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Influence of antidiabetic drugs on glucose metabolism and immune response in patients with metastatic pancreatic ductal adenocarcinoma receiving gemcitabine plus nab-paclitaxel as first-line treatment

Published:December 10, 2022DOI:https://doi.org/10.1016/j.dld.2022.11.012

      Abstract

      Background

      Association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2.

      Method

      Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from AOU Cagliari Medical Oncology and 58 from AOU Ancona Medical Oncology. All patients received gemcitabine plus nab-paclitaxel first-line chemotherapy. We aimed to evaluate the correlation between DM2, anti-diabetic medications and overall survival. Survival distribution was assessed by Kaplan-Meier curves.

      Results

      Median age was 68±9, 127 (55%) were male. 138/232 (59%) patients were not affected by DM2, 94/232 (41%) were affected by DM2. 57 were insulin-treated and 37 were metformin-treated. DM2 treated patients showed an higher median overall survival (26 vs 12 months, p = 0,0002). Among DM2 patients insulin-treated and metformin-treated showed an mOS of 21 months and 33 months, respectively.

      Conclusions

      Results showed a correlation between treated DM2 and higher mOS in patients with mPDAC. Limitations due to retrospective data collection must be considered. Further studies in this setting are needed.
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      References

        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • Laversanne M.
        • Soerjomataram I.
        • Jemal A.
        • Bray F.
        Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • Ilic M.
        • Ilic I.
        Epidemiology of pancreatic cancer.
        World J Gastroenterol. 2016; 22: 9694-9705
        • Renehan A.G.
        • Tyson M.
        • Egger M.
        • Heller R.F.
        • Zwahlen M.
        Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.
        Lancet. 2008; 371: 569-578https://doi.org/10.1016/S0140-6736(08)60269-X
        • Koorstra J.B.
        • Hustinx S.R.
        • Offerhaus G.J.
        • Maitra A.
        Pancreatic carcinogenesis.
        Pancreatology. 2008; 8: 110-125https://doi.org/10.1159/000123838
        • American Diabetes Association
        Diagnosis and classification of diabetes mellitus.
        Diabetes Care. 2014; 37: S81-S90
      1. Diagnosis and classification of diabetes mellitus.
        Diabetes Care. 2004; 27: S5-S10https://doi.org/10.2337/diacare.27.2007.s5
        • Andersen D.K.
        • Korc M.
        • Petersen G.M.
        • et al.
        Diabetes, pancreatogenic diabetes, and pancreatic cancer.
        Diabetes. 2017; 66: 1103-1110https://doi.org/10.2337/db16-1477
        • Li Y.
        • Bian X.
        • Wei S.
        • He M.
        • Yang Y.
        The relationship between pancreatic cancer and type 2 diabetes: cause and consequence.
        Cancer Manag Res. 2019; 11: 8257-8268https://doi.org/10.2147/CMAR.S211972
        • Bosetti C.
        • Rosato V.
        • Li D.
        • Silverman D.
        • Petersen G.M.
        • Bracci P.M.
        • et al.
        Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.
        Ann Oncol. 2014; 25: 2065-2072
        • Ben Q.
        • Xu M.
        • Ning X.
        • Liu J.
        • Hong S.
        • Huang W.
        • et al.
        Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies.
        Eur J Cancer. 2011; 47: 1928-1937
        • Huxley R.
        • Ansary-Moghaddam A.
        • Berrington de Gonz_alez A.
        • Barzi F.
        • Woodward M
        Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies.
        Br J Cancer. 2005; 92: 2076-2083
        • Lowenfels A.B.
        • Maisonneuve P.
        Risk factors for pancreatic cancer.
        J Cell Biochem. 2005; 95: 649-656https://doi.org/10.1002/jcb.20461
        • Gallagher E.J.
        • LeRoith D.
        Hyperinsulinaemia in cancer.
        Nat Rev Cancer. 2020; 20: 629-644https://doi.org/10.1038/s41568-020-0295-5
        • Gallagher E.J.
        • LeRoith D.
        Obesity and diabetes: the increased risk of cancer and cancer-related mortality.
        Physiol Rev. 2015; 95: 727-748https://doi.org/10.1152/physrev.00030.2014
        • Zhang A.M.
        • Wellberg E.A.
        • Kopp J.L.
        • Johnson J.D.
        Hyperinsulinemia in obesity, inflammation, and cancer.
        Diabetes Metab J. 2021; 45: 285-311
        • Bao B.
        • Wang Z.
        • Li Y.
        • et al.
        The complexities of obesity and diabetes with the development and progression of pancreatic cancer.
        Biochim Biophys Acta. 2011; 1815: 135-146https://doi.org/10.1016/j.bbcan.2010.11.003
        • Duan X.
        • Wang W.
        • Pan Q.
        • Guo L.
        Type 2 diabetes mellitus intersects with pancreatic cancer diagnosis and development.
        Front Oncol. 2021; 11730038https://doi.org/10.3389/fonc.2021.730038
        • Olson S.H.
        • Xu Y.
        • Herzog K.
        • Saldia A.
        • DeFilippis E.M.
        • Li P.
        • et al.
        Weight loss, diabetes, fatigue, and depression preceding pancreatic cancer.
        Pancreas. 2016; 45: 986-991
        • Pannala R.
        • Leirness J.B.
        • Bamlet W.R.
        • Basu A.
        • Petersen G.M.
        • Chari S.T.
        Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus.
        Gastroenterology. 2008; 134: 981-987
        • Li D.
        • Mao Y.
        • Chang P.
        • Liu C.
        • Hassan M.M.
        • Yeung S.J.
        • et al.
        Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer.
        Am J Cancer Res. 2015; 5: 3260-3269
        • Wróbel M.P.
        • Marek B.
        • Kajdaniuk D.
        • et al.
        Metformin - a new old drug.
        Endokrynol Pol. 2017; 68 (indexed in Pubmed: 28819951): 482-496https://doi.org/10.5603/EP.2017.0050
        • Saenz A.
        • Fernandez-Esteban I.
        • Mataix A.
        • Ausejo M.
        • Roque M.
        • Moher D.
        Metformin monotherapy for type 2 diabetes mellitus.
        Cochrane Database Syst Rev. 2005 Jul 20; (Update in: Cochrane Database Syst Rev. 2015;9:CD002966. PMID: 1603488122)CD002966https://doi.org/10.1002/14651858.CD002966.pub3
        • Quoc Lam B.
        • Shrivastava S.K.
        • Shrivastava A.
        • Shankar S.
        • Srivastava R.K.
        The impact of obesity and diabetes mellitus on pancreatic cancer: molecular mechanisms and clinical perspectives.
        J Cell Mol Med. 2020; 24: 7706-7716https://doi.org/10.1111/jcmm.15413
        • Bonelli L.
        • Aste H.
        • Bovo P.
        • et al.
        Exocrine pancreatic cancer, cigarette smoking, and diabetes mellitus: a case-control study in northern Italy.
        Pancreas. 2003; 27: 143-149https://doi.org/10.1097/00006676-200308000-00007
        • Ersoy C.
        • Kiyici S.
        • Budak F.
        • et al.
        The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients.
        Diabetes Res Clin Pract. 2008; 81: 56-60https://doi.org/10.1016/j.diabres.2008.02.006
        • Bowker S.L.
        • Majumdar S.R.
        • Veugelers P.
        • Johnson J.A.
        Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin.
        Diabetes Care. 2006; 29: 254-258https://doi.org/10.2337/diacare.29.02.06.dc05-1558
        • Li D.
        • Yeung S.J.
        • Hassan M.M.
        • Konopleva M.
        • Abbruzzese J.L.
        Antidiabetic therapies affect risk of pancreatic cancer.
        Gastroenterology. 2009; 137: 482-488
        • Baur D.M.
        • Klotsche J.
        • Hamnvik O.P.R.
        • et al.
        Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort.
        Metabolism. 2011; 60: 1363-1371
        • Bodmer M.
        • Becker C.
        • Meier C.
        • Jick S.S.
        • Meier C.R.
        Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis.
        Am J Gastroenterol. 2012; 107: 620-626
        • Ding X.Z.
        • Fehsenfeld D.M.
        • Murphy L.O.
        • Permert J.
        • Adrian T.E.
        Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression.
        Pancreas. 2000; 21: 310-320
        • Azar M.
        • Lyons T.J.
        Diabetes, insulin treatment, and cancer risk: what is the evidence?.
        F1000 Med Rep. 2010; 2
        • Weinstein D.
        • Simon M.
        • Yehezkel E.
        • Laron Z.
        • Werner H.
        Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells.
        Diabetes Metab Res Rev. 2009; 25: 41-49https://doi.org/10.1002/dmrr.v25:1
        • Gerstein H.C.
        • Bosch J.
        • et al.
        • ORIGIN Trial Investigators
        Basal insulin and cardiovascular and other outcomes in dysglycemia.
        N Engl J Med. 2012; 367: 319-328
        • Chaitman B.R.
        • Hardison R.M.
        • Adler D.
        • et al.
        The bypass angioplasty revascularization investigation 2 diabetes randomized trial of different treatment Strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction.
        Circulation. 2009; 120: 2529-2540
        • Gerstein H.C.
        • Friedewald W.T.
        • Buse J.B.
        • et al.
        Effects of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008; 358: 2545-2559
        • Patel A.
        • MacMahon S.
        • et al.
        • Advance Collaborative Group
        Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2008; 358: 2560-2572
        • Duckworth W.
        • Abraira C.
        • Moritz T.
        • et al.
        Glucose control and vascular complications in veterans with type 2 diabetes.
        N Engl J Med. 2009; 360: 129-139
        • Gerstein H.C.
        • Miller M.E.
        • Genuth S.
        • et al.
        Long-term effects of intensive glucose lowering on cardiovascular outcomes.
        N Engl J Med. 2011; 364: 818-828
        • Stefansdottir G.
        • Zoungas S.
        • Chalmers J.
        • et al.
        Intensive glucose control and risk of cancer in patients with type 2 diabetes.
        Diabetologia. 2011; : 1-7
        • Zhang Z.J.
        • Zheng Z.J.
        • Kan H.
        • Song Y.
        • Cui W.
        • Zhao G.
        • Kip K.E.
        Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis.
        Diabetes Care. 2011; 34: 2323-2328https://doi.org/10.2337/dc11-0512
        • Jiralerspong S.
        • Palla S.L.
        • Giordano S.H.
        • et al.
        Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.
        J Clin Oncol. 2009; 27: 3297-3302https://doi.org/10.1200/JCO.2009.19.6410
        • Pollak M.
        Insulin and insulin-like growth factor signalling in neoplasia.
        Nat Rev Cancer. 2008; 8: 915-928
        • Jeon C.Y.
        • Li D.
        • Cleary S.
        • et al.
        The association of recently diagnosed diabetes and long-term diabetes with survival in pancreatic cancer patients: a pooled analysis.
        Pancreas. 2018; 47: 314-320
        • Hartwig W.
        • Hackert T.
        • Hinz U.
        • et al.
        Pancreatic cancer surgery in the new millennium: better prediction of outcome.
        Ann Surg. 2011; 254: 311-319
        • Bitterman D.S.
        • Winter K.A.
        • Hong T.S.
        • Fuchs C.S.
        • Regine W.F.
        • Abrams R.A.
        • Safran H.
        • Hoffman J.P.
        • Benson 3rd, A.B.
        • Kasunic T.
        • Mulcahy M.
        • Strauss J.F.
        • DiPetrillo T.
        • Stella P.J.
        • Chen Y.
        • Plastaras J.P.
        • Crane C.H.
        Impact of diabetes and insulin use on prognosis in patients with resected pancreatic cancer: an ancillary analysis of NRG oncology RTOG 9704.
        Int J Radiat Oncol Biol Phys. Jan 2021; 109: 201-211https://doi.org/10.1016/j.ijrobp.2020.08.042
        • Warburg O.
        • Wind F.
        • Negelein E.
        The metabolism of tumors in the body.
        J Gen Physiol. Mar 1927; 8 (PMID: 19872213; PMCID: PMC2140820): 519-530https://doi.org/10.1085/jgp.8.6.519
        • de la Cruz-López K.G.
        • Castro-Muñoz L.J.
        • DO Reyes-Hernández
        • García-Carrancá A.
        • Manzo-Merino J.
        Lactate in the regulation of tumor microenvironment and therapeutic approaches.
        Front Oncol. Nov 2019; 9 (PMID: 31737570; PMCID: PMC6839026): 1143https://doi.org/10.3389/fonc.2019.01143
        • Buescher J.M.
        • Driggers E.M.
        Integration of omics: more than the sum of its parts.
        Cancer Metab. Feb 2016; 4 (PMID: 26900468; PMCID: PMC4761192): 4https://doi.org/10.1186/s40170-016-0143-y
        • Reznik E.
        • Luna A.
        • Aksoy B.A.
        • Liu E.M.
        • La K.
        • Ostrovnaya I.
        • Creighton C.J.
        • Hakimi A.A.
        • Sander C.
        A landscape of metabolic variation across tumor types.
        Cell Syst. Mar 2018; 6 (301-313.e3Epub 2018 Jan 27. PMID: 29396322; PMCID: PMC5876114)https://doi.org/10.1016/j.cels.2017.12.014
        • Ying H.
        • Kimmelman A.C.
        • Lyssiotis C.A.
        • Hua S.
        • Chu G.C.
        • Fletcher-Sananikone E.
        • Locasale J.W.
        • Son J.
        • Zhang H.
        • Coloff J.L.
        • et al.
        Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
        Cell. 2012; 149: 656-670
        • Yun J.
        • Rago C.
        • Cheong I.
        • Pagliarini R.
        • Angenendt P.
        • Rajagopalan H.
        • Schmidt K.
        • Willson J.K.
        • Markowitz S.
        • Zhou S.
        • et al.
        Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
        Science. 2009; 325: 1555-1559
        • Lau A.N.
        • Li Z.
        • Danai L.V.
        • Westermark A.M.
        • Darnell A.M.
        • Ferreira R.
        • Gocheva V.
        • Sivanand S.
        • Lien E.C.
        • Sapp K.M.
        • et al.
        Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma.
        Elife. 2020; 9: e56782
        • Follia L.
        • Ferrero G.
        • Mandili G.
        • et al.
        Integrative analysis of novel metabolic subtypes in pancreatic cancer fosters newprognostic biomarkers.
        Front Oncol. 2019; (Epub ahead of print Feb 27)https://doi.org/10.3389/fonc.2019.00115
        • Daemen A.
        • Peterson D.
        • Sahu N.
        • McCord R.
        • Du X.
        • Liu B.
        • Kowanetz K.
        • Hong R.
        • Moffat J.
        • Gao M.
        • et al.
        Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.
        Proc Natl Acad Sci USA. 2015; 112: E4410-E4417
        • Karasinska J.M.
        • Topham J.T.
        • Kalloger S.E.
        • et al.
        Altered gene expression along the glycolysis–cholesterol synthesis axis is associated with outcome in pancreatic cancer.
        Clin Cancer Res. 2019; (Epub ahead of print November 4)https://doi.org/10.1158/1078-0432.CCR-19-1543
        • Bodmer M.
        • Becker C.
        • Meier C.
        • Jick S.S.
        • Meier C.R.
        Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis.
        Am J Gastroenterol. 2012; 107: 620-626
        • Choi Y.K.
        • Park K.G.
        Metabolic roles of AMPK and metformin in cancer cells.
        Mol Cells. Oct 2013; 36 (Epub 2013 Jun 19. PMID: 23794020; PMCID: PMC3887985): 279-287https://doi.org/10.1007/s10059-013-0169-8
        • Madiraju A.K.
        • Qiu Y.
        • Perry R.J.
        • et al.
        Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo.
        Nat Med. 2018; 24: 1384-1394https://doi.org/10.1038/s41591-018-0125-4
        • Pretta A.
        • Ziranu P.
        • Puzzoni M.
        • Lai E.
        • Orsi G.
        • Liscia N.
        • Molinaro E.
        • Mariani S.
        • Riggi L.
        • Rovesti G.
        • Dubois M.
        • Migliari M.
        • Persano M.
        • Saba G.
        • Impera V.
        • Musio F.
        • Batzella E.
        • Demurtas L.
        • Pusceddu V.
        • Astara G.
        • Faloppi L.
        • Casadei Gardini A.
        • Andrikou K.
        • Cascinu S.
        • Scartozzi M
        Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus.
        Tumori. Dec 2021; 107 (Epub 2020 Nov 26. PMID: 33243068): 550-555https://doi.org/10.1177/0300891620976945
        • Pircher A.
        • Zieher M.
        • Eigentler A.
        • et al.
        Antidiabetic drugs influence molecular mechanisms in prostate cancer.
        Cancer Biol Ther. 2018; 19: 1153-1161
        • Renner K.
        • Singer K.
        • Koehl G.E.
        • Geissler E.K.
        • Peter K.
        • Siska P.J.
        • Kreutz M.
        Metabolic hallmarks of tumor and immune cells in the tumor microenvironment.
        Front Immunol. Mar 2017; 8 (PMID: 28337200; PMCID: PMC5340776): 248https://doi.org/10.3389/fimmu.2017.00248
        • Xia L.
        • Oyang L.
        • Lin J.
        • Tan S.
        • Han Y.
        • Wu N.
        • et al.
        The cancer metabolic reprogramming and immune response.
        Mol Cancer. 2021; 20: 28https://doi.org/10.1186/s12943-021-01316-8
        • Rangel Rivera G.O.
        • Knochelmann H.M.
        • Dwyer C.J.
        • Smith A.S.
        • Wyatt M.M.
        • Rivera-Reyes A.M.
        • et al.
        Fundamentals of T cell metabolism and strategies to enhance cancer immunotherapy.
        Front Immunol. 2021; 12645242https://doi.org/10.3389/fimmu.2021.645242
        • Zhang M.
        • Jin X.
        • Sun R.
        • Xiong X.
        • Wang J.
        • Xie D.
        • et al.
        Optimization of metabolism to improve efficacy during CAR-T cell manufacturing.
        J Transl Med. 2021; 19: 499https://doi.org/10.1186/s12967-021-03165-x
        • Lindau D.
        • Gielen P.
        • Kroesen M.
        • Wesseling P.
        • Adema G.J.
        The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells.
        Immunology. 2013; 138: 105-115https://doi.org/10.1111/imm.12036
        • Peixoto A.
        • Relvas-Santos M.
        • Azevedo R.
        • Santos L.L.
        • Ferreira J.A.
        Protein glycosylation and tumor microenvironment alterations driving cancer hallmarks.
        Front Oncol. 2019; 9: 380https://doi.org/10.3389/fonc.2019.00380
        • Haist M.
        • Stege H.
        • Grabbe S.
        • Bros M.
        The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment.
        Cancers. 2021; 13: 210https://doi.org/10.3390/cancers13020210
        • Chang C.H.
        • Qiu J.
        • O'Sullivan D.
        • Buck M.D.
        • Noguchi T.
        • Curtis J.D.
        • et al.
        Metabolic competition in the tumor microenvironment is a driver of cancer progression.
        Cell. 2015; 162: 1229-1241https://doi.org/10.1016/j.cell.2015.08.016
        • Angelin A.
        • Gil-de-Gómez L.
        • Dahiya S.
        • Jiao J.
        • Guo L.
        • Levine M.H.
        • et al.
        Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments.
        Cel Metab. 2017; 25: 1282-12e7https://doi.org/10.1016/j.cmet.2016.12.018
        • Palsson-McDermott E.M.
        • O'Neill L.A.J.
        Targeting immunometabolism as an anti-inflammatory strategy.
        Cell Res. 2020; 30: 300-314
        • Cao L.
        • Wu J.
        • Qu X.
        • Sheng J.
        • Cui M.
        • Liu S.
        • Huang X.
        • Xiang Y.
        • Li B.
        • Zhang X.
        • et al.
        Glycometabolic rearrangements–aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications.
        J Exp Clin Cancer Res. 2020; 39: 267
        • Helderman J.H.
        • Reynolds T.C.
        • Strom T.B.
        The insulin receptor as a universal marker of activated lymphocytes.
        Eur J Immunol. 1978; 8: 589-595
        • Fischer H.J.
        • Sie C.
        • Schumann E.
        • Witte A.K.
        • Dressel R.
        • van den Brandt J.
        • Reichardt H.M.
        The insulin receptor plays a critical role in T cell function and adaptive immunity.
        J Immunol. 2017; 198: 1910-1920