Breast Cancer

Post-menopausal breast cancer is about 20% more common in women with type 2 diabetes than in those without. Similar associations are described for obesity. Non-modifiable risk factors are increasing age, family history and European descent; modifiable risk factors include obesity, high alcohol consumption and inactivity. The association may be subject to detection bias in that women are more likely to be diagnosed with breast cancer within 3 months of diagnosis of diabetes, but have no increase in risk thereafter. Women on metformin are less likely to receive a diagnosis of breast cancer than those on other glucose-lowering therapies, and the drug has a number of properties that might explain its apparent protective effect. These are currently being tested in prospective trials. Insulin glargine is more mitogenic than other marketed insulins in laboratory studies, but is converted to a less mitogenic form following injection. It has been associated with a modestly increased risk of breast cancer in some observational studies, but this remains controversial.

Epidemiologic Evidence

Post-menopausal breast cancer is associated with type 2 diabetes, an association partly accounted for by its overlap with obesity, which carries a similar risk of this type of cancer.

The authors of the Nurses’ Health Study, the longest and largest study to have examined this association, authors found that women with self-reported diabetes had a small (17%) but significantly elevated risk of breast cancer compared to women without diabetes. This finding was independent of age, obesity, family history of breast cancer, history of benign breast disease, reproductive factors, physical activity, and alcohol consumption[1].

A meta-analysis of 5 case-control studies and 15 cohort studies confirmed a 20% increase in risk of breast cancer in women with type 2 diabetes, but (as in the Nurses’ Health Study), the increased risk was restricted to post-menopausal women with diabetes[2].

Factors Influencing the Association

In addition to several modifiable and non-modifiable risk factors for breast cancer, detection bias and exposure to glucose-lowering therapies might potentially may confound the relationship between type 2 diabetes and breast cancer.

Non-Modifiable Risk Factors:

Age – As with type 2 diabetes, the risk of developing breast cancer increases with age.

Family History of Breast Cancer – There is an increased risk of breast cancer in women with a first-degree relative with breast cancer.

Ethnicity – Caucasian women have a slightly increased risk of developing breast cancer, as compared to African-American, Asian, or Hispanic women.

Modifiable Risk Factors:

Overweight and Obesity – Women who are overweight or obese after menopause have an increased risk of breast cancer. As well, overweight women tend to be hyperinsulinemic, which is also linked to an increased risk of breast cancer.

Alcohol – There is strong evidence supporting an increased risk of breast cancer with alcohol use. There is a dose-response relationship, with the risk of breast cancer increasing in proportion to the amount of alcohol consumed.

Physical Activity – Even modest physical activity reduces a women’s risk of breast cancer[3].

Detection Bias

There is some evidence that the increased risk of breast cancer in women with type 2 diabetes may be related to detection bias. Women with a new diagnosis of type 2 diabetes may have the advantage of increased screening opportunities, which could transpire into more cases of breast cancer being diagnosed in this population. During a diagnostic work-up, clinically detectable but previously undiagnosed health problems, such as breast cancer, may be detected. A visit with the physician provides an opportunity for the doctor to discover symptoms of undiagnosed health problems, such as cancer[4].

One study found that the association between newly diagnosed diabetes and breast cancer was limited to women with more frequent physician contact[5]. Similar findings were observed in a large, population-based cohort study, where a non-significant 31% increased risk of breast cancer was observed in post-menopausal women with type 2 diabetes, but only in the first 3 months following diagnosis of diabetes. In subsequent periods ranging from 3 months-10 years the risk of breast cancer was similar to that of the non-diabetes population[6].

This short term increased risk (or “detection bias”) may blur our understanding of the true long-term risk of breast cancer and other cancers associated with type 2 diabetes. Additional studies are required to determine if the long-term risk of breast cancer is elevated, and by how much.

Exposure to Glucose-lowering therapies

Metformin and Breast Cancer

There has been particular interest in the effects of metformin on breast cancer and its outcomes. Laboratory and animal models suggest that a metformin-mediated reduction of hyperinsulinemia and insulin resistance is associated with a reduction in the risk of tumor development[7]. Epidemiologic studies have observed 15-40% reductions in the risk of breast cancer with metformin use, particularly among peri- or post-menopausal women with type 2 diabetes[8][9][10].

One study found that long-term use of metformin (>5 years duration) was associated with a 56% decreased risk of breast cancer. There is also evidence supporting the role of metformin in reducing insulin levels among non-diabetic hyperinsulinemic women with early stage breast cancer. These observational findings, combined with experimental evidence of the beneficial effects of metformin on breast cancer cell lines in vitro support the increasing body evidence supporting a potential role for metformin in breast cancer chemoprevention[11]. Several prospective trials all registered at ClinicalTrials.gov, are currently underway. These will explore a possible role for metformin as an adjuvant or neoadjuvant therapy for women with breast cancer.

Metformin is also believed to induce inhibitory effects on estrogen receptor (ER)-positive and ER-negative breast cancer cells, suggesting a comprehensive therapeutic benefit for the drug[12]. Recent “window-of-opportunity” studies suggests that short-term pre-operative course of metformin as neoadjuvant therapy for non-diabetic breast cancer patients is well tolerated, and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects.

Insulin Glargine and Breast cancer

A number of observational studies have reported an increased risk of cancer outcomes associated with exogenous insulin use[13]. There has been great interest surrounding recent epidemiologic evidence on the different types of insulins, and in particular, for the long-acting insulin analog, insulin glargine. Given its structural similarity to insulin-like growth factor, insulin glargine has the potential for increased mitogenicity relative to human insulin[14].

There is evidence to suggest that there may be an increased risk of breast cancer associated with longer-term insulin glargine use [15][16][17]. A recent large-scale population-based epidemiologic study found that risk of breast cancer in women with type 2 diabetes was not increased in the first 5 years of insulin glargine use. However, there was a signal for an increased risk of breast cancer associated with longer-term use of glargine, particularly in women who were on other types of insulin prior to starting glargine[18].

References

  1. ^ Michels KB et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care 2003;26:1752-8.

  2. ^ Larsson SC et al. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007;121:856-62.

  3. ^ The American Cancer Society [Internet]. Breast cancer causes, risk factors, and prevention topics. Accessed November 8, 2012; http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-risk-factors

  4. ^ Bowker SL et al. Risk of breast cancer after onset of type 2 diabetes: evidence of detection bias in postmenopausal women. Diabetes Care 2011;34:2542-4.

  5. ^ Johnson JA et al. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia 2011;54:2263–2271.

  6. ^ Johnson JA et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia. 2012;55(6):1607–1618.

  7. ^ Zakikhani M et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66:10269-73.

  8. ^ Libby G et al: New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care 2009;32:1620-5.

  9. ^ Bosco JL et al. Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark. Cancer Epidemiol Biomarkers Prev 2011;20:101-11.

  10. ^ Chlebowski RT et al. Diabetes, metformin, and breast cancer in postmenopausal women. J Clin Oncol 2012;30:Epub ahead of print.

  11. ^ Giovannucci E et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33(7):1674-85.

  12. ^ Alimova IN et al. Metformin inhibits breast cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009;8:909-15

  13. ^ Bowker SL et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006;29:254-8.

  14. ^ Kurtzal P et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005.

  15. ^ Jonasson JM et al. Insulin glargine use and short-term incidence of malignancies – a population-based follow-up study in Sweden. Diabetologia 2009;52:1745-54.

  16. ^ Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52:1755-65.

  17. ^ Ruiter R et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia 2012;55:51-62.

  18. ^ The ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;319-28.

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