Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium

Bosetti, Cristina; Rosato, Valentina; Li, D.; Silverman, Debra T.; Petersen, Gloria M.; Bracci, Paige M.; Neale, Rachel E.; Muscat, Joshua E.; Anderson, Kristin E.; Gallinger, Steven; Olson, Sara H.; Miller, Anthony B.; Bueno-de-Mesquita, H. Bas; Scélo, Ghislaine; Janout, Vladimí­r; Holcátová, Ivana; Λάγιου, Παγώνα; Serraino, Diego; Lucenteforte, Ersilia; Fabiánovà, Eleonóra; Ghadirian, Parviz; Baghurst, Peter; Zatoński, Witold; Foretová, Lenka; Fontham, Elizabeth T.H.; Bamlet, William R.; Holly, Elizabeth A.; Negri, Eva; Hassan, Manal M.; Prizment, Anna E.; Cotterchio, Michelle; Cleary, Sean P.; Kurtz, Robert C.; Maisonneuve, Patrick; Trichopoulos, Dimitrios; Polesel, Jerry; Duell, Eric J.; Boffetta, Paolo; Vecchia, Carlo La

doi:10.1093/annonc/mdu276

Cited by 225 publications

(154 citation statements)

References 46 publications

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“…Tobacco smoking,4, 5, 6 high age4, 7, 8 and heredity9, 10 seem to be the only truly validated risk factors for pancreatic cancer. Several other risk factors have been investigated, and numerous studies claim a significant impact of diabetes,11, 12, 13 pancreatitis,14, 15, 16 alcohol17, 18, 19, 20 and body mass index (BMI)13, 21, 22, 23; however, no consensus has yet been reached.…”

mentioning

confidence: 99%

Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study

Andersson

Borgquist

Jirström

2018

Intl Journal of Cancer

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The incidence of pancreatic cancer is leveling between sexes. Smoking, high age and heredity are established risk factors, but evidence regarding the influence of hormonal factors is unclear. In this study, we investigated the associations of reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) with pancreatic cancer risk in the Malmö Diet and Cancer Study, a prospective, population‐based cohort encompassing 17,035 women. Up until 31 December 2015, 110 women were identified with incident pancreatic cancer through the Swedish Cancer Registry. Higher age at menarche was significantly associated with pancreatic cancer risk (age‐adjusted [hazard ratio] HR = 1.17; 95% confidence interval [CI] 1.04–1.32, and fully adjusted HR = 1.17; 95% CI 1.04–1.32). Ever use of OC was not significantly associated with pancreatic cancer risk but ever use of HRT was significantly associated with a decreased risk of pancreatic cancer (age‐adjusted HR = 0.47, 95% CI 0.23–0.97, and fully adjusted HR = 0.48, 95% CI 0.23–1.00), in particular use of estrogen‐only regimen (age‐adjusted HR = 0.21; 95% CI 0.05–0.87 and fully adjusted HR = 0.22; 95% CI 0.05–0.90). Age at menopause or first childbirth, parity and breastfeeding history were not significantly associated with pancreatic cancer risk. Collectively, these findings suggest a protective role of female hormones against pancreatic cancer. Further studies are needed, and potential modifying genetic factors and indirect hazardous effects of smoking should also be considered.

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confidence: 99%

Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study

Andersson

Borgquist

Jirström

2018

Intl Journal of Cancer

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“…The low survival rate is due to the late stage at which patients are usually diagnosed, with only 20% of patients being eligible for tumor resection at the time of diagnosis (1). Several risk factors for PDAC are firmly established, such as chronic pancreatitis (2), cigarette smoking (3), family history of pancreatic cancer (4), and diabetes mellitus (5).…”

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confidence: 99%

Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma

Grace

Meeks

Chen

et al. 2017

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Abstract. Background: Obesity is an established risk factor for the development of pancreatic ductal adenocarcinoma (PDACPancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, with a 5-year survival rate of less than 6% in the United States (1). The low survival rate is due to the late stage at which patients are usually diagnosed, with only 20% of patients being eligible for tumor resection at the time of diagnosis (1). Several risk factors for PDAC are firmly established, such as chronic pancreatitis (2), cigarette smoking (3), family history of pancreatic cancer (4), and diabetes mellitus (5).Both epidemiological and experimental studies have also linked obesity to the development of PDAC. In a large casecontrol study, Silverman et al. (6) showed obesity portends a 50-60% increased risk of PDAC in both men and women. Similarly, a pooled case-control analysis using data from the Pancreatic Cancer Cohort Consortium (PanScan) comparing 2170 PDAC cases to 2209 controls showed a positive association between increasing body mass index (BMI) and risk of PDAC [adjusted odds ratio (aOR) for the highest vs. lowest BMI quartile=1.33, 95% confidence interval (CI)= 1.12-1.58, p<0.001 (7).The mechanism of how obesity increases PDAC risk is poorly understood. Previous studies have shown that increased peritumoral fat density promotes metastasis and increases mortality in patients with PDAC (8). Adipose triglyceride lipase (ATGL) is a lipase in adipose tissue that catabolizes the first step in triglyceride hydrolysis and is responsible for the release of free fatty acids. Another lipase called monoacylglycerol lipase has been shown to be overexpressed in human cancer cell lines and to promote in vivo tumor growth via 'feeding' cancer cells with free fatty acids (9). Previous studies of breast cancer demonstrated increased peritumoral ATGL expression in fat cells of obese 699 Τhis article is freely accessible online.

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“…The majority of earlier meta-analyses address diabetes as an independent risk factor for pancreatic cancer (18)(19)(20). A recent study shows that a 30% excess risk persists more than two decades following the diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic carcinogenesis, and also stating that oral anti-diabetics may decrease the risk, whereas insulin exhibits an inconsistent duration-risk association (18).…”

Section: Incidence Of Different Types Of Cancer Among Diabetic Patientsmentioning

confidence: 99%

“…The most recent meta-analyses demonstrated that metformin was associated with a 39% lower cancer risk, as compared to reference anti-diabetic therapies taken together (6,10,13,19). In recent in vitro studies on breast cancer cells, downstream signaling pathway of AMK-aktivated protein kinase (AMPK) comprising protein kinase B (AKT) and mTOR inhibition, and cyclin D1 and p53 interference, most likely accounts for the antiproliferative effects of metformin.…”

Section: Diabetes Cancer and Therapiesmentioning

confidence: 99%

Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links

Gristina¹,

Cupri²,

Torchio³

et al. 2014

Biomedical Reports

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Abstract. Diabetes and cancer represent two common, multifactorial, chronic and potentially fatal diseases, not infrequently co-diagnosed in the same patient. Epidemiological data demonstrate significant increases of the cancer incidence in patients with obesity and diabetes, which is more evident for certain site-specific cancers. Although there is increasing evidence that strongly indicates an augmented risk of cancer in diabetic patients, several confounding factors complicate the ability to precisely assess the risk. Mainly in insulin-resistant states (such as in type 2 diabetes mellitus and in metabolic syndrome), direct associations between obesity-related hyperinsulinemia and increasing circulating insulin-like growth factor-1 (IGF-1) levels have been implicated as key factors in the mechanisms involved in carcinogenesis. Whilst anti-diabetic drugs can increase the cancer risk, anti-proliferative drugs may cause diabetes or aggravate pre-existing diabetes. Additionally, an increasing number of targeted anti-cancer therapies may interfere with the pathways shared by IGF-1 and insulin receptors, showing a adverse effect on glucose metabolism through various mechanisms. Although there is a requirement for large-scale randomized evidence, the present review summarizes the majority of the epidemiological association studies between diabetes and various types of cancer, discussing the pathophysiological mechanisms that may be involved in promoting carcinogenesis in diabetes and the potential impact of different anti-diabetic therapies on cancer risk.

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Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium

Cited by 225 publications

References 46 publications

Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study

Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study

Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma

Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links

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