The prevalence and incidence of diabetes continue to rise markedly. The effects of diabetes on breast cancer are complex and have been the subject of recent scrutiny. Diabetes has been found to be a risk factor for breast cancer in some but not all studies, and diabetic patients with breast cancer may have worse outcomes than might their nondiabetic counterparts 1,2. Extensive epidemiological data suggest important roles of type 2 diabetes mellitus (DM2) in carcinogenesis. There is also evidence that DM2 is associated with decreased survival in breast cancer patients 3,4. Obesity associated with type 2 diabetes is itself a risk factor for breast cancer 5 and possibly for poorer breast cancer outcomes 6. The common factor linking diabetes, obesity, and metabolic syndrome to cancer may be the insulin resistance and consequent hyperinsulinemia associated with these conditions. Moreover, there is also increasing evidence that hyperinsulinemia and insulin resistance worsen breast cancer prognosis. Insulin may promote tumorigenesis by a direct effect on epithelial tissues or indirectly by affecting other modulators, such as insulin-like growth factors, sex hormones, and adipokines 7.
Metformin (N’, N’-dimethylbiguanide) belongs to the biguanide class of oral hypoglycemic agents and is a widely used antidiabetic drug for the treatment of type 2 diabetes. Several studies have suggested a possible association between the use of metformin and decreased risk for cancer and cancer-specific mortality in diabetic patients 8–11. The mechanisms involved in the antiproliferative effects of metformin are probably very diverse. Preclinical studies with breast cancer cell lines demonstrate that metformin may have different mechanisms of tumor inhibition through insulin-dependent and insulin-independent pathways 12.
Metformin acts as a growth inhibitor that is mediated by upregulation of AMP-activated protein kinase (AMPK) activity. The AMPK pathway is a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer. Metformin regulates the AMPK/mTOR pathway, implicated in the control of protein synthesis and cell proliferation. Indeed, mTOR is activated by the mitogenic-responsive pathways (Ras/ERK, PI3K/Akt) and the pathways that signal the availability of intracellular energy and nutrients such as amino acids 12. Other mechanisms include, in particular, influences on estrogen biosynthesis and estrogenic signal transduction 13 and suppression of human epidermal growth factor receptor-2 (HER-2) protein expression 14. More recently, Liu et al.15 demonstrated unique apoptotic effects of metformin against triple receptor-negative breast cancer cell lines by peroxisome proliferator-activated receptor cleavage and the activation of both intrinsic and extrinsic caspase signaling cascades. These findings have prompted great interest in metformin as an anticancer agent, including adjuvant trials on nondiabetic women with breast cancer 16.
The objective of the present work was to determine whether metformin use was associated with better survival outcome in diabetic patients with breast cancer receiving adjuvant chemotherapy.
Patients and methods
In this retrospective study, we reviewed the records of 460 consecutive patients with pathologically proved stage I–III breast cancer .These patients presented to the Cancer Management and Research Department, Medical Research Institute, University of Alexandria during the period between 1 January 2008 and 31 December 2008. The data were collected in January 2013. Patients were categorized according to diabetic status and metformin use. Medication records from patient record review were analyzed to divide the diabetic patients into those taking metformin and those not taking metformin during adjuvant chemotherapy. The use of other diabetic medications (insulin, thiazolidinediones, and so on) was also detected. The study was in compliance with the declaration of Helsinki and approved by the ethical committee of our institution.
The exclusion criteria included diagnosis of diabetes after starting of anticancer treatment, resolved gestational diabetes, second concurrent primary cancer, and administration of other antidiabetic therapy for the metformin group.
Patients were subjected to preoperative evaluation including history taking and clinical examination to detect the site, the size of the tumor, and the presence of enlarged lymph nodes. The diagnosis of invasive breast cancer was made by fine-needle aspiration or core-needle biopsy of the breast tumor. Stage was defined by the sixth edition of the Cancer Staging Manual of the American Joint Committee on Cancer 17. The histological grade of each tumor was defined according to the classification system of the WHO. Estrogen receptor (ER) and progesterone receptor status was performed using standard immunohistochemistry procedures. HER-2 status was evaluated by immunohistochemistry or by fluorescence in-situ hybridization.
Adjuvant chemotherapy regimens included three to six anthracycline-based regimens. All patients in this study received FAC or FEC regimens (fluorouracil, doxorubicin or epirubicin, and cyclophosphamide).
Postoperative radiotherapy was received if patients had undergone breast conservative surgery, had locally advanced disease at presentation, primary tumor of equal to 5 cm or greater, and four or more involved axillary nodes. Adjuvant hormonal treatment was administered according to hormonal receptors status.
The dose of metformin in the metformin group ranged from 500 to 2000 mg orally once a day with the evening meal (extended release tablets) or 500 mg twice daily. Maximum daily dose was 2500 mg.
Statistical analyses were conducted using the statistical software package of SPSS version 11.5 (SPSS Inc., Chicago, Illinois, USA). Patients’ characteristics including age, menopausal status, tumor size, nodal status, histology, nuclear grade, presence of lymphovascular invasion, hormonal receptors status, and HER-2 status were compared. Differences between groups were assessed by the Kruskal–Wallis test and χ2-test. The duration of follow-up was calculated from the date of presentation to the date of death or last follow-up. Five-year survival curves were generated using the Kaplan–Meier estimates, and the significant difference between curves was evaluated by the log-rank test. Disease-free survival was calculated from the date of presentation to the date of local recurrence, distant metastasis, contralateral breast cancer, lost follow-up, and death from any cause. Overall survival was calculated from the date of presentation until the date of death from any cause or lost follow-up, respectively. Multivariate Cox proportional hazards regression models were used to model survival as a function of metformin use after adjusting for the various confounders. Statistical significance was set at P-value less than 0.05.
Patients’ clinical characteristics
Patients were divided into three groups:
The metformin group included diabetic breast cancer patients (type 2 diabetes) taking metformin.
The nonmetformin group included diabetic breast cancer patients (type 1 or 2 diabetes) taking antidiabetic treatment other than metformin (insulin, sulfonylureas, thiazolidinediones). The nondiabetic group included nondiabetic breast cancer patients.
Among 460 patients, 27 were found to be in the metformin group (data on the outcome and treatment received were available for 25 patients), 18 were found to be in the nonmetformin group (data on the outcome and treatment received were available for 14 patients), and 415 patients were in the nondiabetic group (data on the outcome and treatment received were available for 400 patients). Hence, the full data were available for 439 patients.
Clinicopathological characteristics of the patients are summarized in Table 1. The standard prognostic factors were not significantly different between the three studied groups.
Disease-free survival according to metformin administration in diabetic breast cancer patients
At a median follow-up of 46 months (range 22–60 months), an exploratory analysis of disease-free survival and overall survival estimates by the Kaplan–Meier method was performed.
Figure 1 represents the Kaplan–Meier plot, which shows that diabetic breast cancer patients taking metformin had longer mean disease-free survival time [55.1 months, 95% confidence interval (CI): 50.23–59.86] than diabetic patients not taking metformin (28.14 months, 95% CI: 19.25–24.75) and nondiabetic patients (41.65 months, 95% CI: 33.43–49.87). On using log-rank test, the difference was statistically significant (P=0.0001 and 0.0249, respectively). Furthermore, nondiabetic breast cancer patients had longer mean disease-free survival time (41.65 months, 95% CI: 33.43–49.87) than diabetic patients not taking metformin (28.14 months, 95% CI: 19.25–24.75) and the difference also was statistically significant (P=0.0326).
Overall survival according to metformin administration in diabetic breast cancer patients
Figure 2 represents the Kaplan–Meier plot, which shows that diabetic breast cancer patients taking metformin had longer mean overall survival time (59.71 months, 95% CI: 59.34–60.09) than diabetic patients not taking metformin (41.79 months, 95% CI: 33.39–46.18) and nondiabetic patients (52.0 months, 95% CI: 48.37–56.87). On using log-rank test, the difference was statistically significant (P=0.0032 and 0.0350, respectively). Furthermore, nondiabetic breast cancer patients had longer mean overall survival time (52.0 months, 95% CI: 48.37–56.87) than diabetic patients not taking metformin (41.79 months, 95% CI: 33.39–46.18) and the difference was statistically significant (P=0.0472).
Association of antidiabetic pharmacotherapy with breast cancer mortality in multivariate analysis
In multivariate regression analysis, we examined predictive factors for breast cancer mortality in patients with breast cancer using Cox-regression model (Table 2). Age at presentation (≥50) and advanced stage disease (stage III) are associated with increased breast cancer mortality (P=0.040 and 0.030, respectively). After adjustment of other factors, metformin use during adjuvant chemotherapy is associated with significantly decreased breast cancer mortality (P=0.003). In contrast, we found that ER and progesterone receptor status, lymph node metastasis, and tumor grade are not associated with breast cancer mortality (P=0.807, 0.776, and 0.639, respectively). Therefore, age at presentation, advanced stage disease, and metformin use during adjuvant chemotherapy are significant predictors of breast cancer mortality.
Despite major diagnostic and therapeutic innovations, the treatment effect on breast cancer-related morbidity and mortality is still limited mainly because of the incomplete knowledge of the disease biology. Major research efforts continue to focus on identifying new agents able to treat or prevent breast carcinoma. Despite recognition of the potential link between type 2 diabetes and cancer (possibly through common mechanism of insulin resistance), very little is known about the possible effect of various antidiabetic therapies on cancer-related mortality. Recent interest has been focused on metformin, a biguanide derivative currently approved for the treatment of non-insulin-dependent diabetes mellitus and an insulin-sensitizing agent 18. Metformin has been associated with a reduction in breast cancer risk and may improve disease-specific survival through direct and indirect tumor-suppressing mechanisms 19.
In the present study, Kaplan–Meier analysis showed that diabetic breast cancer patients taking metformin had longer mean disease-free survival time (55.1 months) than diabetic patients not taking metformin (28.14 months) and nondiabetic patients (41.65 months). The differences were statistically significant (P=0.0001 and 0.0249, respectively). Moreover, nondiabetic breast cancer patients had longer mean disease-free survival time (41.65 months) than diabetic patients not taking metformin (28.14 months) and the difference was also statistically significant (P=0.0326). Regarding overall survival, diabetic breast cancer patients treated with metformin as antidiabetic agent had longer mean overall survival time (59.71 months) than diabetic patients not treated with metformin (41.79 months) and nondiabetic patients (52.0 months). The difference was statistically significant (P=0.0032 and 0.0350, respectively). Furthermore, nondiabetic breast cancer patients had longer mean overall survival time (52.0 months) than diabetic patients not taking metformin (41.79 months) and the difference was statistically significant (P=0.0472).
The above results agreed with the results of He et al.20 who found that metformin therapy and thiazolidinedione therapy were significant predictors of increased overall survival of a defined group of patient population (i.e. diabetic patients with stage≥2 HER-2+ breast cancer). In particular, diabetic patients who received metformin therapy had a significantly longer survival duration compared with patients who did not receive metformin therapy (P=0.045). The median survival of metformin users was 42.2 months compared with 37.8 months in insulin users. He also concluded that metformin±thiazolidinedione therapy was associated with decreased cumulative incidence of breast cancer-specific death in this patient population, whereas insulin±secretagogue therapy was associated with increased cumulative incidence.
In multivariate regression analysis, our study showed that metformin usage is associated with significantly decreased breast cancer mortality (P=0.003) (hazard ratio=0.111, 95% CI: 0.028–0.440). In agreement with our results, Hou et al.21 showed in the multivariate survival analysis using Cox regression model that the metformin-treated subgroup was associated with lower mortality risk, whereas the non-metformin-treated subgroup was associated with higher mortality risk. In contrast to our results, Jiralerspong et al.22 showed that metformin usage was not a predictor of overall survival in breast cancer patients.
Bowker et al.23 found that DM2 patients treated with sulfonylurea and insulin had a significantly higher risk for cancer-related mortality compared with patients treated with metformin. This observed difference was related to the combined effect on both carcinogenesis and cancer progression. Three possible explanations for this difference were offered: (a) a deleterious effect of sulfonylurea and insulin, (b) a protective effect of metformin, or (c) some unmeasured effect related to both choice of therapy and cancer risk.
Alimova et al.14 showed that the anti-type 2 diabetes drug metformin inhibits the proliferation of breast cancer cells through a variety of mechanisms beyond its impact on systemic insulin sensitivity. This effect was independent on ER status and this suggests that metformin may have broad therapeutic efficacy in breast cancer treatment.
Metformin also inhibited cell growth through cell cycle G1 arrest, regardless of the p53 status of the breast cancer cells. Moreover, within the therapeutic dosage range for type 2 diabetes, metformin inhibited HER-2/neu tyrosine kinase activity and downstream signaling. These effects are of particular interest, because they suggest that the addition of metformin may synergistically enhance the anticancer effects of the anti-HER-2/neu agents such as herceptin. Goodwin et al.24 suggested that the possible beneficial action of metformin in breast cancer may be related to activation of AMPK, which may ultimately result in a rapid inhibition of cellular protein synthesis and growth of tumor cells.
In contrast, Bayrakter et al.25 showed that metformin use during adjuvant therapy was not associated with improved survival outcomes in diabetic patients with triple-negative breast cancer; however, there was a trend toward a decrease in the risk of developing distant metastasis in diabetic patients taking metformin compared with nondiabetic patients. In addition, Lega et al.19 failed to show an association between improved survival and increased cumulative metformin duration in older breast cancer patients who had recent-onset diabetes.
There is evidence suggesting that metformin has a positive impact on inflammation and endothelial dysfunction. Metformin was compared with another oral hypoglycemic agent, repaglinide, in nonobese patients with type 2 diabetes and has shown to be more effective in reducing levels of tumor necrosis factor-α, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1, and soluble E-selectin 26. A further study has shown that metformin is capable of producing a significant decrease in the levels of vascular endothelial growth factor 27.
- The main finding of this study is that there is an association between metformin use and better survival outcome in diabetic breast cancer patients who received metformin during adjuvant chemotherapy. This is consistent with the idea that metformin may have an antitumor effect in diabetic patients with breast cancer.
- The choice of antidiabetic pharmacotherapy may influence prognosis of diabetic breast cancer patients.
- Metformin is a readily available, inexpensive, and generally well tolerated oral medication. This warrants additional studies to definitely evaluate its potential as a new class of antitumor agents in breast cancer.
Conflicts of interest
There are no conflicts of interest.
1. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus
and risk of breast cancer
: a meta-analysis. Int J Cancer 2007; 121:856–862.
2. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus
as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004; 159:1160–1167.
3. Richardson LC, Pollack LA. Therapy insight: influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol 2005; 2:48–53.
4. Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE. The impact of diabetes on survival following breast cancer
. Breast Cancer
Res Treat 2008; 109:389–395.
5. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371:569–578.
6. Carmichael AR. Obesity and prognosis of breast cancer
. Obes Rev 2006; 7:333–340.
7. Goodwin PJ. Insulin in the adjuvant breast cancer
setting: a novel therapeutic target for lifestyle and pharmacologic interventions. JClinOncol 2008; 26:833–834.
8. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin
and reduced risk of cancer in diabetic patients. BMJ 2005; 330:1304–1305.
9. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin
are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009; 32:1620–1625.
10. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52:1766–1777.
11. Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin
use is associated with decreased risk of breast cancer
. Diabetes Care 2010; 33:1304–1308.
12. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin
inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer
cells. Cancer Res 2007; 67:10804–10812.
13. Brown KA, Hunger NI, Docanto M, Simpson ER. Metformin
inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer
Res Treat 2010; 123:591–596.
14. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, et al.. Metformin
inhibits breast cancer
cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009; 8:909–915.
15. Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, et al.. Metformin
induces unique biological and molecular responses in triple negative breast cancer
cells. Cell Cycle 2009; 8:2031–2040.
16. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin
selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69:7507–7511.
17. Greene F, Page D, Fleming I, Fritz A, Balch C, Haller D, et al.. AJCC Cancer Staging Manual, sixth edition. Ann Oncol 2003; 14:345–346.
18. Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A. Is it time to test metformin
in breast cancer
clinical trials? Cancer Epidemiol Biomarkers Prev 2009; 18:701–705.
19. Lega I, Austin P, Gruneir A, Goodwin P, Rochon P, Lipscombe L. Association between metformin
therapy and mortality after breast cancer
: a population-based study. Diabetes Care 2013; 36:3018–3026.
20. 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; 23:1771–1780.
21. Hou G, Zhang S, Zhang X, Wang P, Hao X, Zhang J. Clinical pathological characteristics and prognostic analysis of 1013 breast cancer
patients with diabetes. Breast Cancer
Res Treat 2013; 137:807–816.
22. Jiralerspong S, Palla SL, Giordano SH, Bernstam MF, Liedtke C, Barnett CM, et al.. Metformin
and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer
. J Clin Oncol 2009; 27:3297–3302.
23. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29:254–258.
24. Goodwin PJ, Ligibel JA, Stambolic V. Metformin
in breast cancer
: time for action. J Clin Oncol 2009; 27:3271–3273.
25. Bayrakter S, Hernadez AL, Lei X, Meric BF, Liton JK, Hortobagyi GN, et al.. Effect of metformin
on survival outcomes
in diabetic patients with triple receptor-negative breast cancer
. Cancer 2012; 118:1202–1211.
26. Lund SS, Tarnow L, Stehouwer C, Schalkwijk G, Winther K, Frandsen M, et al.. Impact of metformin
versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 2008; 158:631–641.
27. Ersoy C, Kiyici S, Budak F, Oral B, Guclu M, Duran C, et al.. The effect of metformin
treatment on VEGF and PAI 1 levels in obese type 2 diabetic patients. Diabetes Res Clin Pract 2008; 81:56–60.