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The Diabetes - Cancer Connection

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Surgical oncologist, Zubin Bamboat, MD, discusses the association between diabetes and certain common cancers.

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The Diabetes - Cancer Connection

  1. 1. The Diabetes-Cancer Connection Zubin M. Bamboat, MD Division of Surgical Oncology Summit Medical Group, NJ 140 Park Avenue Florham Park, NJ February 2016
  2. 2. Rates of Cancer in New Jersey 2006-2010
  3. 3. Outline 1. Diabetes, cancer incidence and prognosis 2. Diabetes, obesity and cancer 3. Biologic links between diabetes and cancer 4. Metformin and cancer protection 5. Diabetes and pancreatic and breast cancer 6. What you can do to minimize your risk
  4. 4. 40 Million Americans have Diabetes
  5. 5. Diabetes, Breast and Colorectal Carcinoma Incidence (HR) Cancer-specific mortality (HR) DMII vs. Non-diabetics DMII vs. Non-diabetics Breast Cancer 1.23 (1.12-1.34) 1.38 (1.20-1.58) Colorectal Cancer 1.26 (1.14-1.40) 1.30 (1.15-1.47) De Bruijn et al., Br J Surg. 2013 Oct;100(11) Meta-analysis of RCTs and prospective studies since 2007:
  6. 6. Diabetes and cancer incidence – Is there an association? Type II Diabetes: >2 fold increase: Pancreas cancer (insulin theory, reverse causality) Primary liver cancer (insulin theory, NASH, cirrhosis) Endometrial cancer 1.2-1.5 fold increase: Colon and rectal cancer Breast Bladder No association: Kidney Non-Hodgkins lymphoma Diabetes may be associated with a lower risk of: Prostate Cancer (testosterone levels) Type I Diabetes: ??
  7. 7. Diabetes and cancer incidence – common risk factors Diabetes Cancer 1 Age Age 2 Gender Gender 3 Obesity Obesity 4 Activity Activity 5 Diet Diet 6 Alcohol Alcohol Modifiable risk factors
  8. 8. Diabetes and cancer prognosis Is there an association? Poorer prognosis suggested in diabetics with breast, prostate and colon cancer. Association is unclear: Direct (hyperglycemia, insulin) vs. indirect (obesity, comorbidities) No data on: duration of diabetes, degree of glycemic control, and diabetes therapy Strong association between obesity and DMII Obese patients tend to do worse: Colon cancer, pancreatic cancer, breast cancer In 2003, an article in the NEJM estimated that obesity could account for: 14% of all deaths from cancer in men 20% of all deaths from cancer in women New England Journal of Medicine. April 4, 2003
  9. 9. New England Journal of Medicine. April 4, 2003 Prospective Study 9000+ patients 16 yrs follow up Risk of death from cancer stratified by BMI
  10. 10. New England Journal of Medicine. April 4, 2003 Prospective Study 9000+ patients 16 yrs follow up Risk of death from cancer stratified by BMI Obesity: 14% of CRDs in men 20% in women ~90,000 deaths/yr can be avoided by maintaining BMI <25
  11. 11. Diabetes (OBESITY) and cancer Normal weight range: 18.5 – 25 kg/m2 Overweight 25 – 30kg/m2 Obese >30 – 40kg/m2 Morbid Obesity >40kg/m2 34% of Americans are obese (vs. 342 million people worldwide) 11% of Americans are diabetic Obese patients have higher prevalence of of breast, colorectal, endometrial, pancreas, Esophageal, GB, liver and kidney cancer. Direct? Diet >>>>>>>>> Obesity > insulin resistance > DMII > Cancer Weight loss, exercise, surgery inflammation
  12. 12. Weight loss surgery and cancer Gastric bypass Gastric band Indications: BMI >40kg/m2 or 35 with comorbidities. # surgeries performed /yr in US: >150,000 (2012) Excess weight loss: 60-80% Diabetes resolves: 84% 40-60% 60% 30-60% 50% Gastric sleeve
  13. 13. Gastric bypass Gastric sleeve Gastric band Indications: BMI >40kg/m2 or 35 with comorbidities. # surgeries performed /yr in US: >150,000 (2012) Excess weight loss: 60-80% Diabetes resolves: 84% 40-60% 60% 30-60% 50% Ulcers Late cancers? Weight loss surgery and cancer
  14. 14. Biologic links between diabetes and cancer 1. Hyperinsulinemia: Direct & indirect effects Endogenous and exogenous insulin 2. Hyperglycemia 3. Chronic Inflammation Association = Cause
  15. 15. Biologic links between diabetes and cancer: Hyperinsulinemia
  16. 16. Biologic links between diabetes and cancer: Hyperinsulinemia Increased tumor vascularity Insulin Increase in estrogen/testosterone
  17. 17. Untreated hyperglycemia may facilitate tumor growth (data sparse & conflicting): TPN and end stage cancer FDG-PET for cancer staging Tumor targeting: combining anti-cancer treatments to glucose moieties Biologic links between diabetes and cancer: Hyperglycemia Hyperglycemia IGF-1 vascular smooth muscle endothelial cell proliferation Liver IGFR-1 IGFR-1 Tumor growth Metastases
  18. 18. Obesity and high fat/caloric intake >> increased adipose, insulin, glucose >> increased IL-6, MCP-1, PAI-1, TNF-a >> chronic inflammation /immunosuppression >> cancer growth Biologic links between diabetes and cancer: Chronic Inflammation IL-6 -/- OR Stat 6 -/-Wild-type Low Caloric diet Low Caloric diet High Caloric diet High Caloric diet Mammary carcinoma Mammary carcinoma Cytokines Tumor growth Survival TILs: Treg Cytokines Tumor growth Survival TILs: Cytotoxic NOCHANGE
  19. 19. Metformin Most commonly used drug for DMII Mechanism: decreases hepatic gluconeogenesis, and circulating insulin Associated with improved prognosis in breast and pancreatic cancer: Proposed mechanisms metformin-mediated cancer protection: 1. Radiation and chemo sensitizer (pancreas and breast cancer) 2. mTOR pathway inhibition 3. Activation of the AMP kinase pathway in tumors 4. Decrease circulating insulin and glucose Do diabetes treatments influence cancer risk or prognosis?
  20. 20. Retrospective, 302 pts with DMII and PDAC (3 groups) from MDACC, ‘00-’09 Groups: 1: Resectable 2: Unresectable non-metastatic 3: metastatic 2 yr OS in favor of metformin group (30% vs. 15%) Median OS in favor of metformin group (15 vs. 11 months) Metformin use assoc with 36% lower risk of death from PDAC Clinical Cancer Research, 18(10); 2905-12, 2012
  21. 21. Resectable Un-resectable Non-metastatic Metastatic metformin metformin p = NS p = 0.001p = 0.29 Pancreas Adenocarcinoma – Overall survival On MVA: HR with metformin use 0.64 p = 0.003 Association between duration of metformin use (>2yrs) OS benefit Clinical Cancer Research, 18(10); 2905-12, 2012
  22. 22. Journal of Clinical Oncology, July 10, 2009 Retrospective, MDACC, ‘90-’07, ~2500 patients with breast Ca, 3 groups: 1. DMII and metformin use (n=68) 2. DMII no metformin use (n=87) 3. Non-diabetic patients (n=2374) p=0.02 Grp 1 2 3 3yr OS 84% 78% 90% Diabetics do worse
  23. 23. Diabetes and pre-clinical pancreatic cancer Long standing diabetes increases risk of pancreas cancer by 2-4 fold. New onset diabetes in adults is associated with 1-2% risk of PDAC within 3 yrs Pancreas Cancer – Depressing facts Only 15% of patients with PDAC have resectable disease Only 15- 20% of patients with resectable disease are alive at 5yrs 5 yr overall survival of PDAC is 6% US incidence of PDAC is increasing by 1.5%/yr (2020 = 2nd leading cause of cancer death) How can we detect PDAC at earlier stages? Biomarkers to identify patients with new onset DM and preclinical PDAC
  24. 24. Aim: Metabolite biomarkers to identify which patients with new onset DM are at risk for PDAC Methods: PDAC pts (n=36) with DM (within 3 yrs) vs. matched pts (n=22) without PDAC and DM Results: 15 serum metabolites found to discriminate between both groups: elaidic acid, uric acid, 2,3-propanediol, arachidonic acid, docosahexanoic acid, 5-oxo-EET, lysine, LysoPC(18:2), 9(10)-EpOME, LysoPC(16:0), sphingosine-1-phosphate Conclusions: Elevation of 15 serum metabolites may identify pts with new onset DM and PDAC Larger validation studies needed How do you identify the most appropriate control group? Discriminant, identifiable plasma metabolites in pancreatic cancer–associated diabetes J Clin Oncol 32, 2014 (suppl 3; abstr 180)
  25. 25. Conclusions -DMII associated with increased incidence and worse outcomes in some cancers: (liver, pancreas, breast, colorectal, endometrial bladder) - Association b/w DM and cancers may in part be due to shared risk factors - Mechanisms linking DM and cancer: hyperinsulinemia, hyperglycemia, inflammation - Metformin may have direct and indirect anti-tumor effects - Biomarkers linking new onset diabetes and early pancreas cancer are needed
  26. 26. What you can do • Are you at high risk for developing diabetes? • For diabetics: Hgb A1c : less than 6 is the goal • Control: diet, exercise, alcohol, obesity, smoking • Health maintenance: – Annual physical exam (pre-diabetes screening) – Screening colonoscopy (age 50). – Screening mammograms (age 40). – Annual CT scan for lung cancer screening in high risk patients (30 pack-yr smoking history). – Annual Pap smear (age 21 -65)
  27. 27. Thank you zbamboat@smgnj.com

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