Transcript Obese - UNC Lineberger Comprehensive Cancer Center

Obesity in Gynecologic Oncology:
A Growing Epidemic
Paola A. Gehrig, MD
Professor and Chief
Division of Gynecologic Oncology
University of North Carolina
Chapel Hill, NC
Objectives
• To review the impact of obesity
• To discuss the pharmacotherapy options for
the treatment of the obese woman
• To review obesity’s impact on cancer
• To review some very exciting research in
obesity as it relates to gynecologic
malignancies
Objectives
• To review the impact of obesity
• To discuss the pharmacotherapy options for
the treatment of the obese woman
• To review obesity’s impact on cancer
• To review some very exciting research in
obesity as it relates to gynecologic
malignancies
Disclosures
I have nothing to disclose.
25 years in the US
CDC.gov
Link between obesity and income
Obesity
Income
Putting BMI in context
Description
Class
BMI
5’4”
5’10”
Normal
18.5-24.9
110-145
135-175
Overweight
25.0-29.9
146-175
176-210
176-205
211-245
235+
280+
Obesity
I
30.0-34.9
Obesity
II
35-39.9
Extreme
Obesity
III
>40
Globesity
-250 million people (7%) are obese
-2-3 times this are overweight
-Across the globe, more people are overweight than malnourished
-15% of men and 22% of women in Europe are obese
BMI Awareness is poor
• Patient?
– 22.2% of obese women and 6.7% of obese men
correctly classified themselves as obese1
• Provider?
– Majority overweight/obese women deny being
counseled about weight, weight loss2
– Knowledge? Comfort? Time?
– Study ongoing of health care providers’ ability to
correctly recognize BMI
1. Truesdale KP, NC Med J,
2008
2. Evans et al, ASRM, 2010
Obesity in the United States
• Increasing steadily in the United States
– One of the top 2 causes of preventable mortality
• 2/3 of adults are overweight
• 1/3 are obese (BMI >30) or morbidly obese
(BMI >40)
• Obesity increases other co-morbidities
– HTN, Diabetes, Cancer-endometrial
• $190 billion/year
The future: 2030 ?
• Without intervention, the obesity epidemic
escalates:
– 50% US men
– 165 million US adults
– Health care spending increases $66 billion/yr
-Gortmaker et al, Lancet 2011
- Bloomberg News, 8/26/2011
What about our kids?
Newsweek, 2000
Childhood obesity: 2015
•
•
•
•
21% of US children
>1/3 are overweight or obese
Tripled from one generation ago (1980)
Life expectancies projected to decline
for the first time in a thousand years
CDC.gov
NEJM, March 2005
BMI and Mortality
• 115,000+ Nurses
Health Study
– Ages 30-55 in 1976
– 16 yr follow up
– Cancer free
• Mortality is lowest for
BMI 19-26.91-3
Manson et al, NEJM 1995
1. De Gonzalez et al, NEJM 2010
2. Prospective Studies Collaboration, Lancet 2009
3. Manson et al, NEJM 1995
Weight Loss & Mortality
• Lowest mortality
with BMI 19-27
• Weight loss ≥ 20lbs
reduces mortality by
25%1
Manson et al, NEJM 1995
1. Williamson et al, Am J Epi 1995; 141: 1128-41.
Good news from The Lancet
Gortmaker et al, Lancet 2011
Causes of Obesity
Objectives
• To review the impact of obesity
• To discuss the pharmacotherapy options for
the treatment of the obese woman
• To review obesity’s impact on cancer
• To review some very exciting research in
obesity as it relates to gynecologic
malignancies
Why is this?
• Obesity is not only about calories in and
calories out
• Genetic component to obesity?
– “heritability of body fatness1” is polygenetic
• Environmental exposures?
• Early infant feeding?
• Socioeconomic status?
1FM
Biro, M Wien. Am J Clin Nutr 2010;91(suppl):1499S-1505S.
Can we stage Obesity?
FDA-Approved Drugs for the
Treatment of Obesity
-Phentermine-Sympathomimetic action
releases catecholamine from hypothalamus
-Topiramate-anticonvulsant whose anti-obesity effects
are incompletely understood
-Lorcaserin-selective 5-HT2C agonist which decreases
appetite through stimulation of melanocortin receptor
4 (MC4-R) by releasing melanotropin-α (α-MSH)
-Bupropion SR-Decreased energy intake and increased
thermogenesis via secretion of α-MSH and activation
MC4-R; increased β-endorphins
-Naltrexone-opioid receptor antagonist; reduces β-endorphin
induced pleasure associated with eating food
Objectives
• To review the impact of obesity
• To discuss the pharmacotherapy options for
the treatment of the obese woman
• To review obesity’s impact on cancer
• To review some very exciting research in
obesity as it relates to gynecologic
malignancies
Gynecologic surgery in the
Obese Patient
• Increased intra- and post-operative
complications
• Increased length of hospital stay
• Longer OR times
• MIS may be the preferred modality in
the obese woman
McMahon MD. J Minim Invasive Gynecol. 2013 Sep 4
O’Hanlan KA. Gynecol Oncol, 2006; 103:938-41
Camanni M. J Min Inv Gynecol, 2010; 17:576-82
Gehrig PA. Gynecol Oncol. 2008 Oct;111(1):41-5.
Waisbren et al. Percent body fat and prediction of surgical site infection.J Am Coll Surg
2010;210:381-9.
Disadvantages of Minimally Invasive
versus Open Procedures
-Higher operating costs? Probably not1
-Longer operative time?
-Learning curve (? Steeper for conventional L/S as
compared to robotic assisted L/S)
-Need for pneumoperitoneum
-Hernias at port sites?
-Seeding of malignant tissue at port sites? Probably not2
1
Barnett J. Gynecol Oncol 2010:116:685-93.
2Martinez A. Gynecol Oncol 2010;118:145-50.
Anesthesia Concerns
• Steep trendelenberg
• With robotics, patient position cannot be rapidly
changed after docking.
• Paralytic
• Use “anti-skid” measures to decrease nerve injury
• Run patient dry
• Pressure control ventilation
– Minimize peak airway pressures
– Control CO2 by improving ventilation/perfusion ratios
– Increase alveolar recruitment
• Cooperation from the entire OR team
Predicted probability curve for risk of conversion by body mass index (BMI), age, and
metastatic disease.
Walker J L et al. JCO 2009;27:5331-5336
©2009 by American Society of Clinical Oncology
Literature Review
2.Eltabbakh GH,et al. Hysterectomy for obese women with endometrial cancer: laparoscopy or laparotomy?
Gynecol Oncol 2000;78:329-335.
3.Scribner DR, et al. Pelvic and paraaortic lymph node dissection in the obese. Gynecol Oncol 2002;84:426-30.
4.Eisenhauer EL, et al. Comparing surgical outcomes in obese women undergoing laparotomy, laparoscopy, or
laparotomy with panniculectomy for the staging of uterine malignancy. Ann Surg Oncol 2007;14:2384-91.
5. Gehrig, et al. What is the optimal minimally invasive surgical procedure for endometrial cancer staging in the
obese and morbidly obese woman? Gynecol Oncol 2008;111:41-5.
6. Seamon et al. Comprehensive surgical staging for endometrial cancer in obese patients. Obstet Gynecol
2009;114:16-21.
Literature Review
2.Eltabbakh GH,et al. Hysterectomy for obese women with endometrial cancer: laparoscopy or laparotomy?
Gynecol Oncol 2000;78:329-335.
3.Scribner DR, et al. Pelvic and paraaortic lymph node dissection in the obese. Gynecol Oncol 2002;84:426-30.
4.Eisenhauer EL, et al. Comparing surgical outcomes in obese women undergoing laparotomy, laparoscopy, or
laparotomy with panniculectomy for the staging of uterine malignancy. Ann Surg Oncol 2007;14:2384-91.
5. Gehrig, et al. What is the optimal minimally invasive surgical procedure for endometrial cancer staging in the
obese and morbidly obese woman? Gynecol Oncol 2008;111:41-5.
6. Seamon et al. Comprehensive surgical staging for endometrial cancer in obese patients. Obstet Gynecol
2009;114:16-21.
Comprehensive Surgical Staging for Endometrial Cancer
in Obese Patients: Comparing Robotics and
Laparotomy.
Seamon, Leigh; Bryant, Shannon; Rheaume, Patrick;
Kimball, Kristopher; Huh, Warner; Fowler, Jeffrey;
Phillips, Gary; Cohn, David
Obstetrics & Gynecology. 114(1):16-21, July 2009.
DOI: 10.1097/AOG.0b013e3181aa96c7
© 2009 The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins, Inc.
3
Comprehensive Surgical Staging for Endometrial Cancer
in Obese Patients: Comparing Robotics and
Laparotomy.
Seamon, Leigh; Bryant, Shannon; Rheaume, Patrick;
Kimball, Kristopher; Huh, Warner; Fowler, Jeffrey;
Phillips, Gary; Cohn, David
Obstetrics & Gynecology. 114(1):16-21, July 2009.
DOI: 10.1097/AOG.0b013e3181aa96c7
© 2009 The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins, Inc.
5
2015 US Cancer Cases*
Men
848,200
Women
810,170
Prostate
220,800
231,840
Breast
Lung & bronchus
115,610
105,590
Lung & bronchus
Colon & rectum
69,090
63,160
Colon & rectum
Urinary bladder
56,320
54,870
Uterine corpus
Melanoma of skin
42,670
32,000
Non-Hodgkin lymphoma
Non-Hodgkin
lymphoma
39,850
48,340
Thyroid
31,200
Melanoma of skin
Kidney & renal pelvis
38,270
23,290
Kidney & renal pelvis
Oral cavity
32,670
21,290
Ovary
Leukemia
30,900
23,370
Leukemia
Pancreas
24,840
~22%
All Other Sites
All Other Sites
~20%
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2014.
Obesity and GYN Cancers
• UNC ovarian cancer patients
– 33% are obese/morbidly obese
– 58% are overweight/obese/morbidly obese
• UNC Endometrial cancer patients
– 62% are obese/morbidly obese
– 84% are overweight/obese/morbidly
49
4/5/2017
RR of death:
BMI 30-34 ->2.53
BMI >40 -> 6.25
Obesity and Cancer
Risk Factors for Endometrial
Cancer
◦ Obesity (relative risk of 2–11)
▪ Relative risk of 3.0 in women 21–50 lb overweight and 10 in
women more than 50 lb overweight
◦ Nulliparity (relative risk of 2–3)
◦ Late menopause, i.e., occurring in women older than 52 years (relative
risk of 2.4)
◦ Exogenous unopposed estrogen (relative risk of 1.6–12)
◦ Tamoxifen (relative risk of 1.7–2.5)
◦ Diabetes (relative risk of 1.3–2.7)
◦ Hypertension (relative risk of 1.2–2.1)
◦ High dietary fat consumption (relative risk of 1.1–2.0)
◦ Radiation therapy (relative risk of 8)
◦ Hereditary Non-polyposis Colorectal Cancer (HNPCC; 39– 60% lifetime
risk of EC)
-Approximately 60% of endometrial cancer
incidence is attributable to obesity and obese
women diagnosed with endometrial cancer
have six-times the risk of dying of non-obese
women…
-25% of endometrial cancer cases are in preor peri-menopausal women.
-50% of women are unaware of the
association between being overweight or
gaining weight and endometrial cancer.
For each 5 kg/m2 increase in BMI,
there is an increased risk of
development of endometrial cancer
(relative risk 1.59)
Lancet 2008;371:569
Adult BMI gain and endometrial
cancer risk
• 50,376 women in the Multiethnic Cohort Study
• 10.3 year of f/u with 463 endometrial cancer cases
• Women who were heavier at age 21 had increased risk
of endometrial cancer
• BMI gain >35% had a RR of 4.12 compared to no BMI
gain group (even if BMI <25)
• Women with annual BMI gain >1%/year had a 3.21 RR
as compared to women with stable BMI
• AA and white women showed increase risk at a BMI gain
>35%, however, Asian women showed an increased risk
with >5% gain
Park et al. Int J Cancer 2010;126:490-9.
So the jury is still out but
increasing evidence does not
suggest that BMI impacts DSS
in women with EC but all cause
may be worse.
Increased BMI is also associated with
an increased risk of ovarian cancer
(odds ratio 1.3)
30% of women with ovarian cancer
are overweight and 12% are obese
-? Negative prognostic factor
-? Inflammation
-? Inadequate surgery
-? Inadequate chemotherapy dosing
SCOTROC
-BMI not associated with PFS, OS,
tumor stage, grade, debulking status…
Jury still out
Olsen CM, Eur. J. Cancer 2007;43:690
Effect of Obesity on Survival in Epithelial
Ovarian Cancer
N=216
OS for obese patients was 62 months vs. a median of 80
months for ideal body weight patients, P = .30.
Pavelka JC et al. Effect of Obesity on Survival in Epithelial Ovarian Cancer.
Cancer 2006;107:1520-4.
Survival for Women with Stage
III-IV Epithelial Ovarian Cancer
P=0.02
P=0.02
Pavelka JC et al. Cancer 2006;107:1520-4.
Obesity and Ovarian
Cancer in KpB Mice
• K18-gT121+/-; p53fl/fl; Brca1fl/fl (KpB)
– Deletion of BRCA1 and p53
– Inactivation of retinoblastoma proteins
– Invasive cancer develops over 6 months
– High Fat versus Low Fat Diet
Obesity and Tumor Size
Genomic Differences in Ovarian Tumors from
Obese vs Lean Mice
• 131 up- or down-regulated genes
– Lipid metabolism
– Fatty acid metabolism
– Metabolic signaling pathways (AMPK)
Lean
Obese
What about in Humans?
12,042 genes in high grade serous ovarian cancer samples
•Gene Expression
•Linear regression modeling
•Covariates:
– Age, race, stage, grade, residual tumor
– BMI status
• Normal weight: BMI <25
• Overweight and obese: BMI ≥25
Demographics
BMI < 25
Normal Weight
(N=99)
BMI ≥ 25
Overweight/Obese
(N=138)
Age (mean)
57.9
59.4
Race
White
Black
Other
89 (90%)
5 (5%)
5 (5%)
125 (91%)
11 (8%)
2 (1%)
Grade
2
3
11 (11%)
88 (89%)
12 (9%)
126 (91%)
Stage
I/II
III/IV
2 (2%)
97 (98%)
4 (3%)
134 (97%)
Residual Disease
Optimal
Suboptimal
75 (76%)
24 (24%)
99 (72%)
39 (28%)
Genomic Differences in Ovarian
Tumors Related to BMI
• 347 up- or down-regulated
genes (q-value <0.1)
– Lipid metabolism
– Fatty acid metabolism
– Metabolic signaling
pathways (AMPK)
– Ras pathway
• Cross-species comparison
- AMPK on both gene lists.
Metformin’s Anti-Tumorigenic Effects
• Indirect – improvement in insulin resistance, decrease in circulating
insulin and glucose levels
• Direct – inhibits mitochondrial complex 1, AMPK activation, leading to
inhibition of the PI3K/Akt/mTOR pathway
Metformin and Ovarian Cancer Cell Lines
•
•
•
•
Inhibits ovarian cancer cell growth.
Induces ovarian cancer cell death.
Inhibits targets of the mTOR pathway.
Behaves synergistically with paclitaxel and platinums.
Metformin Inhibits Tumor Growth
4
Tumor weight (gms)
3.5
3
2.5
Control
2
Metformin
1.5
1
p=0.0003
0.5
0
Non-obese
Lean
Obese
Obese
Metformin in KpB Mice
• Induced obesity through HFD
• Induced ovarian cancer through
adenovirus injection
• Treated for 4 weeks with:
– Placebo
– Metformin 200 mg/kg/day PO
• Tumors were evaluated for:
– Size
– Immunohistochemistry
– Metabolomics
Immunohistochemistry
Obese
Ki67
Caspase 3
P-AMPK
P-S6
Obese+Met
Lean
Lean+Met
Open Clinical Trials of Metformin in Ovarian Cancer
Center
Title
Trial type
Tumor types
Study interventions
University of Chicago
NCT02122185
Metformin Hydrochloride and
Combination Chemotherapy in
Treating Patients With Stage IIIIV Ovarian, Fallopian Tube, or
Primary Peritoneal Cancer
A Phase II Evaluation of
Metformin, Targeting Cancer
Stem Cells for the Prevention of
Relapse in Patients With Stage
IIC/III/IV Ovarian, Fallopian
Tube, and Primary Peritoneal
Cancer
Randomized, placebo
controlled, phase II trial
Ovarian /Fallopian
tube/Primary
peritoneal
Patients receive metformin BID or placebo
BID in combination with standard
chemotherapy for 6 courses.
Open label, efficacy trial
Ovarian/ Fallopian
tube/ Primary
Peritoneal
(1) Patients receiving primary surgical
debulking followed by standard
chemotherapy will initiate metformin prior
to primary surgery.
Fox Chase Cancer Center
NCT02050009
The Use and Safety of
Metformin, Carboplatin and
Paclitaxel in Non-Diabetic
Patients With Recurrent,
Platinum Sensitive Ovarian
Cancer and the Feasibility of
Using a Core Biopsy for RNASeq
Open label, efficacy trial
Ovarian
UNC Lineberger
Comprehensive
Cancer Center
& Gynecologic Oncology
Associates
A Phase II, Open-Label, NonRandomized, Pilot Study of
Paclitaxel, Carboplatin and Oral
Metformin for Patients Newly
Diagnosed with
Stage II-IV Epithelial Ovarian,
Fallopian Tube or Primary
Peritoneal Carcinoma
Open label, efficacy trial
Ovarian/ Fallopian
tube/ Primary
Peritoneal
University of Michigan
Cancer Center
NCT01579812
(2) Patients treated with neoadjuvant
chemotherapy will be initiated on
metformin prior to the initiation of
chemotherapy.
Patients receive metformin BID on days 121, paclitaxel IV over 3 hours on day 1,
and carboplatin IV over 30 minutes on day
1.
(1) Patients receiving primary surgical
debulking followed by standard
chemotherapy + metformin
(2) Patients treated with neoadjuvant
chemotherapy + metformin followed by
surgery
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• 20,531 genes in endometrioid endometrial
cancer samples
• Gene Expression
• Linear regression modeling
• Covariates
• Age, grade, stage, race
• BMI status
• Non-obese: BMI < 30
• Obese: BMI ≥ 30
Demographics
Obese
(N=185)
Non-obese
(N=105)
60.8
64.5
White
83%
81%
Black
9%
9%
Other
8%
10%
I and II
77%
83%
III and IV
23%
17%
G1
30%
28%
G2
35%
28%
G3
35%
44%
Age (mean)
Race
Stage
Grade
78
4/5/2017
Genomic Differences in Endometrial Tumors Related
to BMI
• 181 genes significantly up- or down-regulated with
increasing BMI (q-value<0.01)
– Lipoprotein Lipase
– Insulin receptor substrate-1
– Insulin-like growth factor binding protein 7
– Insulin-like growth factor binding protein 4
– Progesterone
receptor
• DAVID analysis
– Cell cycle
– DNA metabolism
Obesity and Endometrial Cancer in
LKB1/p53 Mice
• LKB1fl/flp53fl/fl
»
»
»
»
Deletion of LKB1 and p53
Invasive cancer develops over 8 weeks
High Fat versus Low Fat Diet
Exposure to metformin or placebo
80
4/5/2017
Obesity and Metformin in
LKB1/p53 Mice
*
4
T u m o r w e ig h t ( g m s )
• Endometrial tumors are
double in size in the
obese mice.
• Metformin has increased
efficacy in the obese
mice.
• Genomics and
metabolomics are
ongoing…
C o n tra l
*
M e tfo rm in
3
2
**
1
0
Le an
4/5/2017
O be se
81
Conclusions
• Ovarian/endometrial tumors arising in the setting
of obesity are genomically and metabolically
different than their lean counterparts – may have
different targets for treatment.
• The association between obesity, insulin
resistance and increased risk and poor outcomes
in ovarian/endometrial cancer patients makes
metformin an attractive agent for the prevention
and treatment of this disease.
• Multiple clinical trials are in progress.
• Other pharmacologic interventions – statins,
orlistat…..
Thank you!
• Choice
• CHois/noun: choice; plural noun:
choices
1. an act of selecting or making a
decision when faced with two or
more possibilities."the choice
between good and evil"synonyms:
option, alternative, possible
course of action