Int. J.
Cancer: 121, 856–862 (2007)
' 2007 Wiley-Liss, Inc.
Diabetes mellitus and risk of breast cancer: A meta-analysis
Susanna C. Larsson1*, Christos S. Mantzoros2 and Alicja Wolk1
1
Division of Nutritional Epidemiology, The National Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden
2
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Diabetes mellitus has been associated with an increased risk of sev-
eral types of cancers, but its relationship with breast cancer
remains unclear. We conducted a meta-analysis of case–control and
cohort studies to assess the evidence regarding the association
between diabetes and risk of breast cancer. Studies were identified
by searching MEDLINE (1966–February 2007) and the references
of retrieved articles. We identified 20 studies (5 case–control and 15
cohort studies) that reported relative risk (RR) estimates (odds ra-
tio, rate ratio/hazard ratio, or standardized incidence ratio) with
95% confidence intervals (CIs) for the relation between diabetes
(largely Type II diabetes) and breast cancer incidence. Summary
RRs were calculated using a random-effects model. Analysis of all
20 studies showed that women with (versus without) diabetes had a
statistically significant 20% increased risk of breast cancer (RR,
1.20; 95% CI, 1.12–1.28). The summary estimates were similar for
case–control studies (RR, 1.18; 95% CI, 1.05–1.32) and cohort stud-
ies (RR, 1.20; 95% CI, 1.11–1.30). Meta-analysis of 5 cohort studies
on diabetes and mortality from breast cancer yielded a summary
RR of 1.24 (95% CI, 0.95–1.62) for women with (versus without) di-
abetes. Findings from this meta-analysis indicate that diabetes is
associated with an increased risk of breast cancer.
' 2007 Wiley-Liss, Inc.
Key words: breast cancer; epidemiology; diabetes; meta-analysis;
systematic review
Diabetes mellitus is a serious and growing health problem world-
wide.1 Type 2 diabetes accounts for 90–95% of all diagnosed cases
of diabetes2 and is characterized by insulin resistance and hyperinsu-
linemia in the early phases of the disease.3 It has been hypothesized
that hyperinsulinemia may increase the risk of breast cancer through
direct effects on breast tissue or indirectly by increasing circulating
concentrations of estrogens, testosterone and insulin-like growth fac-
tors.4,5 Thus, Type 2 diabetes may confer an excess risk of breast
cancer. Diabetes has been related to an elevated risk of several can-
cers. Meta-analyses have indicated that diabetes is associated with a
1.2-fold increased risk of bladder cancer,6 1.3-fold increased risk of
colorectal cancer,7 1.7-fold increased risk of pancreatic cancer8 and
2.5-fold increased risk of hepatocellular carcinoma.9 Wolf et al.
combined the results of 4 case–control and 6 cohort studies and
found that diabetes was associated with a 13 and 25% increased risk
of breast cancer in case–control and cohort studies, respectively.10
The purpose of the present study was to summarize all available
evidence from case–control and cohort studies on the relationship
between diabetes and breast cancer incidence and mortality fol-
lowing the meta-analysis of observational studies in epidemiology
(MOOSE) guidelines for meta-analyses of observational studies.11
This meta-analysis includes a total of 23 studies, thus providing
more precise risk estimates than the previous analysis by Wolf
et al.10 that was based on only 10 studies. In this study, we also
examined whether the association between diabetes and breast
cancer incidence differs according to various study characteristics
and menopausal status.
Material and methods
Search strategy
We searched the MEDLINE database (from 1966 to February
2007) using the search terms diabetes and breast cancer or breast
Publication of the International Union Against Cancer
neoplasm. We also reviewed the reference lists of retrieved
articles to search for more studies. No language restrictions were
imposed.
Inclusion and exclusion criteria
Studies were eligible for inclusion in the meta-analysis if they
met the following criteria: (i) had a case–control or prospective
study design; (ii) the exposure of interest was diabetes mellitus;
(iii) the outcome was breast cancer incidence or mortality; and (iv)
reported relative risk estimates with 95% confidence intervals
(CIs) or provided sufficient information to calculate them. Studies
of Type 1 diabetes, defined as diagnosis before age 30, were not
included. To avoid violating independent assumptions, studies
were included only once. We therefore decided, a priori, on the
following hierarchy: when there were multiple publications from
the same study population, the study that controlled for the most
appropriate confounders were included; otherwise, the study that
had the largest number of case subjects was used.
Data extraction
The following information was extracted from each study: first
author’s last name, the year of publication, study design, control
source (in case–control studies), study location, age of subjects,
sample size (cases and controls or cohort size), diabetes assess-
ment (self-report, blood glucose, hospitalized diabetic patients),
adjustment factors and relative risk estimates with 95% CIs for
breast cancer associated with diabetes. From each study, we
extracted the relative risk estimate that was adjusted for the great-
est number of potential confounders.
Statistical analysis
We included in this meta-analysis studies reporting different
measures of relative risk (RR): case–control studies (odds ratio),
prospective cohort studies (rate ratio/hazard ratio) and cohort stud-
ies of hospitalized diabetic patients with an external population
comparison group (standardized incidence/mortality ratio).
Because the absolute risk of breast cancer is low, the 3 measures
of association yield similar estimates of relative risk; we present
all results as relative risk for simplicity. Studies of breast cancer
incidence and breast cancer mortality were analyzed separately.
Summary relative risks with 95% CIs were calculated with the
method of DerSimonian and Laird by use of the assumptions of a
random effects model, which considers both within-study and
between-study variation.12 We examined statistical heterogeneity
in results across studies using the Q test (p < 0.1 was considered
representative of statistically significant heterogeneity) and the I2
statistic.13 I2 is the proportion of total variation contributed by
Grant sponsor: The Swedish Cancer Society.
*Correspondence to: Division of Nutritional Epidemiology, The
National Institute of Environmental Medicine, Karolinska Institutet, Box
210, SE-171 77 Stockholm, Sweden. Fax: 146-8-304571.
E-mail: susanna.larsson@ki.se
Received 3 January 2007; Accepted after revision 26 February 2007
DOI 10.1002/ijc.22717
Published online 30 March 2007 in Wiley InterScience (www.interscience.
wiley.com).
 TABLE I – CHARACTERISTICS OF CASE–CONTROL AND COHORT STUDIES OF DIABETES AND INCIDENCE OF BREAST CANCER1
Years of No. of Controls or Diabetes assessment Breast cancer 2
Study and country Age, year ascertainment Adjusted RR (95% CI) Adjustments
follow-up cases cohort size (age at diagnosis)

Case–control studies
O’Mara et al., 198515; 30–89 – 1883 2420 (H)3 Self-report (29 years) Medical records 1.2 (0.9–1.6)4 Age
United States
Franceschi et al., 199016; Italy 25–74 – 2663 2344 (H) Self-report (all ages) Medical records 1.0 (0.8–1.3) Age, study area, education,
age at first birth,
menopausal status, BMI
Talamini et al., 199718; Italy 23–74 – 2569 2588 (H) Self-report (all ages) Medical records 1.4 (1.0–1.8) Age, study area, education,
parity, menopausal status, BMI
19
Weiss et al., 1999 ; United States 20–54 – 2158 1980 (P) Self-report (30 years) Cancer registries 1.13 (0.70–1.90) Age, race, previous breast biopsy,
family history, parity, age
at first birth,
menopausal status, BMI, alcohol
Baron et al., 200120; United States 50–75 – 5101 5430 (P) Self-report (35 years) State-wide 1.2 (1.0–1.4) Age, state, family history,
tumor registries parity, age at first birth,
menopausal status, age
at menopause, OC use,
PMH use, BMI, alcohol
Cohort studies
de Waard and 55–75 8.1 70 7259 Self-report (all ages) Medical records 1.5 (0.6–3.3)5 Age
Baanders-van Halewijn,
197421; Netherlands
Raggozzino et al., 198222; NA 25 14 1135 Blood glucose levels Medical records 1.3 (0.7–2.2)5 Age
United States
Sellers et al., 199424; 55–69 5 611 41 837 Self-report (30 years) State Health 0.96 (0.68–1.36) Age
United States Registry of Iowa
Steenland et al., 199525; 25–74 7.7 163 NA Self-report (all ages) Medical records 1.40 (0.70–2.78) Age, income, menopausal status,
United States smoking, BMI, physical
activity, alcohol
Goodman et al., 199726; Japan NA 8.3 161 22 200 Self-report (all ages) Cancer registry 2.06 (1.27–3.34) Age, city, age at the
time of the bombings,
radiation dose
Weiderpass et al., 199727; Sweden 40 24 1145 70 110 Discharge diagnosis Cancer registry 1.3 (1.2–1.4) Age, calendar year
(hospitalized DM patients;
40 years)
Hjalgrim et al., 199728; Denmark 30 20 7 402 Hospitalized DM Cancer registry 0.72 (0.29–1.48) Age, calendar year
DIABETES MELLITUS AND RISK OF BREAST CANCER

patients (30 years)

29
Wideroff et al., 1997 ; Denmark 50 17 493 109 581 Discharge diagnosis Cancer registry 1.2 (1.1–1.2) Age, calendar year
(hospitalized DM patients;
50 years)
Mink et al., 200230; United States 45–64 7.1 187 7894 Self-report (all ages) Cancer registry 1.39 (0.86–2.23) Age, race, study center,
and medical records family history, age at menarche,
age at first birth, age
at menopause, smoking,
BMI, alcohol
Michels et al., 200331; United States 30–55 22 5605 116 488 Self-report (30 years) Self-report, 1.17 (1.01–1.35) Age, family history, history
verified by medical of benign breast disease,
records and age at menarche, parity,
pathology reports age at first birth, menopausal status,
age at menopause, PMH use,
height, BMI, physical
activity, alcohol
857
858 LARSSON ET AL.

between-study variation.13 To assess for publication bias, we con-

BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; NA, information not available; OC, oral contraceptive; PMH, postmenopausal hormone; RR, relative risk.–2The measure
of relative risk is an odds ratio (case–control studies),15,16,18–20 rate ratio/hazard ratio,24–26,30,31,33–36 or a standardized incidence ratio.21,22,27–29,32–3Type of controls in parentheses (H 5 hospital-
based; P 5 population-based).–4The confidence interval was estimated based on data provided in the article.–5The relative risk (and its 95% confidence interval) was calculated from observed and
Age, smoking, BMI, drinking

of cardiovascular disease,
structed a funnel plot, and applied regression methods to deter-

smoking, BMI, physical

mine funnel plot asymmetry as suggested by Egger et al.14 We

Age, study area, history

country of residence
Age, smoking, alcohol
Adjustments performed subgroup analyses and used meta-regression models to
Age, calendar year,

activity, alcohol,
evaluate potential sources of heterogeneity. Study characteristics

dietary factors
examined included study design, diabetes assessment, geographic
region, publication year, and adjustment for body mass index,

Age, income
physical activity and alcohol consumption. We also conducted
analyses stratified by menopausal status. All statistical analyses
were carried out with Stata, version 9.0 (StataCorp, College Sta-
tion, TX).
TABLE I – CHARACTERISTICS OF CASE–CONTROL AND COHORT STUDIES OF DIABETES AND INCIDENCE OF BREAST CANCER1 (CONTINUED)

Adjusted RR (95% CI)

0.87 (0.62–1.17)

1.51 (1.26–1.80)

1.27 (0.51–3.14)
1.08 (1.01–1.16)

0.83 (0.44–1.57)

Results
Breast cancer incidence
2

We identified 6 case–control studies15–20 and 16 cohort stud-

ies21–36 that presented results on diabetes and breast cancer inci-
dence. Two studies (1 case–control17 and 1 cohort23) were
excluded because of duplicate publications from the same study
population. Of the 20 eligible studies, 9 were from North America,
Breast cancer ascertainment

7 from Europe and 4 from Asia (Table I).

and medial records

Of the 20 studies, 15 found an increased risk of breast cancer in

women with diabetes, and in 8 studies the relationship was statisti-
Cancer registry

Cancer registry

Cancer registry
Cancer registry

Cancer registry

cally significant (Fig. 1). In analysis of all studies, the summary

relative risk of breast cancer was 1.20 (95% CI, 1.12–1.28) for
women with diabetes compared with women with no diabetes.
There was statistically significant heterogeneity among studies (Q
5 36.53, p 5 0.01, I2 5 48.0%). Three studies, all based on a dis-
charge diagnosis of diabetes,27,29,35 contributed significantly to the
DM patients (30–49 years)0000

summary estimate. In a sensitivity analysis excluding these 3 stud-

(hospitalized DM patients)

ies, the summary relative risk remained unchanged but the CI

Hospitalized insulin-treated

slightly widened (RR, 1.20; 95% CI, 1.09–1.33) and heterogeneity

Diabetes assessment

among studies was reduced (Q 5 23.60, p 5 0.10, I2 5 32.2%).

(age at diagnosis)

and medication use

Blood glucose levels

Stratification by study design showed that diabetes was associated

Self-report (all ages)

Self-report (all ages)

Discharge diagnosis

with a statistically significant 18 and 20% increased risk of breast

cancer in case–control and cohort studies, respectively (Fig. 1 and
Table II). The relation between diabetes and breast cancer was
similar in population-based case–control studies and hospital-
based case–control studies (Table II).
To examine whether differences in diabetes assessment
accounted for the heterogeneity in results, we stratified studies by
diabetes assessment. Summary estimates were similar for studies
Controls or
cohort size

468 615

33 503
465 510

51 223
5066

where diabetes was defined based on self-report, blood glucose

levels or a discharge diagnosis (patients with diabetes); there was
no statistically significant heterogeneity only among studies based
on self-reported diabetes (Table II). Stratifying study results by
control for potential confounders, we found that there was no sta-
451
1139
6107
41
No. of
cases

NA

tistical significant heterogeneity within strata of studies that

adjusted for body mass index, physical activity, alcohol intake or
use of postmenopausal hormones (Table II). In meta-regression
follow-up

analysis, the association between diabetes and breast cancer varied

Years of

30

10

14
9
8

statistically significantly by geographic region (stronger associa-

tion in Asia than in North America; p 5 0.02), but not by study
expected number of cases reported in the article.

design, diabetes assessment, publication year or control for poten-

tial confounders.
Age, year

30–49

30–95

40–79
55–79

40–69

Three studies provided results stratified by menopausal

status,16,18,31 and 5 studies included only or predominantly post-
menopausal women.20,21,24,29,35 In stratified analysis by menopau-
Inoue et al., 200636; Japan
Khan et al., 2006 ; Japan

sal status, diabetes was associated with an increased risk of breast

Lipscombe et al., 200635;
Swerdlow et al., 200532;

Jee et al., 200533; Korea

cancer in postmenopausal women but not in premenopausal

women (Table II). The difference in summary relative risks across
United Kingdom

34

strata of menopausal status was not statistically significant (p 5

Study and country

0.27).
There was no indication of publication bias on the funnel plot
Canada

(data not shown) or by Egger’s test (p 5 0.94).

Breast cancer mortality

We identified 5 cohort studies that reported results on diabetes
1

and mortality from breast cancer (Table III).32,33,37–39 Combining

 FIGURE 1 – Relative risks for the association between diabetes and incidence of breast cancer in case–control and cohort studies. Studies are
ordered by study design and year of publication. Squares represent study-specific relative risks (the square sizes are proportional to the weight of
each study in the summary estimate); horizontal lines represent 95% confidence intervals (CIs); diamonds represent summary relative risks with
95% CIs. Test for heterogeneity among studies: Q 5 36.53; p 5 0.01; I2 5 48.0%.

TABLE II – SUMMARY RELATIVE RISKS AND 95% CONFIDENCE INTERVALS FOR THE ASSOCIATION BETWEEN DIABETES AND BREAST CANCER
INCIDENCE BY STUDY CHARACTERISTICS
Heterogeneity tests
No. of studies RR (95% CI)
Q p I2 (%)

Study design
Case–control studies 5 1.18 (1.05–1.32) 3.16 0.53 0
Population-based 2 1.19 (1.02–1.40) 0.05 0.82 0
Hospital-based 3 1.17 (0.96–1.43) 3.06 0.22 34.7
Cohort studies 15 1.20 (1.11–1.30) 33.31 0.003 58.0
Diabetes assessment
Self-report 13 1.19 (1.09–1.29) 11.66 0.47 0
Blood glucose levels 2 1.49 (1.26–1.77) 0.25 0.62 0
Patients with diabetes 5 1.16 (1.05–1.27) 17.84 0.001 77.6
Geographic region
North America 9 1.12 (1.06–1.18) 4.37 0.82 0
Europe 7 1.19 (1.08–1.31) 12.68 0.05 52.7
Asia 4 1.45 (1.07–1.97) 5.11 0.16 41.3
Publication year
1970–1994 5 1.08 (0.93–1.26) 2.21 0.70 0
1995–1999 7 1.27 (1.16–1.38) 10.24 0.12 41.4
2000–2006 8 1.17 (1.04–1.32) 16.79 0.02 58.3
Adjustment for body mass index
No 10 1.19 (1.09–1.30) 26.47 0.002 66.0
Yes 10 1.20 (1.09–1.33) 10.06 0.35 10.5
Adjustment for physical activity
No 17 1.20 (1.12–1.29) 35.00 0.004 54.3
Yes 3 1.16 (1.01–1.33) 1.36 0.51 0
Adjustment for alcohol intake
No 13 1.17 (1.08–1.27) 27.67 0.006 56.5
Yes 7 1.26 (1.13–1.40) 7.37 0.29 18.6
Adjustment for postmenopausal hormone use
No 18 1.20 (1.11–1.30) 36.46 0.004 53.4
Yes 2 1.18 (1.06–1.32) 0.05 0.82 0
Menopausal status
Premenopausal 3 0.91 (0.62–1.34) 0.35 0.84 0
Postmenopausal 8 1.16 (1.08–1.23) 11.56 0.12 39.4
860
TABLE III – CHARACTERISTICS OF COHORT STUDIES OF DIABETES AND MORTALITY FROM BREAST CANCER1
Years of Age, No. of Cohort
Study and country size
follow-up year deaths2
Kessler, 197037; 26 NA 21 21 447
United States
Verlato et al., 200338; Italy 10 NA 28 7148
Coughlin et al., 200439; 16 30 4346 588 321
United States
Swerdlow et al., 200532; 30 30–49 17 5066
United Kingdom
Jee et al., 200533; Korea 10 30–95 NA 468 615
1
BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; NA, information not available; RR, relative risk.–2Deaths from breast
cancer.–3The measure of relative risk is a rate ratio/hazard ratio33,39 or a standardized mortality ratio.32,37,38–4The confidence interval was calcu-
lated from observed and expected number of deaths reported in the article.
the results from these studies yielded a summary relative risk of
1.24 (95% CI, 0.95–1.62) for women with (versus without) diabe-
tes. There was statistically significant heterogeneity among studies
(Q 5 20.54, p < 0.001, I2 5 80.5%). There was no evidence of
publication bias (Egger’s test: p 5 0.89).
Discussion
Findings from this meta-analysis support a positive association
between diabetes (largely Type II diabetes) and breast cancer risk.
Summary results showed that women with diabetes may have
20% increased risk of breast cancer. The association between
diabetes and breast cancer was consistent for case–control and
cohort studies and for studies carried out in North America,
Europe and Asia.
There are several potential limitations that should be considered
when interpreting the results of this meta-analysis. First, most of
the studies did not distinguish between Type I and Type II diabe-
tes. Because Type I diabetes (which accounts for 5–10% of all
diagnosed cases of diabetes2) may not be a risk factor for breast
cancer,28,32,40 the magnitude of the relationship between diabetes
and breast cancer may have been somewhat underestimated. Fur-
thermore, because diabetes is an underdiagnosed disease, some
misclassification of exposure is likely to have occurred and this
misclassification would tend to attenuate any true association
between diabetes and breast cancer risk. Based on data from a
population-based study in the United States, about 3–4% of adults
(aged 40 years) have undiagnosed diabetes.41 In cohort studies
of hospitalized diabetic patients, the comparison group (i.e., the
general population) includes individuals with diabetes; this would
also lead to attenuated relative risk estimates. A second limitation
is methodologic issues related to study design. Case–control stud-
ies are susceptible to recall and selection biases. The association
between diabetes and breast cancer risk was similar in case–con-
trol and cohort studies, which argues against the possibility that
the observed association was the result of recall or selection bias.
Third, as our analyses are based on observational studies, uncon-
trolled confounding cannot be entirely excluded as a potential ex-
planation for the observed association. Nevertheless, many studies
adjusted for potential confounders and the association was similar
for studies that controlled for body mass index, physical activity
and alcohol consumption, and for studies that did not adjust for
these variables. It is remarkable that only 2 studies20,31 adjusted
for postmenopausal hormone use, a risk factor for breast cancer.
In the study by Michels et al.,31 women with diabetes were less
likely to use postmenopausal hormones. Hence, failure to adjust
for postmenopausal hormone use may result in an underestimation of
LARSSON ET AL.
Diabetes assessment 3
(age at diagnosis) Adjusted RR (95% CI) Adjustments
Blood glucose level 0.88 (0.70–1.08)4 Age
Diabetes clinics, 1.40 (1.06–1.81) Age
drug prescriptions,
or family physicians
Self-report (all ages) 1.27 (1.11–1.45) Age, education, race,
smoking, physical activity,
BMI, alcohol,
dietary factors
Hospitalized 0.86 (0.50–1.38) Age, calendar year,
insulin-treated country of residence
DM patients (30–49 y)
Blood glucose 2.23 (1.49–3.33) Age, smoking, alcohol
levels or medication use
the true relationship between diabetes and risk of breast cancer.
Finally, inherent in meta-analysis of published studies is the possibility
of publication bias. However, we found no evidence of such bias in
this meta-analysis.
None of the studies included in this meta-analysis provided
results stratified by insulin-dependent versus noninsulin-dependent
Type II diabetes. We therefore could not examine whether risks
may differ in these 2 types of Type II diabetics. One cohort study
consisted entirely of patients with insulin-treated diabetes, and in
this study no association was found between insulin-dependent
Type II diabetes and breast cancer incidence or mortality.32
The mechanisms underlying the relation between diabetes and
breast cancer risk may be related to alterations in circulating concen-
trations of insulin, insulin-like growth factors (IGFs) and endoge-
nous sex hormones. Type II diabetes is usually associated with
insulin resistance and increased pancreatic insulin secretion for long
periods both before and after disease onset. Insulin has been demon-
strated to have mitogenic effects on breast tissue,42,43 and insulin
receptors are frequently over-expressed in breast cancer cells.44,45 A
positive association between circulating concentrations of insulin or
C-peptide (a marker of insulin secretion) and breast cancer risk has
been observed in several,46–50 but not in all epidemiologic stud-
ies.30,51,52 High fasting insulin concentrations53 and Type II diabe-
tes54 have also been associated with adverse prognostic factors and
poor outcomes in women with breast cancer. Elevated insulin con-
centrations may also stimulate tumor growth by increasing bioavail-
able IGF-I.5 High circulating IGF-I concentrations have been shown
to predict premenopausal breast cancer risk.55 Insulin inhibits the
production of sex hormone-binding globulin,56 which leads to an
increase in bioavailable estradiol and testosterone.57 Compared to
healthy women, diabetes patients have been found to have higher
concentrations of circulating estrogens and androgens.58,59 Epide-
miologic studies have generally indicated positive relationships
between estrogen and testosterone concentrations and risk of breast
cancer in postmenopausal women.60,61 Some studies have found
positive relations between estrogen and testosterone concentrations
and breast cancer risk in premenopausal women62,63 but the associa-
tions seem to be weaker than in postmenopausal women. In this
meta-analysis, the relation between diabetes and breast cancer
appeared to be confined to postmenopausal women, but this finding
was based on a limited number of studies of premenopausal breast
cancer and a test for difference in association by menopausal status
was not statistically significant. Thus, this may be a chance finding.
In summary, this meta-analysis supports the hypothesis that
women with diabetes may have an increased risk of breast cancer.
Whether this association varies by menopausal status or type of
Type II diabetes (insulin-dependent versus noninsulin-dependent)
warrants further investigation.
 DIABETES MELLITUS AND RISK OF BREAST CANCER
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