OncologyCan metformin change the prognosis of pancreatic cancer? Retrospective study for pancreatic cancer patients with pre-existing diabetes mellitus type 2
Introduction
Pancreatic cancer is the tenth most common cancer, accounting for approximately 3% of all cancers and 7% of cancer deaths in the United States [1]. Despite recent advances in molecular biology and the development of new chemotherapeutic agents, such as targeted cancer treatments, pancreatic cancer remains extremely lethal, with a 5-year survival rate of only 6% [2]. Surgical resection is the only potentially curative treatment modality for pancreatic cancer, but only 15–20% of patients are considered surgical candidates [3]. Novel strategies for primary prevention, early detection, and treatment are needed for this catastrophic disease.
The association between diabetes mellitus (DM) and pancreatic cancer has been recognized for a long time. Long-standing type 2 diabetes (more than 10 years) is considered an established risk factor for pancreatic cancer, increasing the risk thereof by 1.51-fold (95% confidence interval [CI] = 1.16–1.96) [4]. On the contrary, up to 80% of patients present with either new-onset (<2–3 years) DM or impaired glucose tolerance, as a manifestation of pancreatic cancer, at the time of diagnosis [5]. Several recent studies illustrated that metformin, one of the most widely prescribed drugs for type 2 DM, was associated with a lower incidence of pancreatic cancer compared to insulin or insulin secretagogues [6], [7], [8]. Although the anti-cancer mechanism of metformin is not fully understood, the principal mechanism of metformin's action is the alteration of the energy metabolism in the cell through the inhibition of mitochondrial oxidative respiration [9]. Also, the anti-cancer activity of metformin has been primarily attributed to its ability to directly activate the serine-threonine liver kinase B (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway, which suppresses the mammalian target of rapamycin (mTOR) pathway [10]. Metformin additionally inhibit insulin-induced tumor growth by decreasing circulating levels of insulin and insulin-like growth factor-1 (IGF-1) [11], [12]. Several in vitro studies discovered that metformin probably inhibits cancer cell proliferation, migration, and invasion and preferentially kills cancer stem cells [13], [14]. These results were also supported by in vivo studies [15]. Considering the aforementioned findings, metformin can be regarded as a novel, promising, and well-tolerated drug for the prevention and treatment of pancreatic cancer.
To date, two retrospective studies have reported the effect of metformin on survival in patients with pancreatic cancer. One study by Sadeghi et al. revealed a survival benefit of metformin with an overall hazard ratio (HR) of 0.68 (95% CI = 0.52–0.89; P = 0.004) [16]. According to this report, the survival benefit of metformin use was statistically significant in non-metastatic stages. In another study by Hwang et al., metformin exposure during the peri-diagnosis period was not associated with a survival benefit in patients with an advanced stage of pancreatic cancer (locally advanced and metastatic stages) [17]. The effect of metformin on survival in patients with pancreatic cancer remains debatable. Therefore, the aim of this study was to investigate the anti-tumor effect of metformin in patients with pancreatic cancer and pre-existing DM.
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Study population
A total of 1339 patients with pancreatic cancer diagnosed between January 2005 and December 2013 at a single medical center, Severance Hospital at the Yonsei University Health System (Seoul, South Korea), were screened. Among these, 1102 patients were excluded based on the following exclusion criteria: no history of pre-existing type 2 DM (n = 777); follow-up loss of less than 1 months (n = 102); patients treated with just supportive care only (n = 92); incomplete records, including medication
Baseline characteristics
The baseline characteristics of the 237 enrolled patients, consisting of 117 patients in the metformin group (49.4%) and 120 patients in non-metformin group (50.6%), are summarized in Table 1. The patient population consisted of 237 patients. 157 patients were male and the median age of 66 (range 34–85) years. The average BMI was 21.8 kg/m2, and the duration of DM before a diagnosis of pancreatic cancer was 5.0 (range 0.2–32.0) years. At the time of cancer diagnosis, 157 (66.2%) patients had
Discussion
In this retrospective study of patients with pancreatic cancer and pre-existing type 2 DM, we concluded that metformin exposure was associated with favorable survival outcomes, as OS was prolonged by 4.8 months in the metformin group, compared to that in the non-metformin group. In multivariate analysis, metformin use was also independently associated with a 39% reduction in mortality risk. Additionally, among patients in the metformin group, the cumulative duration of metformin use was
Conflict of interest
None declared.
Acknowledgements
Hee Seung Lee, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Si Young Song, Jae Bock Chung, and Seungmin Bang are gratefully acknowledged.
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These authors have contributed equally to this work.