Cancer. 2013 Feb 1;119(3):555-62. doi: 10.1002/cncr.27706. PMID:23208739

Metformin intake associates with better survival in ovarian cancer. 

Sanjeev Kumar, MBBS1, Alexandra Meuter, MD1, Prabin Thapa, MS2 Carrie Langstraat, MD1, Shailendra Giri, PhD4, Jeremy Chien, PhD3, Ramandeep Rattan, PhD4, William Cliby, MD1,Viji Shridhar, PhD

1Department of Gynecologic Surgery, Mayo Clinic College of Medicine, Rochester MN.
2Department of Biostatistics and Health Sciences Research; Mayo Clinic College of Medicine, Rochester MN.
3Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kan.
4Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester MN.

 

Introduction

The National Cancer Institute (NCI) estimates that ovarian cancer causes equal number of deaths as compared to the cancers of the uterus, cervix, vagina and vulva; all combined [1].  75% of patients have extensive (>stage III) disease at diagnosis, and the currently available therapies in upfront and recurrent setting have limited efficacy [2].  While majority of the patients initially have a favorable response to currently existing standard front line chemotherapy agents (platinum and taxanes), resistance invariably develops; accounting for poor cure rates. Consequently, there is great need to develop improved up-front and salvage therapies for ovarian cancer [2].

One avenue to find novel therapies for ovarian cancer is “drug repositioning”, which is an approach whereby already existing drugs are used to treat a different and new disease. This approach carries the promise of accelerating the translation of laboratory research to the clinical practice in a shorter time frame. One such repurposing drug is metformin.  A tremendous amount of work to test metformin in vitro against a variety of cancers has been conducted and potent anticancer effects have been observed. [6] [7] [8] [9] [10]. The present study was conducted to find any association of metformin intake to that of survival in ovarian cancer.

Methods

This study was approved by the Institutional Review Board (IRB) of the Mayo Clinic, Rochester, MN, USA. Patients with a diagnosis of ovarian cancer who were prescribed metformin were identified by inpatient hospital records as well as outpatient pharmacy prescription records. Patients were only included in the study if they used metformin for 1 year or more. In this single institution retrospective case control study, ovarian cancer patients who took metformin (cases) were compared with patients having ovarian cancer but were not on metformin (controls). In preliminary analysis, all cases (n=72) with Ovarian Cancer (OC cohort) were compared with controls in 1:2 ratio. Subsequently in definitive analysis, only Epithelial Ovarian Cancer cases (EOC) were compared with controls in 1:3 ratio. In EOC cohort, cases were matched with controls for age (+/-5 years), FIGO stage and residual disease. Prognostic variables and Disease Specific Survival (DSS) were compared with chi square, Kaplan-Meier (log rank) and Cox proportional hazards.

Results

For the initial analysis, data were available for 72 patients with ovarian cancer who took metformin (cases) and 143 randomly selected controls. One case had only one control (hence a total of 143 controls rather than 144). Mean duration of metformin intake was 2.3 years (range 1-11). The distribution of age, year of diagnosis, optimal surgical cytoreduction and platinum based chemotherapy utilization remained similar in cases and controls. The entire cohort had a median disease specific survival of 5.5 (95% CI 4.1-7.5) years. While the median survival for the controls was 4.1 years, the median survival for the cases was not reached (log rank p=0.0002, Figure 1).Figure 1

In the definitive analysis, we identified 61 cases of epithelial ovarian cancer and matched them with 178 controls (total cohort of epithelial ovarian cancer, n=239). This was our definitive analysis where matching variables were age, FIGO stage and residual disease on surgical cytoreduction (optimal versus suboptimal). The mean duration of follow up for the cases was 3.7 years (SD 2.6) versus 4.3 years (SD 3.1) for the controls. Here, the 5 year survival of the entire cohort was 52%. The 5 year survival for the cases (67%) was significantly better when compared to controls (47%, log rank p=0.04) (Figure 2).Figure 2

Discussion

Originating from the French Lilac plant (Galega officinalis), metformin is one of the most commonly used medications for diabetes worldwide. This is a retrospective case control study evaluating the association of metformin with prognosis in ovarian cancer. Although causation could not be assessed; we found that metformin is associated with significantly better prognosis in ovarian cancer.  The interest in metformin as an anticancer compound was initially ignited by two key epidemiologic reports.

Before metformin can be used in patients for its anticancer effects, the most important question is to decipher if the observations made by our study are merely by chance or a true clinical effect. It is striking that in our initial analysis on the OC cohort incorporating all metformin associated ovarian cancers, metformin associated tumors were more likely to be lower grade, earlier stage and had a more favorable histology profile. One could attribute the association of better prognosis in ovarian cancer with that of metformin on the constellation of these lower risk attributes in the cases of the OC cohort. Part of our data lends some support to this hypothesis as confounding is definitively at play for a small fraction of our cases in the OC cohort. For example, 4 cases (5.6%) in the OC cohort had granulosa cell tumors where diabetes and obesity are commonly a result of the hormonal effects of the tumor itself [13], leading to prescription of metformin and Granulosa cell tumors tend to have a much better prognosis than epithelial ovarian cancer. Similarly, tumors of low malignant potential may have a better prognosis when compared to their frankly invasive epithelial ovarian cancers.

Figure 3

To overcome the limitations posed by the non-uniform distribution of FIGO stage and tumor types, we performed the definitive analysis incorporating only epithelial ovarian cancer (EOC cohort) and matching the cases for age, FIGO stage and residual disease after cytoreductive surgery; the factors most notably affecting the survival in ovarian cancer patients. In this analysis, the association of metformin with better prognosis in ovarian cancer persisted in the overall analysis as well as in the subgroup analysis of complete cytoreduction and incomplete cytoreduction subgroups (Figures 3 and 4). Secondly, when the analysis was restricted to serous histology only or stage III & IV tumors only, the survival advantage associated with metformin persisted (Figure 5). Finally, the multivariable analysis after controlling for age, stage, histology, year of diagnosis, type of chemotherapy and tumor grade suggested metformin to be an independent predictor of survival for ovarian cancer. These observations suggest that confounding is unlikely to be the sole factor accounting for a remarkable difference in prognosis between cases and controls.

Figure 4

Cumulatively, metformin was associated with better prognosis in ovarian cancer patients. Although causation could not be assessed by our retrospective study; metformin nevertheless is a strong contender for further clinical studies in ovarian cancer. These may be retrospective confirmatory studies by other institutions and/or prospective phase I/II studies in ovarian cancer patients.

Figure 5

REFERENCES

[1]        Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.

[2]        Cannistra SA. Cancer of the ovary. N Engl J Med l1993;329: 1550-9.

[3]        Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect l2009;22: 119-25.

[4]        Campas C. Drug repositioning summit: finding new routes to success. Drug News Perspect l2009;22: 126-8.

[5]        Richardson P. Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide. Semin Hematol l2005;42: S9-15.

[6]        Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med 15: 166-78.

[7]        Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene l2008;27: 3576-86.

[8]        Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila) l2008;1: 369-75.

[9]        Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res l2009;69: 6539-45.

[10]      Isakovic A, Harhaji L, Stevanovic D, Markovic Z, Sumarac-Dumanovic M, Starcevic V, Micic D, Trajkovic V. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci l2007;64: 1290-302.

 

Acknowledgements: This work was supported in part by the grants from the Fred C. and Katherine B. Andersen Foundation (VS) and National Institutes of Health Grants P50 CA123249 and CA136393 (VS).

 

Contact:

Email: Viji Shridhar PhD (shridhar.vijayalakshmi@mayo.edu); Sanjeev Kumar, MBBS (sanje45@gmail.com)

 

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