Skip to main content

Advertisement

SpringerLink
Log in

The Relationship of Type 2 Diabetes, Oral Diabetes Medications, and Insulin Therapy to Risk for Breast Cancer

  • Cancer (MF Leitzmann, Section Editor)
  • Published:
Current Nutrition Reports Aims and scope Submit manuscript

Abstract

The interaction between type 2 diabetes mellitus (DM) and breast cancer has become an important focus of research. DM appears to increase the risk of breast cancer and to negatively impact on breast cancer prognosis and screening. While evidence suggests that DM medications can modulate the relationship between DM and cancer, relatively few studies have specifically examined the association between medication exposure and breast cancer risk. Current evidence suggests that insulin plays a central role in the relationship between DM and breast cancer, but that other shared risk factors such as oxidative stress and inflammation may also contribute significantly. Further research is necessary to better understand the mechanisms underlying the relationship between DM and breast cancer and to fully realize the modulating effects of medication exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and pre-diabetes in the United States, 2011. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011.

    Google Scholar 

  2. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.

    Google Scholar 

  3. Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol. 2005;6:103–11.

    Article  CAS  PubMed  Google Scholar 

  4. Onitilo AA, Engel JM, Glurich I, Stankowski RV, Williams GM, Doi SA. Diabetes and cancer I: risk, survival, and implications for screening. Cancer Causes Control. 2012;23:967–81.

    Article  PubMed  Google Scholar 

  5. Boyle P, Boniol M, Koechlin A, Robertson C, Valentini F, Coppens K, et al. Diabetes and breast cancer risk: a meta-analysis. Br J Cancer. 2012;107:1608–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. De Bruijn KM, Arends LR, Hansen BE, Leeflang S, Ruiter R, van Eijck CH. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br J Surg. 2013;100:1421–9.

    Article  PubMed  Google Scholar 

  7. Hardefeldt PJ, Edirimanne S, Eslick GD. Diabetes increases the risk of breast cancer: a meta-analysis. Endocrinol Relat Cancer. 2012;19:793–803.

    Article  Google Scholar 

  8. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121:856–62.

    Article  CAS  PubMed  Google Scholar 

  9. Liao S, Li J, Wei W, Wang L, Zhang Y, Li J, et al. Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature. Asian Pac J Cancer Prev. 2011;12:1061–5.

    PubMed  Google Scholar 

  10. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of current evidence. Am J Clin Nutr. 2007;86:s823–35.

    PubMed  Google Scholar 

  11. Bertram MY, Vos T. Quantifying the duration of pre-diabetes. Aust N Z J Public Health. 2010;34:311–4.

    Article  PubMed  Google Scholar 

  12. Johnson JA, Bowker SL. Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia. 2011;54:25–31. This meta-analysis summarizes the effects of diabetes-related hyperglycemia on cancer risk, demonstrating that intensive glycemic control has no effect on risk.

    Article  CAS  PubMed  Google Scholar 

  13. Onitilo AA, Stankowski RV, Berg RL, Engel JM, Glurich I, Williams GM, Doi SA. Type 2 diabetes mellitus, glycemic control, and cancer risk. Eur J Cancer Prev. 2013 Aug 19. [Epub ahead of print]

  14. Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE. Increased prevalence of prior breast cancer in women with newly diagnosed diabetes. Breast Cancer Res Treat. 2006;98:303–9.

    Article  PubMed  Google Scholar 

  15. Onitilo AA, Stankowski RV, Berg RL, Engel JM, Glurich I, Williams GM, Doi SA. Breast cancer incidence before and after diagnosis of type 2 diabetes mellitus in women: increased risk in the prediabetes phase. Eur J Cancer Prev. 2013 Apr 6. [Epub ahead of print] This is the first and only study to date to describe breast cancer incidence in carefully delineated time periods before and after clinical onset of type 2 diabetes mellitus, demonstrates increased risk in the pre-diabetes phase.

  16. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA. 2008;300:2754–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Peairs KS, Barone BB, Snyder CF, Yeh HC, Stein KB, Derr RL, et al. Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol. 2011;29:40–6. This meta-analysis summarizes breast cancer prognosis in women with diabetes and discusses additional study findings with the potential to contribute to poorer breast cancer prognosis in this population.

    Article  PubMed  Google Scholar 

  18. Villarreal-Garza C, Shaw-Dulin R, Lara-Medina F, Bacon L, Rivera D, Urzua L, et al. Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients. Exp Diabetes Res. 2012;2012:732027.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Erickson K, Patterson RE, Flatt SW, Natarajan L, Parker BA, Heath DD, et al. Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol. 2011;29:54–60.

    Article  PubMed  Google Scholar 

  20. Minicozzi P, Berrino F, Sebastiani F, Falcini F, Vattiato R, Cioccoloni F, Calagreti G, Fusco M, Vitale MF, Tumino R, Sigona A, Budroni M, Cesaraccio R, Candela G, Scuderi T, Zarcone M, Campisi I, Sant M. High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease. Eur J Cancer. 2013 Sept 3. pii: S0959-8049(13)00759-4. [Epub ahead of print]

  21. Marshall JG, Cowell JM, Campbell ES, McNaughton DB. Regional variations in cancer screening rates found in women with diabetes. Nurs Res. 2010;59:34–41.

    Article  PubMed  Google Scholar 

  22. Zhao G, Ford ES, Ahluwalia IB, Li C, Mokdad A. Prevalence and trends of receipt of cancer screenings among US women with diagnosed diabetes. J Gen Intern Med. 2009;24:270–5.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Beckman TJ, Cuddihy RM, Scheitel SM, Naessens JM, Killian JM, Pankratz VS. Screening mammogram utilization in women with diabetes. Diabetes Care. 2001;24:2049–53.

    Article  CAS  PubMed  Google Scholar 

  24. Fleming ST, Love MM, Bennett K. Diabetes and cancer screening rates among Appalachian and Non-Appalachian residents of Kentucky. J Am Board Fam Med. 2011;24:682–92.

    Article  PubMed  Google Scholar 

  25. Ives DG, Lave JR, Traven ND, Schulz R, Kuller LH. Mammography and pap smear use by older rural women. Public Health Rep. 1996;111:244–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. McBean AM, Yu X. The underuse of screening services among elderly women with diabetes. Diabetes Care. 2007;30:1466–72.

    Article  PubMed  Google Scholar 

  27. Karathanasi I, Kamposioras K, Cortinovis I, Karampoiki V, Alevizaki P, Dambrosio M, et al. Moving ahead in diabetics’ cancer screening; food for thought from the Hellenic experience. Eur J Cancer Care (Engl). 2009;18:255–63.

    Article  CAS  Google Scholar 

  28. Lipscombe LL, Hux JE, Booth GL. Reduced screening mammography among women with diabetes. Arch Intern Med. 2005;165:2090–5.

    Article  PubMed  Google Scholar 

  29. Pereira MA, de Magalhães AV, da Motta LD, Santos AM, Segura ME, Pereira CF, et al. Fibrous mastopathy: clinical, imaging, and histopathologic findings of 31 cases. J Obstet Gynaecol Res. 2010;35:326–35.

    Article  Google Scholar 

  30. Dorokhova O, Fineberg S, Koenigsberg T, Wang Y. Diabetic mastopathy, a clinicopathological correlation of 34 cases. Pathol Int. 2012;62:660–4.

    Article  PubMed  Google Scholar 

  31. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203.

    Article  CAS  PubMed  Google Scholar 

  32. Onitilo AA, Engel JM, Glurich I, Stankowski RV, Williams GM, Doi SA. Diabetes and cancer II: role of diabetes medications and influence of shared risk factors. Cancer Causes Control. 2012;23:991–1008. This review details the risk factors shared by cancer and type 2 diabetes mellitus and describes the effect of anti-diabetes medications in the context of these shared risk factors.

    Article  PubMed  Google Scholar 

  33. Feng YH, Velazquez-Torres G, Gully C, Chen J, Lee MH, Yeung SC. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med. 2011;15:825–36. This in vitro study provides important insight into the effects of anti-diabetic medications on tumor cell growth.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Chakraborty A, Chowdhury S, Bhattacharyya M. Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract. 2011;93:56–62.

    Article  CAS  PubMed  Google Scholar 

  35. Da Ros R, Assaloni R, Ceriello A. The preventive anti-oxidant action of thiazolidinediones: a new therapeutic prospect in diabetes and insulin resistance. Diabet Med. 2004;21:1249–52.

    Article  PubMed  Google Scholar 

  36. Qayyum R, Adomaityte J. Meta-analysis of the effect of thiazolidinediones on serum C-reactive protein levels. Am J Cardiol. 2006;97:655–8.

    Article  CAS  PubMed  Google Scholar 

  37. Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat. 2012;135:639–46.

    Article  CAS  PubMed  Google Scholar 

  38. Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A. Metformin therapy and risk of cancer in patients with type 2 diabetes: a systematic review. PLoS One. 2013;3:e71583.

    Article  Google Scholar 

  39. Berstein LM, Boyarkina MP, Tsyrlina EV, Turkevich EA, Semiglazov VF. More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin. Med Oncol. 2011;28:1260–3.

    Article  CAS  PubMed  Google Scholar 

  40. He X, Esteva FJ, Ensor J, Hortobagyi GN, Lee MH, Yeung SC. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Ann Oncol. 2012;23:1771–80.

    Article  CAS  PubMed  Google Scholar 

  41. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297–302.

    Article  CAS  PubMed  Google Scholar 

  42. Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA, et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat. 2011;126:215–20. This article describes the rationale behind a phase III trial of metformin as an adjuvant therapy for breast cancer and a novel paradigm for the testing of anti-cancer agents.

    Article  CAS  PubMed  Google Scholar 

  43. Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012;30:2593–600. This article reports findings from one of the first randomized pre-surgical trials of metformin use in patients with type 2 diabetes mellitus and breast cancer and describes differences in drug effects by metabolic profile, which is likely to prove important in further studies.

    Article  CAS  PubMed  Google Scholar 

  44. Niraula S, Dowling RJ, Ennis M, Chang MC, Done SJ, Hood N, et al. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat. 2012;135:821–30. This article describes important preliminary data from a window of opportunity study of neoadjuvant therapy for breast cancer and demonstrates changes in tumor cells compatible with anti-cancer effects.

    Article  CAS  PubMed  Google Scholar 

  45. Monami M, Dicembrini I, Mannucci E. Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials. Acta Diabetol. 2013 Jul 14. [Epub ahead of print] This meta-analysis provides the most comprehensive review to date regarding the effects of thiazolidinedione exposure on cancer risk, demonstrates difference by both cancer and drug type.

  46. Bosetti C, Rosato V, Buniato D, Zambon A, La Vecchia C, Corrao G. Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis. Oncologist. 2013;18:148–56.

    Article  CAS  PubMed  Google Scholar 

  47. Bodmer M, Meier C, Krähenbühl S, Jick JJ, Meier CR. Long term metformin use is associated with decreased breast cancer risk. Diabetes Care. 2010;33:1304–8.

    Article  CAS  PubMed  Google Scholar 

  48. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM. Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97:E1170–5.

    Article  CAS  PubMed  Google Scholar 

  49. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766–77.

    Article  CAS  PubMed  Google Scholar 

  50. Ahmadieh H, Azar ST. Type 2 diabetes mellitus, oral diabetic medications, insulin therapy, and overall breast cancer risk. ISRN Endocrinol. 2013;2013:181240. This recent review provides a well-organized overview of the association between type 2 diabetes and breast cancer, including information about the influence of antidiabetic medications.

    PubMed Central  PubMed  Google Scholar 

  51. Grimaldi-Bensouda L, Cameron D, Marty M, Barnett AH, Penault-Llorca F, Pollak M, Charbonnel B, Riddle M, Mignot L, Boivin JF, Khachatryan A, Rossignol M, Bénichou J, Alpérovitch A, Abenhaim L; for the ISICA Group. Risk of breast cancer by individual insulin use – an international multicenter study. Diabetes Care. 2013 Aug 15. [Epub ahead of print]

  52. Lind M, Fahlén M, Eliasson B, Odén A. The relationship between the exposure time of insulin glargine and risk of breast and prostate cancer: an observational study of the time-dependent effects of antidiabetic treatments in patients with diabetes. Prim Care Diabetes. 2012;6:53–9.

    Article  PubMed  Google Scholar 

  53. Suissa S, Azoulay L, Dell’Aniello S, Evans M, Vora J, Pollak M. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011;54:2254–62.

    Article  CAS  PubMed  Google Scholar 

  54. Janghorbani M, Dehghani M, Salehi-Marzijarani M. Systematic review and meta-analysis of insulin therapy and risk of cancer. Horm Cancer. 2012;3:137–46.

    Article  CAS  PubMed  Google Scholar 

  55. Williams GP. The role of oestrogen in the pathogenesis of obesity, type 2 diabetes, breast cancer and prostate disease. Eur J Cancer Prev. 2010;19:256–71.

    Article  CAS  PubMed  Google Scholar 

  56. Pan B, Ren H, He Y, Lv X, Ma Y, Li J, et al. HDL of patients with type 2 diabetes mellitus elevates the capability of promoting breast cancer metastasis. Clin Cancer Res. 2012;18:1246–56.

    Article  CAS  PubMed  Google Scholar 

  57. Pan B, Ren H, Ma Y, Liu D, Yu B, Ji L, et al. High-density lipoprotein of patients with type 2 diabetes mellitus elevates the capability of promoting migration and invasion of breast cancer cells. Int J Cancer. 2012;131:70–82.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Marie Fleisner of the Marshfield Clinic Research Foundation Office of Scientific Writing and Publication for assistance with manuscript preparation and the Marshfield Clinic Research Foundation for internal support of the authors’ work.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Trista J. Stankowski-Drengler, Rachel V. Stankowski, Jessica M. Engel, and Adedayo A. Onitilo declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI, 54449, USA

    Trista J. Stankowski-Drengler & Rachel V. Stankowski

  2. Marshfield Clinic Cancer Care at St. Michaels Hospital, 900 Illinois Avenue, Stevens Point, WI, 54481, USA

    Jessica M. Engel

  3. Department of Hematology/Oncology, Marshfield Clinic Weston Center, 3501 Cranberry Boulevard, Weston, WI, 54476, USA

    Adedayo A. Onitilo

Authors
  1. Trista J. Stankowski-Drengler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rachel V. Stankowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessica M. Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adedayo A. Onitilo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adedayo A. Onitilo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stankowski-Drengler, T.J., Stankowski, R.V., Engel, J.M. et al. The Relationship of Type 2 Diabetes, Oral Diabetes Medications, and Insulin Therapy to Risk for Breast Cancer. Curr Nutr Rep 3, 1–8 (2014). https://doi.org/10.1007/s13668-013-0066-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13668-013-0066-y

Keywords

Search

Navigation