The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts☆
Introduction
Endometrial cancer (EC) is the third most common gynecologic malignancy worldwide after breast and cervical cancers [1]. The age-adjusted incidence of EC continues to increase in parallel with progression of the epidemic of obesity and physical inactivity [2]. Diabetes mellitus (DM) is a well-known risk factor for EC, with similar prevalence in both type I and II EC [3], [4]. The paradigm of obesity, DM, and insulin resistance may have a critical role in the pathogenesis of EC [5], [6]. Additionally, diabetic women with EC appear to have an increased risk of all-cause mortality compared with nondiabetic women [6]. It has been suggested that whereas insulin resistance and DM may facilitate the initiation and progression of EC, effective DM control may prevent or modulate EC [7].
Metformin is an oral insulin-sensitizing agent used as first-line therapy for type II DM [8]. It inhibits hepatic gluconeogenesis and enhances insulin sensitivity and glucose utilization in peripheral tissues [9]. In vitro data have shown that metformin inhibits growth and decreases invasion and metastasis of EC cell lines [10], [11]. Furthermore, the inhibition of oxidative phosphorylation and modulation of the mTOR pathway by metformin suggests that it has potential therapeutic benefits in EC [12]. A multi-institutional study recently showed that metformin use was associated with improvement in recurrence-free survival and overall survival in patients with EC [13]. The survival benefits of metformin have been particularly highlighted in nonendometrioid EC subtypes, which suggests a role for its use in adjuvant therapy for type II EC [14]. It is unclear whether the benefits of metformin in diabetic patients with EC are attributed to the direct antineoplastic effects of the drug, alteration in the metabolic and hormonal milieu, or modification of underlying patient- and disease-specific factors. The aim of this study was to investigate the effects of metformin on overall survival (OS) and progression-free survival (PFS) in patients with EC after controlling for multiple confounding patient-, disease-, and treatment-specific factors.
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Study patients
We retrospectively searched our patient database for the records of all patients who underwent primary surgical intervention for EC at Mayo Clinic, Rochester, Minnesota, from January 1, 1999, through December 31, 2008. Patients who received neoadjuvant chemotherapy, had synchronous invasive cancers, or who denied access to their medical information for research purposes were excluded. The study was approved by the Mayo Clinic Institutional Review Board.
Data collection
As in a prior report addressing the
Results
A total of 1415 patients underwent surgery for EC during the study period. After exclusion of patients with synchronous invasive cancers, receipt of neoadjuvant therapy, or without consent for research, 1303 patients were evaluable. Among the 1303 patients, 277 (21.3%) had a preexisting diagnosis of DM at the time of EC diagnosis, and 1026 (78.7%) were not diabetic. Among patients with DM, 116 (41.9%) were being treated with metformin, 57 (20.6%) with other oral agents, 51 (18.4%) with insulin
Discussion
Worldwide, approximately 400 million people have a diagnosis of DM, with 85% to 95% characterized as type II DM [23]. Multiple studies have suggested an association between type II DM and risk of and mortality from liver, pancreatic, colorectal, breast, and endometrial cancer [24]. However, the evidence to support this conclusion has been criticized for its methodological limitations and lack of robustness [25], [26], [27]. From an epidemiologic perspective, the development of EC has been
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
Funding source: No specific intra- or extramural funding was obtained.
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Reprints: Division of Gynecologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States.