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Energy Balance and Cancer Energy Balance and Cancer SurvivalSurvival
Michelle D. Holmes, MD, DrPH
November 11, 2005
Cancer Survivorship
• 62% 5 year survival over all adult cancers
• 8.9 million US cancer survivors– 22% breast cancer (2 million)– 19% prostate cancer (1.7 million)– 11% colorectal cancer (1 million)
Aziz; J Nutr 2002; 132: 3494S
Topics
• Energy balance
(obesity, weight gain, activity)• Breast Cancer• Colon Cancer
• Dietary fat and breast cancer
Energy BalanceObesity
BMI kg/m2 WHO definition Lbs, 5’4”
<21 underweight <122
21-24.9 normal weight 122-144
25-29.9 Overweight 145-173
30-34.9 Obese 174-203
35-39.9 Severe obesity 204-231
≥ 40 Morbid obesity ≥ 232
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1987
No Data <10% 10%– 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1987
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1989
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1989
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1991
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1991
No Data <10% 10% – 14% 15% – 19%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1993
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1993
No Data <10% 10% – 14% 15% – 19%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1995
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1995
No Data <10% 10% – 14% 15% – 19%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1997
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1997
No Data <10% 10%– 14% 15%– 19% ≥20
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 1999
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1999
No Data <10% 10% – 14% 15% – 19% ≥20
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 2001
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 2001
No Data <10% 10% – 14% 15% – 19% 20% – 24% ≥25%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity Trends* Among U.S. AdultsBRFSS, 1985
No Data <10% 10% – 14%
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
Energy BalanceObesity
1985 vs. 2003
Source: Behavioral Risk Factor Surveillance System, CDC.
Obesity* Trends Among U.S. AdultsBRFSS, 2003
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10% – 14% 15% – 19% 20% – 24% ≥25%
Obesity Decreased Survival
Author, date Comparison Mortality (HR)
Daling JR, 2001 4th vs 1st BMI quartile 2.5 (1.6-3.9)
Galanis DJ, 1998 1 BMI unit increase 9% increase
Newman SC, 1995 4th vs 1st BMI quartile 2.5 (1.2-5.2)
Zhang S, 1995 3rd vs 1st BMI tertile 1.5 (0.7-2.9)
Bastarrachea, 1994 Obese vs normal weight 1.33 (1.05-1.68)
Weight Gain → ↓Survival
Category of BMI Change
BMI loss Maintain Gain 0.5-<2.0
kg/m2
Gain ≥2.0 kg/m2
p
Never smokers, N 514 677 712 272
Breast cancer death 38 48 77 46
1.01
(0.65,1.58)
1.00 1.35
(0.93,1.95)
1.64
(1.07,2.51)
0.03
Kroenke CH, J Clin Onc 2005;23: 1370
Relative risk of breast cancer death by category of weight change among 5,204 women with breast cancer from the NHS
• Improves body esteem and mood
• Enhances quality of life
• Can it improve survival?• Might prevent weight gain with chemotherapy• Might lower hormone levels known to stimulate
cancer growth
Exercise and Breast Cancer Survivors
Metabolic Equivalent ConversionsMETS for 1 hour of that activity
Normal pace walking (2-2.9 mph) 3
Brisk pace walking (3-3.9 mph) 4
Very brisk pace walking (4+ mph) 4.5
Jogging (slower than 10 minutes/mile) 7
Running (faster than 10 min/mile) 12
Bicycling 7
Tennis, squash, racquetball 7
Lap swimming 7
Calisthenics, ski or stair machine, other aerobic
6
Yoga, stretching, toning, lower intensity exercise
4
Other vigorous activities (lawn mowing) 6
NHS Study Participants
• Invasive breast cancer 1984-2002
• Stages I, II, III
• Activity assessment ≥ 2 years after diagnosis
Physical activity after diagnosis
– This is what a woman with breast cancer can change
Avoided women with occult metastatic disease
– Likely to affect activity levels
MET-hrs/week
< 3 3-8.9 9-14.9 15-23.9 24+ P-value
Deaths
RR
95% CI
188
1.00
-----
126
0.71
(0.56-0.89)
38
0.59
(0.41-0.84)
51
0.56
(0.41-0.77)
60
0.65
(0.48-0.88)
0.003
Breast Cancer Deaths 110 84 20 32 34
RR 1.00 0.80 0.50 0.56 0.60 0.004
95% CI ----- (0.60-1.06) (0.31-0.82) (0.38-0.84) (0.41-0.89)
Multivariate RR of Death, and Breast Cancer Death, by Physical Activity
Holmes MD, JAMA 2005;293:2479
Multivariate RR of Death from Breast Cancer, by Physical Activity,Stratified by
ER/PR status
MET-hrs/week
<9 ≥9
ER- and PR-
# deaths/N
RR (95% CI)
27/272
1.00 (- - -)
13/149
0.91 (0.43-1.96)
ER+ and PR+
# deaths/N
RR (95% CI)
99/955
1.00 (- - -)
36/609
0.50 (0.34-0.74)
P for interaction = 0.08
Mean Serum Hormones x BMI in 503 Women with Breast Cancer
BMI
<22 22-25 25-27.5 27.5-30 >30 P
Estrone (pg/mL) 19.7 22.3 21.2 22.7 26.5 0.005
Estradiol (pg/mL) 4.7 8.3 8.0 10.6 10.7 0.002
DHEAS (ng/dL) 50.5 53.2 55.6 60.0 59.3 0.21
SHBG (nmol/L) 73.9 66.2 52.1 43.4 38.1 .0001
Testosterone(pg/mL) 94.5 188.1 127.4 126.0 176.5 .0001
Free estradiol (pg/mL) 0.10 0.18 0.20 0.28 0.28 .0001
Free testosterone(pg/mL) 2.1 2.9 4.0 4.6 7.6 .0001
McTiernan A, JCO 2003; 21:1961
RTC
• 173 overweight postmenopausal women• Moderate exercise 5 days/week x 12 months• Controls=stretching
• Exercisers vs. Controls
Irwin ML, JAMA 2003;289:323
↓1.3 kg ↑0.1 kg p=0.01
↓abdominal fat
(8.5 g/cm2)
↑ abdominal fat
(0.1 g/cm2 )
p=0.05
Estradiol (pg/mL) levels
Exercisers Controls
Baseline 12 mos %∆ Baseline 12 mos %∆ Difference in %∆
Gained body fat
19.1 20.3 6.3 20.6 19.3 -6.3 12.6
Lost >2% fat 18.3 15.8 -13.7 16.9 17.7 4.7 -18.1
P=0.008
McTiernan A, CEBP 2004;13:1099
• Cohort study 3759 men & women• Stage II, III colon cancer• INT-0089 trial
– 4 treatment aims– No survival difference by treatment– f/u = 9.4 years
• Categorized by BMI (kg/m2) at time of Rx
• Meyerhardt, Cancer 2003
Energy Balance (Obesity)
Energy Balance (Obesity)
BMI
<21 21-24.9 25-27.49 27.5-29.9 ≥30 p
Women
Overall mortality
Disease recurrence
1.08
1.01
ref.
ref.
1.18
1.14
1.23
1.20
1.34(1.07-1.67)
1.24(0.98-1.59)
0.007
0.061
Men
Overall mortality
Disease recurrence
1.33
1.22
ref.
ref.
1.03
1.00
0.96
1.05
0.94(0.77-1.15)
0.98(0.79-1.23)
0.39
0.93
Adjusted HR (85% CI)By BMI
Mechanisms for Energy Balance Affecting Colon cancer survival
•Insulin/C-peptide/IGFs•Leptin/Adiponectin/Inflammatory markers
Energy intake, Physical activity, High Glycemic diet
PituitaryGH secretion IGF-I response to GH
Obesity Insulin resistance
Competentbeta-cell secretion C-peptideHyperinsulinemia(Fasting or Post-Prandial)
Bioactive IGF-I
Cell survival and proliferation
Direct effect?
IGFBP-1
0
1
2
3
4
5
No Diagnosis 1-9 11-15 >15
Years Since Diagnosis of Diabetes
Hu et al., JNCI 1999
RR Colon Cancer (NHS)
High insulinproduction Low insulin
production
C-peptide Levels & Colorectal Cancer Risk in Men (PHS)
0
0.5
1
1.5
2
2.5
3
3.5
Q1 Q2 Q3 Q4 Q5
Overall
Control for IR factors
Excluding cases Dx within five years of blood collection
RR
Plasma C-peptide
Ptrend <0.05
ref
Ma, et al. J Natl Cancer Inst 2004
Biological Function of White Adipose Tissue
appetite and energy balance (leptin)
haemostasis
insulin sensitivity (adiponectin)
immunity
blood pressure
lipid metabolism
Angiogenesis (VEGF)
inflammation ´-phase response (IL-6, CRP, TNF-)
(Trayhurn and Wood et al. 2004)
Leptin, BMI and Risk of Colorectal Cancer (Sweden)
0
0.5
1
1.5
2
2.5
3
Q1 Q2 Q3 Q4
Men
Women
0
0.5
1
1.5
2
2.5
3
Q1 Q2 Q3 Q4
Men
Women
Leptin BMI
Stattin et al. Oncology Reports, 2003
Ptrend=0.08Ptrend=0.02
ref ref
OR OR
Cohort studies of fat intake and breast cancer survival, by timing of dietary assessment
(Author & year, N, Hazard Ratio)
Before
Jain, 1994 678 1.4 (1.2-1.8)
Zhang, 1995 698 2.1 (1.1-4.3)
After
Ewertz, 1991 2445 ---------------
Holmes, 1999 1982 ---------------
Mixed
Gregorio, 1985 933 1.44, p<0.01
Newman, 1986 300 -----------
Nomura, 1991 182 white 3.2 (1.2- 8.5)
Kyogoku, 1992 212 -----------
Holm, 1993 240 1.1 (1.0-1.5)
Rohan, 1993 412 -----------
Hebert, 1998 472 1.3 (1.0-1.6)
Goodwin, 2003 477 2.1
WINSRTC of low fat diet
2437 women with postmenopausal breast
cancer
975 womenLow fat diet(33.3 g/day)
1462 womenStandard diet(51.3 g/day)
5 yrs
WINSlow fat diet vs. control
RR (95% CI) p-value
All women 0.76 (0.60-1.00) 0.03
ER+ 0.85 (0.63-1.14) 0.28
ER- 0.58 (0.37-0.91) 0.02
WINS Trial
• Pilot studies showed– Good adherence to diet– Average weight decrease 2 kg– Average estradiol decrease 20%
Conclusions
• Adjuvant treatments for breast & colon cancer lowers disease mortality 25-40%
• Weight maintenance after breast cancer may lower disease mortality 40%∼
• Moderate exercise after breast & colon cancer may lower disease mortality 40-∼50%