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

zbamboat@smgnj.com