The Diabetes - Cancer Connection
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Transcript of The Diabetes - Cancer Connection
The Diabetes-Cancer Connection
Zubin M. Bamboat, MD
Division of Surgical OncologySummit Medical Group, NJ
140 Park AvenueFlorham Park, NJ
February 2016
Rates of Cancer in New Jersey 2006-2010
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
40 Million Americans have Diabetes
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:
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 cancerBreastBladder
No association:Kidney Non-Hodgkins lymphoma
Diabetes may be associated with a lower risk of:Prostate Cancer (testosterone levels)
Type I Diabetes: ??
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
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
New England Journal of Medicine. April 4, 2003
Prospective Study9000+ patients16 yrs follow up
Risk of death from cancer stratified by BMI
New England Journal of Medicine. April 4, 2003
Prospective Study9000+ patients16 yrs follow up
Risk of death from cancer stratified by BMIObesity: 14% of CRDs in men
20% in women
~90,000 deaths/yr can be avoided by maintaining BMI <25
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
Weight loss surgery and cancerGastric 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
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%
UlcersLate cancers?
Weight loss surgery and cancer
Biologic links between diabetes and cancer
1. Hyperinsulinemia: Direct & indirect effects Endogenous and exogenous insulin
2. Hyperglycemia
3. Chronic Inflammation
Association = Cause
Biologic links between diabetes and cancer: Hyperinsulinemia
Biologic links between diabetes and cancer: Hyperinsulinemia
Increased tumor vascularity
Insulin
Increase in estrogen/testosterone
Untreated hyperglycemia may facilitate tumor growth (data sparse & conflicting):TPN and end stage cancerFDG-PET for cancer stagingTumor targeting: combining anti-cancer treatments to glucose moieties
Biologic links between diabetes and cancer: Hyperglycemia
Hyperglycemia IGF-1
vascular smooth muscle
endothelial cell proliferation
LiverIGFR-1
IGFR-1
Tumor growthMetastases
Obesity and high fat/caloric intake >> increased adipose, insulin, glucose >> increasedIL-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
HighCaloric
diet
HighCaloric
diet
Mammary carcinoma
Mammary carcinoma
CytokinesTumor growthSurvivalTILs: Treg
CytokinesTumor growthSurvivalTILs: Cytotoxic
NO
CHA
NGE
MetforminMost commonly used drug for DMIIMechanism: decreases hepatic gluconeogenesis, and circulating insulinAssociated 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?
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
Resectable Un-resectableNon-metastatic
Metastatic
metforminmetformin
p = NS
p = 0.001p = 0.29
Pancreas Adenocarcinoma – Overall survival
On MVA: HR with metformin use 0.64p = 0.003
Association between duration of metforminuse (>2yrs) OS benefit
Clinical Cancer Research, 18(10); 2905-12, 2012
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
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 factsOnly 15% of patients with PDAC have resectable diseaseOnly 15- 20% of patients with resectable disease are alive at 5yrs5 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
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 PDACLarger 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)
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
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)
Thank you