Cancer and Obesity: Is there a Prevention Connection?
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Cancer and Obesity: Is there a Prevention Connection?
Yvonne Collins, MD, FACOGGynecologic OncologistAdvocate Medical Group
Obesity Awareness Symposium: [email protected]
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Disclosure• I have no relevant conflicts of
interest
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I think this is hilarious! I NEVER HEARD
CREATION EXPLAINED THIS WAY BEFORE !!!
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Objectives• Review obesity statistics• Review cancers directly associated with
obesity• Discuss mechanisms of obesity and cancer• Discuss the health outcomes related to
weight control and weight cancer• Explain obesity reduction efforts
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Prevalence of Obesity• Greater than two thirds of US adults
were overweight or obese by 2000
• About 25% of Americans are obese as defined by a BMI of 30 > kg/M2 301.6 million people world wide are obese
• Significant health risks are related to obesity
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2000
Obesity Trends* Among U.S. AdultsBRFSS, 1990, 2000, 2010
(*BMI 30, or about 30 lbs. overweight for 5’4” person)
2010
1990
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
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Obesity no longer limited to the US
• 1.6 billion people world wide are at least overweight
• Almost 25% of people in the UK are overweight or obese.
• Even Asian countries are noticing and increase
• One can be obese yet malnourished
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How is Obesity Assessed?• BMI• Weight
– Weight in earlier life– Adult weight gain
• Waist circumference; WHR• Skin folds• Body fat (DXA, BIA)• Intramuscular fat (CT scan)
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By 2020, 75% of the US will be overweight
OECD Report, September 2010
Background
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Body Fatness, and the Risk of Cancer
AICR/WCRF 2007
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Background
Fair AM, Montgomery K. Methods Mol Biol. 2009;472:57-88.
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Impact Factors
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Candidate Mechanisms• Insulin and insulin like growth
factor axis• Sex steroids• Adipokines• Obesity induced hypoxia• Shared genetic susceptibility• Migrating adipose stromal cells
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High Insulin Levels are an adverse prognostic factor
associated with:• Breast cancer• Colon cancer• Prostate cancer
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Sex Hormones• Higher rates of conversion of
androgenic precursors to estradiol• Increased aromatase activity
through adipose tissue• Data indicates that estrogen is
both mitogenic and mutagenic
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Endogenous Hormones and Breast Cancer
Collaborative Group (EHBCCG)• Nine prospective studies
• Risk of breast cancer increases at least two fold with increased levels of sex steroids– DHEA– DHEAS– Androstendione– Estrone– Estradiol– Testsosterone
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Estrogen stimulation in endometrial cancer
• Increases cellular proliferation• Inhibits apoptosis• Induces synthesis of IGF-1• Progesterone induces synthesis of
IGFBP-I which inhibits IGF-I
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Effect of obesity on hormones
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Obesity, Hormones and Endometrial Cancer
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Leptin• Leptin deficient mice overfeed and
rapidly become hyperinsulinemic• Long arm of leptin receptor (LRb)
activates– PI3 kinase– MAPK– STAT (signal transduce and activator
transcription)– C-fos
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Adiponectin• Most abundant adipokine• Important insulin sensitizing agent• Inverse association of adiponecitn
concentrations and cancer• Antiproliferative effects
– ERK– ERK1– MAPK kinases– Induces p53 and Bax
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Obesity Related Hypoxia
• Adipose tissue hypoxia is a key factor in the development of insulin resistance
• Regulation of chronic inflammation• Reduced adiponectin• Increased leptin• High levels of tumor hypoxia correlate
with high mortality• HIF-1 alpha is associated with poor
prognosis
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Obesity related hypoxia• White adipose tissue in obese mice
is more hypoxic than in lean mice (15.2 mmHg versus 47.9 mmHg– Ye et al Am J Phys. Endo Met 2007
• Low oxygen concentrations have been associated with stimulation of melanocytes and development of melanoma – Through the AKT, ras/raf, PI-3-Kinase
pathways– Bedogni Cancer Cell 2005
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Shared Genetic Susceptibility
• Genome wide studies show at least 15 loci associated with obesity
• Cancer genome maps are derived from a number of parallel genome wide associated regions
• Overlap may exist for breast on 11p and 16q– Hofker et al Nat Genetic 2009
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Obesity related inflammatory markers
• Increased C-reactive protein• Activation of c-Jun NH2-terminal kinase• Activation of IkB kinase beta increases
with adiposity• Increased activated macrophage
infiltration– Now recognized as a mechanism of
insulin resistance
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Mechanical Markers• Hypertension• Acid reflux• Increased iodine uptake
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Breast Cancer
• Increased postmenopausal breast cancer• Decreased premenopausal cancer• Increased weight gain 18-50 increases risk
of breast cancer after menopause
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Colon Cancer
• For men, increased BMI = increased risk• The strongest association with abdominal
obesity (waist circumference)• Also, increased BMI is associated with
rectal cancer
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Esophageal Cancer
• Esophageal adenocarcinoma is 2X’s higher in those who are overweight and obese
• Associated link with gastroesophageal reflux and Barrett’s esophagus
• Obesity exacerbates esophageal inflammation
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Prostate Cancer
• Pooled data: obesity is associated with a slight increased risk
• Obese men have more aggressive cancers• Linked to hormone and growth factors (esp
IGF-1
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Other Cancers
• Obesity is associated with renal cell cancer– Related to high insulin levels
• Associated with thyroid cancer– Mechanism is unknown
• Associated with gallbladder cancer– Possible mechanism related to frequency of
gallstones
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So what do we know thus farrelated to GYN cancers?
• Obesity is NOT clearly associated with:–Vaginal cancer–Vulvar cancer
• Obesity is possibly associated with:–Cervical Cancer–Ovarian cancer -
premenopausal
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Obesity and Adult Weight Gain
• Strongly associated with endometrial cancer
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Endometrial Cancer• Most common gynecologic cancer• We perceive it to be associated
with obesity• Increasing incidence• Hormone related cancer
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Obesity• Strongest risk factor for endometrial cancer1
– RR 4.0 - BMI>32 kg/m2
– RR 6.0 - BMI>35 kg/m2
• Elevated endogenous estrogens • “Hyper-estrogenic” state does not account for
all cases2
• Other obesity-related factors may contribute to increased risk for endometrial cancer
1Brinton et al. Am J Obstet Gynecol 19922Potishman et al. JNCI 1996
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Progression of the Endometrium to Cancer
• 23% of complex atypical hyperplasia (CAH) progresses to endometrial cancer
• Excess of estrogen and lack of progesterone causes abnormal proliferative drive
• Subset of aggressive histologies that do not follow this progression pathway
Normal Complex atypical hyperplasia (CAH)
Grade 1 Endometrial cancer
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Endometrial Cancer: Annual Incidence and Mortality
Year Cases Deaths
1987 35,000 2,900
2008 40,100 7,170*
ACS Estimates
*250% increaseAmerican Cancer Society 2008
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Goal: Prevention of deaths
40,000+ cases 7,000+ deaths34,000 endometrioid 3,71028,800 G1-2 1,820 5,200 G 3 1,890
4,000 UPSC 2,8001,200 Clear Cell 560 800 Sarcoma/CarcinoSarc 400
How do we identify these patients and prevent death?
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Background
HealthyEndometrium
Complex Atypical Hyperplasia
&Endometrial
Adenocarcinoma
Estrogen Insulin Adipokines
OBESITY
DietExercise
Hormone therapyChemoprevention
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Prevention of Obesity-associated Endometrial
cancer• Oral contraceptives• Progestins (including IUD w/Progestin)• Weight loss• Bariatric surgery• ? Metformin
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ImplicationsEmployment/ Support system/ Cancer therapies
↓ Hormones and activity
↓ Muscle Mass
↓ Metabolic Rate ↓
Energy Needs
Weight Gain, Reduced physical
functionCo-morbidity
Changing hormonal environment
Fatigue Intake
Caffeine, sugar
PoorSleep
ReducedQOL
IncreasedMortality
LifestyleInterventionsdiet, physical
activity, weight, sleep,
etc. Reversal or
Primary prevention
Improved QOLWeight control
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Implications: Obesity- related Co-morbidity
• Cardiovascular• Neurologic• Psychiatric• Pulmonary• Vascular
• Gastrointestinal• Genitourinary• Metabolic• Musculoskeletal
Modesitt, Obstet Gyn Survey, 2005
Taking care of patients can beextremely challenging…
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Opportunities• Prevention of weight gain during
adolescence and early adulthood– Weight trajectory “mapping”
• Monitor for central adiposity– Waist circumference
• Monitor for risk of obesity-related disease– Metabolic syndrome
• Intervene early if weight increases• Do not under-estimate the role of
regular, moderate physical activity
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Therapy: Don’t wait, Don’t hesitate
• Cancer diagnosis is an opportunity for behavior change
• Support systems are active
• Consequences (risk vs benefit) are high
• Engage healthcare team• Small changes can
translate to significant improvements in health indices and greater health and well-being
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Questions?
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GOG-225 Can Diet and Physical Activity
Modulate Ovarian Cancer Progression Free Survival?
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Schema-GOG-225
Ovarian Cancer Diagnosis: Successful first line treatment consolidation
Comparison Lifestyle
Intervention Lifestyle: 7 servings of
vegetables and fruit , low fat (< 20%)
+ 4000 additional steps daily (weight control)
1:1intervention: comparison
Progression-free survival (@ 2 years)
RANDOMIZE
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Primary Objective
• Determine if disease-free women who completed therapy for Stage II-IV ovarian, fallopian tube or primary peritoneal cancer randomized to a healthy lifestyle intervention have increased progression free survival compared to those randomized to usual care
• Opportunity to evaluate pre-randomization body mass index as a modifier of lifestyle intervention efficacy
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Status
• Protocol approved• Sites processing Human Subjects
approvals• Recruitment / active enrollment • Estimate 20 new enrollees
monthly
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Summary• BMI associated with cancers• Obesity is a complex system –no
on size fits all• Bariatrics (less obesity related
cancers)• Prevention methods include
– Exercise– Weight loss– Diet control
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Opportunities• Cancer prevention• Much needed research
– MD Anderson endometrial SPORE• TREC (Transdisciplinary Reseach on
Energetics and Cancer)– Washington University– University California San Diego– Harvard University– University of Pennsylvania– University of Washington
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References
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THANKS!!!!