Diabetes mellitus and risk of breast cancer: A meta-analysis
Version of Record online: 30 MAR 2007
Copyright © 2007 Wiley-Liss, Inc.
International Journal of Cancer
Volume 121, Issue 4, pages 856–862, 15 August 2007
How to Cite
Larsson, S. C., Mantzoros, C. S. and Wolk, A. (2007), Diabetes mellitus and risk of breast cancer: A meta-analysis. Int. J. Cancer, 121: 856–862. doi: 10.1002/ijc.22717
- Issue online: 22 JUN 2007
- Version of Record online: 30 MAR 2007
- Manuscript Accepted: 26 FEB 2007
- Manuscript Received: 3 JAN 2007
- The Swedish Cancer Society
- breast cancer;
- systematic review
Diabetes mellitus has been associated with an increased risk of several 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 ratio, 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 studies (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) diabetes. Findings from this meta-analysis indicate that diabetes is associated with an increased risk of breast cancer. © 2007 Wiley-Liss, Inc.
Diabetes mellitus is a serious and growing health problem worldwide.1 Type 2 diabetes accounts for ∼90–95% of all diagnosed cases of diabetes2 and is characterized by insulin resistance and hyperinsulinemia 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 factors.4, 5 Thus, Type 2 diabetes may confer an excess risk of breast cancer. Diabetes has been related to an elevated risk of several cancers. 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 following 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
We searched the MEDLINE database (from 1966 to February 2007) using the search terms diabetes and breast cancer or breast 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.
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 assessment (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 greatest number of potential confounders.
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 studies 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.13I2 is the proportion of total variation contributed by between-study variation.13 To assess for publication bias, we constructed a funnel plot, and applied regression methods to determine funnel plot asymmetry as suggested by Egger et al.14 We performed subgroup analyses and used meta-regression models to evaluate potential sources of heterogeneity. Study characteristics examined included study design, diabetes assessment, geographic region, publication year, and adjustment for body mass index, 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 Station, TX).
Breast cancer incidence
We identified 6 case–control studies15, 16, 17, 18, 19, 20 and 16 cohort studies21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 that presented results on diabetes and breast cancer incidence. 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, 7 from Europe and 4 from Asia (Table I).
|Study and country||Age, year||Years of follow-up||No. of cases||Controls or cohort size||Diabetes assessment (age at diagnosis)||Breast cancer ascertainment||Adjusted RR2 (95% CI)||Adjustments|
|O'Mara et al., 198515; United States||30–89||–||1883||2420 (H)3||Self-report (≥29 years)||Medical records||1.2 (0.9–1.6)4||Age|
|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|
|Weiss et al., 199919; 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 tumor registries||1.2 (1.0–1.4)||Age, state, family history, parity, age at first birth, menopausal status, age at menopause, OC use, PMH use, BMI, alcohol|
|de Waard and Baanders-van Halewijn, 197421; Netherlands||55–75||8.1||70||7259||Self-report (all ages)||Medical records||1.5 (0.6–3.3)5||Age|
|Raggozzino et al., 198222; United States||NA||25||14||1135||Blood glucose levels||Medical records||1.3 (0.7–2.2)5||Age|
|Sellers et al., 199424; United States||55–69||5||611||41 837||Self-report (≥30 years)||State Health Registry of Iowa||0.96 (0.68–1.36)||Age|
|Steenland et al., 199525; United States||25–74||7.7||163||NA||Self-report (all ages)||Medical records||1.40 (0.70–2.78)||Age, income, menopausal status, 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 (hospitalized DM patients; ≥40 years)||Cancer registry||1.3 (1.2–1.4)||Age, calendar year|
|Hjalgrim et al., 199728; Denmark||≥30||20||7||402||Hospitalized DM patients (≥30 years)||Cancer registry||0.72 (0.29–1.48)||Age, calendar year|
|Wideroff et al., 199729; Denmark||≥50||17||493||109 581||Discharge diagnosis (hospitalized DM patients; ≥50 years)||Cancer registry||1.2 (1.1–1.2)||Age, calendar year|
|Mink et al., 200230; United States||45–64||7.1||187||7894||Self-report (all ages)||Cancer registry and medical records||1.39 (0.86–2.23)||Age, race, study center, 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, verified by medical records and pathology reports||1.17 (1.01–1.35)||Age, family history, history of benign breast disease, age at menarche, parity, age at first birth, menopausal status, age at menopause, PMH use, height, BMI, physical activity, alcohol|
|Swerdlow et al., 200532; United Kingdom||30–49||30||41||5066||Hospitalized insulin-treated DM patients (30–49 years)||Cancer registry||0.87 (0.62–1.17)||Age, calendar year, country of residence|
|Jee et al., 200533; Korea||30–95||10||NA||468 615||Blood glucose levels and medication use||Cancer registry and medial records||1.51 (1.26–1.80)||Age, smoking, alcohol|
|Khan et al., 200634; Japan||40–79||9||1139||33 503||Self-report (all ages)||Cancer registry||1.27 (0.51–3.14)||Age, smoking, BMI, drinking|
|Lipscombe et al., 200635; Canada||55–79||8||6107||465 510||Discharge diagnosis (hospitalized DM patients)||Cancer registry||1.08 (1.01–1.16)||Age, income|
|Inoue et al., 200636; Japan||40–69||14||451||51 223||Self-report (all ages)||Cancer registry||0.83 (0.44–1.57)||Age, study area, history of cardiovascular disease, smoking, BMI, physical activity, alcohol, dietary factors|
Of the 20 studies, 15 found an increased risk of breast cancer in women with diabetes, and in 8 studies the relationship was statistically 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 = 36.53, p = 0.01, I2 = 48.0%). Three studies, all based on a discharge diagnosis of diabetes,27, 29, 35 contributed significantly to the summary estimate. In a sensitivity analysis excluding these 3 studies, the summary relative risk remained unchanged but the CI slightly widened (RR, 1.20; 95% CI, 1.09–1.33) and heterogeneity among studies was reduced (Q = 23.60, p = 0.10, I2 = 32.2%). Stratification by study design showed that diabetes was associated 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).
|No. of studies||RR (95% CI)||Heterogeneity tests|
|Case–control studies||5||1.18 (1.05–1.32)||3.16||0.53||0|
|Cohort studies||15||1.20 (1.11–1.30)||33.31||0.003||58.0|
|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|
|North America||9||1.12 (1.06–1.18)||4.37||0.82||0|
|Adjustment for body mass index|
|Adjustment for physical activity|
|Adjustment for alcohol intake|
|Adjustment for postmenopausal hormone use|
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 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 statistical 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 analysis, the association between diabetes and breast cancer varied statistically significantly by geographic region (stronger association in Asia than in North America; p = 0.02), but not by study design, diabetes assessment, publication year or control for potential confounders.
Three studies provided results stratified by menopausal status,16, 18, 31 and 5 studies included only or predominantly postmenopausal women.20, 21, 24, 29, 35 In stratified analysis by menopausal status, diabetes was associated with an increased risk of breast cancer in postmenopausal women but not in premenopausal women (Table II). The difference in summary relative risks across strata of menopausal status was not statistically significant (p = 0.27).
There was no indication of publication bias on the funnel plot (data not shown) or by Egger's test (p = 0.94).
Breast cancer mortality
We identified 5 cohort studies that reported results on diabetes and mortality from breast cancer (Table III).32, 33, 37, 38, 39 Combining the results from these studies yielded a summary relative risk of 1.24 (95% CI, 0.95–1.62) for women with (versus without) diabetes. There was statistically significant heterogeneity among studies (Q = 20.54, p < 0.001, I2 = 80.5%). There was no evidence of publication bias (Egger's test: p = 0.89).
|Study and country||Years of follow-up||Age, year||No. of deaths2||Cohort size||Diabetes assessment (age at diagnosis)||Adjusted RR3 (95% CI)||Adjustments|
|Kessler, 197037; United States||26||NA||21||21 447||Blood glucose level||0.88 (0.70–1.08)4||Age|
|Verlato et al., 200338; Italy||10||NA||28||7148||Diabetes clinics, drug prescriptions, or family physicians||1.40 (1.06–1.81)||Age|
|Coughlin et al., 200439; United States||16||≥30||4346||588 321||Self-report (all ages)||1.27 (1.11–1.45)||Age, education, race, smoking, physical activity, BMI, alcohol, dietary factors|
|Swerdlow et al., 200532; United Kingdom||30||30–49||17||5066||Hospitalized insulin-treated DM patients (30–49 y)||0.86 (0.50–1.38)||Age, calendar year, country of residence|
|Jee et al., 200533; Korea||10||30–95||NA||468 615||Blood glucose levels or medication use||2.23 (1.49–3.33)||Age, smoking, alcohol|
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 diabetes. 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. Furthermore, 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 studies are susceptible to recall and selection biases. The association between diabetes and breast cancer risk was similar in case–control 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, uncontrolled confounding cannot be entirely excluded as a potential explanation 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 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 concentrations of insulin, insulin-like growth factors (IGFs) and endogenous 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 demonstrated 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, 47, 48, 49, 50 but not in all epidemiologic studies.30, 51, 52 High fasting insulin concentrations53 and Type II diabetes54 have also been associated with adverse prognostic factors and poor outcomes in women with breast cancer. Elevated insulin concentrations may also stimulate tumor growth by increasing bioavailable 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 Epidemiologic 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 associations 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.
- 2Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2005. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2005. Accessed at http://www.cdc.gov/diabetes/pubs/factsheet05.htm on November 1, 2006.
- 34Site-specific cancer risk due to diabetes mellitus history: evidencefrom the Japan Collaborative Cohort (JACC) Study. Asian Pac J Cancer Prev 2006; 7: 253–9., , , , , , .
- 41Centers for Disease Control and Prevention (CDC). Prevalence of diabetes and impaired fasting glucose in adults—United States, 1999–2000. MMWR Morb Mortal Wkly Rep 2003; 52: 833–7.