatin study groups [12]
(RR =1.15, 95 % CI =0.37,
3.55), Blais et al. [10]
(RR =0.67, 95 % CI =0.33,
1.38) and Eaton et al. [27]
(RR =1.30, 95 % CI =0.70,
2.50) were excluded due to their
large CIs and no effect on the
final combined estimated RR}
comprising 265,482 statin users
and 76,759 incident breast
cancer cases. Squares indicate
RR in each study. The square
size is proportional to the
weight of the corresponding
study in the meta-analysis; the
length of horizontal lines
represents the 95 % CI. The
unshaded diamond indicates the
combined RR and 95 % CI
(random-effects model)
266 Breast Cancer Res Treat (2012) 135:261–269
123
nC8 confounders, subgroup of cohort, published before
Bonovas et al. [18] analysis as well as in studies repre-
senting long-term statin use and recurrence of breast
cancer.
In our subgroup analyses, the results were not substan-
tially affected by study design, confounder adjustment and
studies in the time frame of Bonovas et al. [18] and
afterward. Cohort and case–control studies alone showed
no association between statin use and risk of breast cancer.
There is no deviation in the association by remaining
subgroup analyses of studies like thorough adjustment
(nC8) of confounders, adjusted for B7 confounders,
covered in Bonovas et al. and after Bonovas et al. The test
of interaction was not statistically significant in any of
these subgroup analyses but was significant among sub-
groups representing long-term statin use. Cumulative meta-
analysis showed a change in trend of reporting risk of
breast cancer from positive to negative in statin users
between 1993 and 2011.
Although we found no association between statin use
and breast cancer risk, it remains plausible that statins’
reduce breast cancer risk. The mechanistic data are rela-
tively strong and suggest that statins’ inhibit cancer cell
growth and lead to apoptotic cell death through their
inhibition of the mevalonate pathway, although other
mechanisms have also been suggested [44]. Many products
of the mevalonate pathway are necessary for critical cel-
lular functions such as membrane integrity, cell signaling,
protein synthesis, and cell cycle progression. Disruption of
these processes in neoplastic cells by statins’ may result in
control of tumor initiation, growth, and metastasis [45].
In a review of rodent carcinogenicity tests [46], it was
reported that lipid-lowering drugs, including statins’, ini-
tiate or promote cancer in rats and mice. In contrast, sev-
eral recent laboratory studies indicated that statins’ may
have chemopreventive potential against cancer at various
sites, including breast. However, the inhibitory effect of
statins’ on breast cancer cells has thus far been tested only
in vitro and may behave differently in vivo. Specifically,
statins’ are selectively localized to the liver, and less than
5 % of a given dose reaches the systemic circulation.
Thereby, the usefulness of statins’ as chemopreventive
agents for breast cancer is doubted given their selective
hepatic uptake and low systemic availability [47,48].
The strength of the present analysis lies in inclusion of
24 observational studies, reporting data of more than 2.4
million participants, including 76,759 breast cancer cases.
Our meta-analysis has several limitations. First, we did
not search for unpublished studies or for original data.
Second, the included studies were different in terms of
Table 4 Overall effect estimates for breast cancer and statin use according to study characteristics
No. of studies Pooled estimate Tests of heterogeneity P
interaction
Tests of publication
bias
RR 95 % CI Qvalue (d.f.)
b
Pvalue I
2
(%)
c
Begg’s P
f
Egger’s P
f
All studies 24 0.99 0.94–1.04 52.83 (23) \0.001 57 0.71 0.32
Study design 0.35
Cohort 13 1.01 0.98–1.04 13.29 (12) 0.35
d
10
d
0.77 0.45
Case–control 11 0.95 0.84–1.08 39.29 (10) \0.001 75 0.36 0.54
Adjusted for confounders 1.00
nC8 confounders 8 0.99 0.94–1.04 5.10 (7) 0.65
d
0
d
0.55 0.77
nB7 confounders 16 0.99 0.92–1.06 46.99 (15) \0.001 68 0.35 0.37
Bonovas et al. [18] analysis 0.20
Before 8 1.06 0.95–1.18 8.86 (7) 0.26
d
21
d
0.40 0.15
After 16 0.98 0.93–1.03 43.04 (15) \0.001 65 0.76 0.32
Results for long-term statin use 10 1.03 0.96–1.11 12.14 (9) 0.21
d
26
d
0.02
e
0.29 0.56
Cohort studies 6 1.07 0.99–1.17 4.16 (5) 0.53
d
0
d
0.72 0.93
Case–control studies 4 0.84 0.70–1.02 2.89 (3) 0.41
d
0
d
0.75 0.63
Results for recurrence of BC 2 0.53 0.37–0.76
a
1.43 (1) 0.23
d
0––
RR Relative risk, CI confidence interval, d.f. degree of freedom
a
Statistically significant for inverse association between statin use and breast cancer recurrence
b
As tested by Cochran’s Qtest
c
As tested by I
2
statistic
d
Statistically significant for homogeneity (pooled effect estimates from ‘‘fixed-effects model’’, remaining from ‘‘random-effects model’’)
e
Test of interaction was statistically significant
f
Statistically significant for no publication bias
Breast Cancer Res Treat (2012) 135:261–269 267
123
study design and definitions of drug exposure. Finally, our
analysis was restricted to the articles in the English lan-
guage, which may have somewhat biased the results.
In conclusion, the findings of this meta-analysis, using
observational studies do not support the hypothesis that
statins’ use reduced the risk of breast cancer. However, we
cannot rule out a reduction in risk of breast cancer recur-
rence in statin users. More RCTs and observational studies
were needed to confirm this association with underlying
biological mechanisms in the future.
Acknowledgments The authors thank Dr. Dimple Kondal, Senior
scientist (Biostatistician), Centre for excellence, Public Health
Foundation, India, for helping with the data analysis and Ms. Sahaja
Banda for checking the accuracy of English usage.
Conflict of interest No potential conflicts of interest relevant to this
article were reported. No funding was provided for the analysis.
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