13 January 2014

Ko and colleagues have recently reported that metformin may improve survival in women with endometrial cancer [1]. They retrospectively studied 1495 women who were diagnosed between 2005 and 2010 at two tertiary US academic institutions. Median follow-up was 33 months. Demographic, pathological, clinical and follow-up data were obtained from medical records. Body mass index (BMI) and data on use of metformin, insulin, sulfonamide and thiazolidinedione at the time of cancer diagnosis were obtained. Information on recurrence and death were recorded from clinical and/or electronic data and/or from the Social Security Death Index. Causes of death were not available for all patients. A total of 363 women (24%) had diabetes mellitus, of whom 55% used metformin (n = 200). Some metformin-treated women were also using other treatments, including 34% on sulfonylureas, 18% on thiazolidinediones, 15% on insulin, and 7% on other anti-diabetics. Metformin users were younger (median 62.2 vs. 64.8 years) and heavier (median (interquartiles] BMI = 38 [33–34] vs. 36 [31–42] kg/m2; p = 0.004) than non-metformin-users. Pathologic findings were similar by stage and grade in both groups, although histology was significantly different between groups (despite this, 75% in both groups were endometrioid endometrial carcinomas).

Recurrence-free survival (RFS; %) was decreased more while overall survival was increased more in metformin users than in non-metformin users: non-metformin users had a 1.7% worse RFS (adjusted value 1.8%) and were 2.0 (adjusted value 2.3) times more likely to die as compared with metformin users. Time to recurrence was not significantly different between the groups.

Comment

Obesity, metabolic syndrome and insulin resistance have been related with increased prevalence of several types of cancers, including endometrial, breast, colon, and prostate malignancies [2-4]. Physical activity has the potential to reduce the risk of many of these cancers [5]. As excessive body weight and life expectancy are increasing, these tumors are becoming more frequent. Concerning endometrial cancer, the results from the meta-analysis of seven cohort studies and 11 case-control studies report that excessive body weight (≥ 25 kg/m2) is associated with an increased risk of endometrial cancer, and the strength of the relationship is augmented with increasing BMI [6].

In the developed countries, endometrial cancer is the most frequent malignant genital tumor. Some genes and molecular alterations have a pivotal role in the initiation of endometrial cancer, although the precise mechanisms of development and progression are not well understood. The majority of women with this tumor are postmenopausal and the most common symptom is bleeding which requires an appropriate assessment [7]. Endometrial cancer is a hormone steroid- and metabolic syndrome-dependent tumor whose precise mechanisms of development and growth have not clearly defined [8]. The majority of cases are curable, although a subset (15–20%) has an aggressive phenotype. There are two types of non-hereditary endometrial cancer: type I (e.g. endometrioid or typical adenocarcinoma) or estrogen-related which tends to have a histologically lower grade, while type II (e.g. papillary serous or clear cell carcinomas) is unrelated to steroid hormones and usually has a higher grade and stage. Conventional clinical risk factors for endometrial cancer are only helpful to identify women at risk for the first type. The molecular pathology is also different: type I shows microsatellite instability and mutations in PTEN, PIK3CA, K-RAS and CTNNB1 (beta-catenin), whereas type II shows TP53 mutations and chromosomal instability [9].

The results from Ko and co-workers [1] suggest that, in diabetic women, metformin treatment produces benefits in morbidity and mortality unrelated to cancer which are similar to those previously reported in diabetic subjects with other types of tumors such as prostate, colon, ovary and breast. The benefits are on all-cause mortality, although it remains unclear in cancer-related outcomes such as time to recurrence. It is important to mention that, after adjusting for grade and histology, metformin may have benefits in women with the most aggressive cancers (type II). Nevadunsky and colleagues [10] also reported a cohort of women with endometrial cancer from a single US hospital. They were diabetic women who were treated with metformin (n = 114) and compared to diabetic women not receiving metformin (n = 136) and to those who had not been diagnosed with diabetes (n = 735). Metformin produced a greater overall survival rate in metformin users with non-endometrioid endometrial cancer than in diabetic cases not using metformin and non-endometrioid endometrial cancer cases without diabetes. There were no significant differences in overall survival rate for metformin users with endometrioid endometrial cancer versus non-users of metformin. The data from these two studies should be confirmed by well-designed prospective studies.

Metformin is a biguanide antihyperglycemic agent that, unlike the sulfonylureas, does not act primarily by increasing insulin secretion. It rather lowers the rate of gluconeogenesis in the presence of insulin. Thus, it may be considered an insulin-sensitizer; increased insulin sensitivity may improve the insulin metabolic effect and may decrease its mitogenic effects. In addition, metformin is an inhibitor of endometrial cancer proliferation, induces apoptosis, suppress the insulin growth factor I receptor pathway, may reduce telomerase activity, inhibits tumor cell migration, and decreases tumor growth in preclinical endometrial cancer models. Another relevant aspect to be considered about metformin it that its target tissue levels may be higher than in circulating blood [11,12]. The greatest response is produced in cells with K-Ras mutations [13]. Therefore, metformin is an antidiabetic drug that may have potential antineoplastic actions or may serve in selective drug design for treatment of metabolic syndrome-related cancers, including endometrial cancer.

Further basic and clinical investigations are needed to define the role of metformin in the future management of the different endometrial cancer types. In the mean time, lifestyle changes (diet, weight reduction, exercise, coffee consumption) and appropriate treatment of insulin resistance and diabetes are encouraged to prevent and treat this malignancy. Despite the accumulation of evidence linking lifestyle and weight with cancer risk, many people (including health workers) are still unaware of the connection.

Faustino R. Pérez-López

Professor of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University, Hospital, Zaragoza, Spain

References

1. Ko EM, Walter P, Jackson A, et al. Metformin is associated with improved survival in endometrial cancer. Gynecol Oncol 2013 Nov 22. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/24269517 

2. 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;371:569-78 http://www.ncbi.nlm.nih.gov/pubmed/18280327 

3. Inoue M, Tsugane S. Insulin resistance and cancer: epidemiological evidence. Endocr Relat Cancer 2012;19:F1-8 http://www.ncbi.nlm.nih.gov/pubmed/22851686 

4. Esposito K, Chiodini P, Capuano A, Bellastella G, Maiorino MI, Giugliano D. Metabolic syndrome and endometrial cancer: a meta-analysis. Endocrine 2013 May 3. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/23640372 

5. Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. Eur J Cancer 2010;46:2593-604 http://www.ncbi.nlm.nih.gov/pubmed/20843488 

6. Zhang Y, Liu H, Yang S, Zhang J, Qian L, Chen X. Overweight, obesity and endometrial cancer risk: results from a systematic review and meta-analysis. Int J Biol Markers 2013 Sep 30:0. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/24170556 

7. Dreisler E, Poulsen LG, Antonsen SL, et al. EMAS clinical guide: assessment of the endometrium in peri and postmenopausal women. Maturitas 2013;75:181-90. http://www.ncbi.nlm.nih.gov/pubmed/23619009 

8. Pérez-López FR. Endometrial cancer and adipokines. Climacteric 2013;16:725-6 9. Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology 2013; 62:111–23. http://www.ncbi.nlm.nih.gov/pubmed/23240673 

10. Nevadunsky NS, Van Arsdale A, Strickler HD, et al. Metformin use and endometrial cancer survival. Gynecol Oncol 2013 Nov 2. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/24189334 

11. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol 2010;116:92-8 http://www.ncbi.nlm.nih.gov/pubmed/19822355 

12. Sarfstein R, Friedman Y, Attias-Geva Z, Fishman A, Bruchim I, Werner H. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. PLoS One 2013;8:e61537 http://www.ncbi.nlm.nih.gov/pubmed/23620761 

13. Iglesias DA, Yates MS, van der Hoeven D, et al. Another surprise from metformin: Novel mechanism of action via K-Ras influences endometrial cancer response to therapy. Mol Cancer Ther 2013 Nov 21. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/24077915