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  • Komen Perspectives - Diabetes and Breast Cancer (November 2014)

    What Is Diabetes?

    Diabetes mellitus, often called diabetes, is a group of diseases characterized by high levels of glucose in the blood. Most of what we eat is broken down into glucose, a form of sugar in the blood that is the main source of fuel for our bodies.

    When food is digested, glucose makes its way into the bloodstream and our cells use the glucose for energy and growth. However, glucose cannot enter cells without insulin being present.

    Insulin is a hormone that is produced by the pancreas. After eating, the pancreas automatically makes and releases insulin which moves the glucose present in our blood into the cells. As soon as glucose enters the cells, blood glucose levels drop quickly. Diabetes occurs when insulin production is inadequate, or when the body's cells do not respond properly to insulin, or both.

    Why is it important to control my blood glucose levels?

     Having diabetes causes damage to the blood vessels in the circulatory system. As a result, diabetes is the leading cause of kidney failure, lower limb amputations (other than those caused by injury) and vision loss due to damage to the retina.

    So what does this all have to do with breast cancer? Studies show having diabetes is associated with an increased risk of developing cancer, such as breast cancer.[1][2]. This is why maintaining the right amount of glucose in our bodies is so important.  


    Does Diabetes Affect My Risk for Breast Cancer?
    It was first observed 50 years ago that cancer, including breast cancer, is more commonly found in people with diabetes [1]. More recent studies have reinforced a link between cancer and diabetes and have been able to specifically identify a link between breast cancer risk and type 2 diabetes[3][4].


    There are three types of diabetes and a “pre” diabetes condition. For each type of diabetes, there is a different level of risk for breast cancer discussed below.


    Type 2 diabetes


    In type 2 diabetes, the body does not produce enough insulin to function properly, or the cells in the body do not react normally to the insulin it does produce (insulin resistance). Being overweight, physically inactive and eating an unhealthy diet all contribute to our risk of developing type 2 diabetes. Approximately 90-95 percent of all cases of diabetes worldwide are of this type [5].


    Postmenopausal women 50 years or older who have type 2 diabetes have about a 20-27 percent increased risk of breast cancer [4].


    It’s not entirely clear why people with type 2 diabetes are at increased risk for breast cancer.  Type 2 diabetes causes several changes that could increase breast cancer risk such as high glucose levels, high insulin levels and increased inflammation. Studies have shown a link between all of these changes and the development of breast cancer.  


    In addition, many risk factors for developing type 2 diabetes and breast cancer overlap – such as being older, being overweight or obese and lack of regular physical activity. These risk factors may separately, and together, contribute to the increased risk of breast cancer in postmenopausal women with diabetes.


    See Tables 1 (Risk Factors You Cannot Change) and 2 (Risk Factors You Can Change) below for more details on risk factors for type 2 diabetes and breast cancer.


    Type 1 diabetes


    In type 1 diabetes, also referred to as insulin-dependent diabetes, juvenile diabetes or early-onset diabetes, the body does not produce insulin. People usually develop type 1 diabetes before they are 40 years old, often in early adulthood or teenage years. Type 1 diabetics live with this disease for their entire lives and control their blood sugar levels with a combination of medication and proper diet.


    Unlike type 2 diabetes, women with type 1 diabetes do not appear to have an increased risk of breast cancer [3][4].  


    Gestational Diabetes


    Gestational diabetes affects women during pregnancy who have never had diabetes, but have high blood glucose levels. Some pregnant women are unable to produce enough insulin to transfer all of the glucose into their cells, resulting in high blood glucose levels. The majority of gestational diabetes patients can control their diabetes with exercise and diet. It is also important to know that blood glucose levels usually go back to normal after pregnancy.


    Women with gestational diabetes do not appear to have an increased risk of breast cancer [3]. While having gestational diabetes does not appear to be directly associated with increased risk of breast cancer, women who have had gestational diabetes have a 35 to 65 percent chance of developing type 2 diabetes in the next 10-20 years [5].  


    Pre-Diabetes


    Pre-diabetes is a condition in which blood glucose levels are higher than normal, but not high enough to have diabetes. This condition is also commonly associated with obesity and can often lead to type 2 diabetes[5]. However, pre-diabetes has not been shown to directly increase the risk of developing breast cancer.

    Does Having Type 2 Diabetes Impact Breast Cancer Prognosis?


    People with breast cancer who also have type 2 diabetes have as much as a 50 percent increased chance of dying (mortality) from any cause [6].  


    Increased mortality could be due to a number of factors. For example, people with breast cancer who also have type 2 diabetes are more likely to be diagnosed with late stage breast cancer, when the disease is more difficult to treat[7]. Differences in how treatment is given for diabetic patients have also been also observed.  For example, diabetic patients are more likely to be treated with surgery and hormone therapy alone - and tend not to receive more aggressive treatments, such as the addition of chemotherapy. This may be due to their increased risk of having side effects from aggressive treatments [7][6].   


    Diabetes has many serious associated medical conditions (co-morbidities) which on their own negatively influence breast cancer outcomes and mortality – such as poor cardiovascular health, being overweight and a sedentary lifestyle. Researchers are working to determine the exact relationship between breast cancer and diabetes and how it influences risk.

    Are the Risk Factors for Type 2 Diabetes Similar to Breast Cancer?


    As shown in Tables 1 and 2, type 2 diabetes and breast cancer share many risk factors – some that you can change and others you cannot.   Because of the significant overlap, this adds to the challenge of knowing why women with diabetes have a higher risk for breast cancer.


    Note: there are other known risk factors for breast cancer, such as age at first pregnancy and age at menopause. A complete list can be found in our Risk Factors web page

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    Table 1: RISK FACTORS YOU CANNOT CHANGE  (NON-MODIFIABLE)

    Comparing  RISK FACTORS:

    TYPE 2 DIABETES

    BREAST CANCER

    Being older

    26.9 percent of adults aged ≥65 yrs or older have been diagnosed or have undiagnosed diabetes compared to 3.7% in adults aged 20-44.[5]

    The older an individual is, the more likely she or he will develop breast cancer.

    Rate of breast cancer increases after age 40 and are highest over age 70.

     

    Gender

    11.8 percent of all men ≥ 20 yrs of age have diabetes vs. 10.8 percent of all women.[5]

    Men are more likely to have undiagnosed diabetes.

    Being female is the most common risk factor for breast cancer. Breast cancer is 100 times more common in women than in men.

     

    Having a family history of the disease

    If your siblings or parents have diabetes, you have a higher risk.[5]

    A family history of certain types of cancer can increase your risk of breast cancer. This increased risk may be due to genetic factors (known and unknown) and lifestyle.

     

    Learn more about the role of family history.

     

    Race plays a limited role

    Compared to non-Hispanic whites, the risk of diagnosed diabetes was 18 percent higher in Asian Americans, 66 percent higher among Hispanics and 77 percent higher among non-Hispanic blacks. *age adjusted figures. [5]

    Non-Hispanic white women have the highest breast cancer incidence overall. However, African American women have the highest breast cancer mortality overall.[8]

     

    Learn more about the association of race & ethnicity and breast cancer risk.

     

    Table 2: RISK FACTORS YOU CAN CHANGE (MODIFIABLE)

    Comparing RISK FACTORS:

    TYPE 2 DIABETES

    BREAST CANCER

    Having high blood pressure

    2 out of 3 people with diabetes report having high blood pressure (140-90 or higher).[5]

     

    Not directly associated with breast cancer risk.

    Being physically inactive

    Being active helps maintain normal levels of blood sugar and keeps your body sensitive to insulin.[9]

    Regular exercise[1] appears to lower breast cancer risk by about 10-20 percent. This benefit is most clearly seen in postmenopausal women.

     

    Learn more about exercise and risk.

     

    Being overweight or obese

    Being overweight[2] raises your risk.[5]

     

    For most people, losing weight can reverse type 2 diabetes.

    Before menopause, being overweight or obese modestly decreases risk.

    After menopause, being overweight or obese increases risk.

    Learn more about the effects of being overweight.

    Eating an unhealthy diet

    Diets low in red and processed meats and high in vegetable, fruit, whole grains cereals and dietary fiber may protect against type 2 diabetes by improving insulin sensitivity.[3]

     

    Note: While low carbohydrate, high protein and fat diets have been shown to reduce weight and lower insulin levels, large randomized clinical trials have only been performed on low fat, low calorie diets to date.

    Studies now show that eating vegetables may slightly lower the risk of some breast cancers.

    [10]

     

    No link between high-fat diet in adulthood and an increased risk of breast cancer has been shown. Eating a high fat diet during adolescence may be associated with increased risk of premenopausal breast cancer.

     

    Learn more about dietary fat and breast cancer risk.

     

    Smoking

    May be an independent risk factor for developing type 2 diabetes.

    Smoking increases risk for complications from diabetes, such as – cardiovascular disease, damage to the retina of the eye and other diabetes-related health outcomes.[11]

     

    Smoking’s effect on breast cancer is still under study. Although there is growing evidence that smoking may slightly increase the risk of breast cancer, overall, study findings remain mixed.

     

    Learn more about smoking and breast cancer risk.

     

    Alcohol

    Excessive alcohol consumption has been associated with increased risk for type 2 diabetes. However, moderate alcohol (about 2 drinks per day) consumption appears to lower risk slightly.[12]

     

    Studies show that women who had more than two alcoholic drinks per day had a 20 percent higher risk of breast cancer.

     

    However, drinking low to moderate amounts of alcohol may lower the risks of heart disease, high blood pressure and mortality.

     

    Learn more about alcohol and breast cancer risk.

     

    Pre-diabetes

     

    If pre-diabetes is left untreated, it often progresses to type 2 diabetes.[5]

    Not directly associated with breast cancer risk

     

     

    Gestational Diabetes

     

    If you had gestational diabetes, your risk for developing type 2 diabetes later on increases by about 35-65%. [5]

    Not directly associated with breast cancer risk

     

    Metabolic Syndrome or insulin resistance syndrome[4]

    A diagnosis of metabolic syndrome can result in up to a 5 fold increase risk for developing type 2 diabetes. [13]

    Associated with a moderately increased risk for postmenopausal breast cancer. [14] This is still an area of active investigation.

     



    [1] The American Cancer Society recommends about 150 minutes of physical activity a week. Activity equal to walking for 30 minutes a day.

    [2] Overweight is defined as having a body mass index (BMI) value of 25.0 to 25.9. Obese is defined as having a BMI of 30 or greater.

    [4]Metabolic Syndrome is also known as insulin resistance syndrome, obesity syndrome, dysmetabolic syndrome, hypertryglyceridemic waist.  It is generally accepted that a diagnosis of metabolic syndrome should include at least three of the following conditions (or be on drug treatment for): increased waist circumference, elevated trigycerides, reduced high density lipoprotein cholesterol levels (HDL), elevated blood pressure, and elevated fasting glucose [22].

    Anti-Diabetic Medications and Breast Cancer
     Anti-diabetic medications work by:
     
    •    reintroducing insulin production in an effort to reduce blood sugar levels
    •    sensitizing patients to insulin
    •    or a combination of both
    The effect of anti-diabetic medications on breast cancer risk and prognosis is an active area of research.
     
    The possible effects of specific anti-diabetic medications on breast cancer risk are discussed below.  However, it is important to emphasize that the benefits of taking anti-diabetic medications far outweigh any effect on breast cancer risk or prognosis.

    Metformin

      Metabolic Syndrome is also known as insulin resistance syndrome, obesity syndrome, dysmetabolic syndrome, hypertryglyceridemic waist.  It is generally accepted that a diagnosis of metabolic syndrome should include at least three of the following conditions (or be on drug treatment for): increased waist circumference, elevated trigycerides, reduced high density lipoprotein cholesterol levels (HDL), elevated blood pressure, and elevated fasting glucose [22]. 

     

     

    Metformin (also known as Glucophage®) is one of the most commonly prescribed oral medicines used to treat type 2 diabetes.  Diabetic patients taking metformin have a lower incidence of invasive breast cancer compared those who took other anti-diabetic medications, like sulfonylureas (e.g. Glucotrol®, Micronase®) [15].

    Studies on the use of metformin and outcomes for breast cancer are mixed.  One often referenced study found that diabetic breast cancer patients that received chemotherapy and metformin were much more likely to have a “complete response”, meaning they did not find an remaining cancer  in the affected breast(s) or lymph node(s)[16].  However, other studies found no link between improved survival and metformin use [17][18][19]. 

    We don’t yet know if people with breast cancer, who are not diabetic, would benefit from taking metformin. Some studies suggest that breast cancer may affect how a cell uses glucose and that treating with metformin may correct this change. Currently a number of clinical trials are trying to determine if metformin benefits breast cancer patients independent of diabetes.

    Insulin replacements

    Synthetic insulins, like insulin glargine (Lantus®), are manufactured and have small differences compared to insulin produced by our pancreas.  Insulin replacements and breast cancer risk is still an active area of investigation. Studies have found mixed results but for now indicate there is little to no effect on breast cancer incidence with use of insulin replacements[18][20][21]. However, studies examining the long term (>6 yrs) use of insulin replacements, such as glargine, and incidence of breast cancer are needed.

    Other anti-diabetic therapies

    Sulfonyureas, like glipizide (Glucotrol®) are another class of drugs that have been used to treat type 2 diabetes for more than 50 years. They work by stimulating the pancreas to produce more insulin. A slightly elevated risk of developing breast cancer has been observed with the use of sulfonylurea[18]. However, sulfonyureas are often prescribed with metformin as a combination therapy.  When used in combination with metformin, the slightly elevated risk for breast cancer associated with sulfonyureas is not seen [18]. 

    Thiazolidinediones (TZDs; i.e. Avandia® or rosigliaizone) are a class of anti-diabetic medication that makes the person more sensitive to insulin, but does not appear to increase insulin secretion or cause low blood sugar (also known as hypoglycemia).  The role of TZDs and breast cancer risk has been explored in studies that also looked at other cancers. TZDs do not appear to affect breast cancer risk when used alone or in combination with chemotherapy and hormone therapy [25][26].

     

    Summary:

    ·         Having type 2 diabetes appears to increase your risk of breast cancer by about 20-27 percent.

    ·         Many risk factors for type 2 diabetes, such as being overweight, being older and lacking regular exercise overlap with risk factors for breast cancer. 

    ·         It is difficult to determine if diabetes alone is a risk factor for breast cancer since there are many other conditions associated with diabetes that may also contribute to breast cancer risk.

    ·         The anti-diabetic medication metformin appears to reduce risk and improve outcomes for diabetic breast cancer patients, but more research is needed to confirm results and to determine whether it has a positive benefit for non-diabetic breast cancer patients.

    ·         Other common anti-diabetic medications and their effect on breast cancer risk and prognosis is still an active area of research.

    Obesity is a strong, overlapping risk factor for both type 2 diabetes and breast cancer in postmenopausal women.

      Read more about how body weight can affect your breast cancer risk in our Komen Perspectives article.  

      Learn more about what Komen is doing to understand how body weight and weight gain affect your risk of breast cancer by reading our Research Fast Facts on Obesity and Breast Cancer.

     

    What Is Komen Doing?

    Since 1982, Komen has invested more than $14.4 million in grants to support research related to the metabolic and hormonal changes that occur in diabetics, such as high levels of insulin (hyperinsulimia), high blood sugar (hyperglycemia), and use of anti-diabetic drugs and how they affect breast cancer risk. Examples of research projects include:

    ·         Determining whether diabetes affects the life expectancy of breast cancer patients from minority populations or low socio-economic backgrounds.  

    ·         Conducting laboratory research and clinical trials to determine if the anti-diabetic drug metformin can improve outcomes for breast cancer patients without type 2 diabetes.

    ·         Identifying biomarkers to more accurately predict which diabetic patients are at an increased risk of developing breast cancer. 

    ·         Developing targeted therapies to key proteins which are thought to play a role in both breast cancer and type 2 diabetes.

     

     

    Citations

    [1]         A. S. GLICKSMAN and R. W. RAWSON, “Diabetes and altered carbohydrate metabolism in patients with cancer.,” Cancer, vol. 9, no. 6, pp. 1127–34.

    [2]         E. Giovannucci, D. M. Harlan, M. C. Archer, R. M. Bergenstal, S. M. Gapstur, L. a Habel, M. Pollak, J. G. Regensteiner, and D. Yee, “Diabetes and cancer: a consensus report.,” Diabetes Care, vol. 33, no. 7, pp. 1674–85, Jul. 2010.

    [3]         P. J. Hardefeldt, S. Edirimanne, and G. D. Eslick, “Diabetes increases the risk of breast cancer: a meta-analysis.,” Endocr. Relat. Cancer, vol. 19, no. 6, pp. 793–803, Dec. 2012.

    [4]         P. Boyle, M. Boniol, A. Koechlin, C. Robertson, F. Valentini, K. Coppens, L.-L. Fairley, T. Zheng, Y. Zhang, M. Pasterk, M. Smans, M. P. Curado, P. Mullie, S. Gandini, M. Bota, G. B. Bolli, J. Rosenstock, and P. Autier, “Diabetes and breast cancer risk: a meta-analysis.,” Br. J. Cancer, vol. 107, no. 9, pp. 1608–17, Oct. 2012.

    [5]         Centers for Disease Control and Prevention, “National diabetes fact sheet,” 2011.

    [6]         K. S. Peairs, B. B. Barone, C. F. Snyder, H.-C. Yeh, K. B. Stein, R. L. Derr, F. L. Brancati, and A. C. Wolff, “Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis.,” J. Clin. Oncol., vol. 29, no. 1, pp. 40–6, Jan. 2011.

    [7]         L. V van de Poll-Franse, S. Houterman, M. L. G. Janssen-Heijnen, M. W. Dercksen, J. W. W. Coebergh, and H. R. Haak, “Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis.,” Int. J. Cancer, vol. 120, no. 9, pp. 1986–92, May 2007.

    [8]         “American Cancer Society - Breast Cancer Facts & Figures 2013-2014,” 2014.

    [9]         D. E. R. Warburton, C. W. Nicol, and S. S. D. Bredin, “Health benefits of physical activity: the evidence.,” CMAJ, vol. 174, no. 6, pp. 801–9, Mar. 2006.

    [10]      S. Jung, D. Spiegelman, L. Baglietto, L. Bernstein, D. A. Boggs, P. A. van den Brandt, J. E. Buring, J. R. Cerhan, M. M. Gaudet, G. G. Giles, G. Goodman, N. Hakansson, S. E. Hankinson, K. Helzlsouer, P. L. Horn-Ross, M. Inoue, V. Krogh, M. Lof, M. L. McCullough, A. B. Miller, M. L. Neuhouser, J. R. Palmer, Y. Park, K. Robien, T. E. Rohan, S. Scarmo, C. Schairer, L. J. Schouten, J. M. Shikany, S. Sieri, S. Tsugane, K. Visvanathan, E. Weiderpass, W. C. Willett, A. Wolk, A. Zeleniuch-Jacquotte, S. M. Zhang, X. Zhang, R. G. Ziegler, and S. A. Smith-Warner, “Fruit and vegetable intake and risk of breast cancer by hormone receptor status.,” J. Natl. Cancer Inst., vol. 105, no. 3, pp. 219–36, Feb. 2013.

    [11]      “Diet, Lifestyle, and the Risk of Type 2 Diabetes Mellitus in Women — NEJM.” [Online]. Available: http://www.nejm.org/doi/full/10.1056/NEJMoa010492. [Accessed: 18-Jun-2014].

    [12]      L. L. J. Koppes, J. M. Dekker, H. F. J. Hendriks, L. M. Bouter, and R. J. Heine, “Moderate Alcohol Consumption Lowers the Risk of Type 2 Diabetes: A meta-analysis of prospective observational studies,” Diabetes Care, vol. 28, no. 3, pp. 719–725, Mar. 2005.

    [13]      E. S. Ford, C. Li, and N. Sattar, “Metabolic syndrome and incident diabetes: current state of the evidence.,” Diabetes Care, vol. 31, no. 9, pp. 1898–904, Sep. 2008.

    [14]      K. Esposito, P. Chiodini, A. Capuano, G. Bellastella, M. I. Maiorino, C. Rafaniello, and D. Giugliano, “Metabolic syndrome and postmenopausal breast cancer: systematic review and meta-analysis.,” Menopause, vol. 20, no. 12, pp. 1301–9, Dec. 2013.

    [15]      R. T. Chlebowski, A. McTiernan, J. Wactawski-Wende, J. E. Manson, A. K. Aragaki, T. Rohan, E. Ipp, V. G. Kaklamani, M. Vitolins, R. Wallace, M. Gunter, L. S. Phillips, H. Strickler, K. Margolis, and D. M. Euhus, “Diabetes, metformin, and breast cancer in postmenopausal women.,” J. Clin. Oncol., vol. 30, no. 23, pp. 2844–52, Aug. 2012.

    [16]      S. Jiralerspong, S. L. Palla, S. H. Giordano, F. Meric-Bernstam, C. Liedtke, C. M. Barnett, L. Hsu, M.-C. Hung, G. N. Hortobagyi, and A. M. Gonzalez-Angulo, “Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.,” J. Clin. Oncol., vol. 27, no. 20, pp. 3297–302, Jul. 2009.

    [17]      I. C. Lega, P. C. Austin, A. Gruneir, P. J. Goodwin, P. A. Rochon, and L. L. Lipscombe, “Association between metformin therapy and mortality after breast cancer: a population-based study.,” Diabetes Care, vol. 36, no. 10, pp. 3018–26, Oct. 2013.

    [18]      C. J. Currie, C. D. Poole, and E. A. M. Gale, “The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.,” Diabetologia, vol. 52, no. 9, pp. 1766–77, Sep. 2009.

    [19]      A. M. Thompson, “Molecular pathways: preclinical models and clinical trials with metformin in breast cancer.,” Clin. Cancer Res., vol. 20, no. 10, pp. 2508–15, May 2014.

    [20]      H. C. Gerstein, J. Bosch, G. R. Dagenais, R. Díaz, H. Jung, A. P. Maggioni, J. Pogue, J. Probstfield, A. Ramachandran, M. C. Riddle, L. E. Rydén, and S. Yusuf, “Basal insulin and cardiovascular and other outcomes in dysglycemia.,” N. Engl. J. Med., vol. 367, no. 4, pp. 319–28, Jul. 2012.

    [21]      L. Grimaldi-Bensouda, D. Cameron, M. Marty, A. H. Barnett, F. Penault-Llorca, M. Pollak, B. Charbonnel, M. Riddle, L. Mignot, J.-F. Boivin, A. Khachatryan, M. Rossignol, J. Bénichou, A. Alpérovitch, and L. Abenhaim, “Risk of breast cancer by individual insulin use: an international multicenter study.,” Diabetes Care, vol. 37, no. 1, pp. 134–43, Jan. 2014.

    [22]      K. G. M. M. Alberti, R. H. Eckel, S. M. Grundy, P. Z. Zimmet, J. I. Cleeman, K. A. Donato, J.-C. Fruchart, W. P. T. James, C. M. Loria, and S. C. Smith, “Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International,” Circulation, vol. 120, no. 16, pp. 1640–5, Oct. 2009.

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