energy balance and cancer survival michelle d. holmes, md, drph november 11, 2005

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

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)



No Data <10% 10%– 14%



1985 vs. 1987



No Data <10% 10% – 14%



1985 vs. 1989



No Data <10% 10% – 14%




No Data <10% 10% – 14%



1985 vs. 1991



No Data <10% 10% – 14% 15% – 19%




No Data <10% 10% – 14%



1985 vs. 1993



No Data <10% 10% – 14% 15% – 19%




No Data <10% 10% – 14%



1985 vs. 1995



No Data <10% 10% – 14% 15% – 19%




No Data <10% 10% – 14%



1985 vs. 1997



No Data <10% 10%– 14% 15%– 19% ≥20




No Data <10% 10% – 14%



1985 vs. 1999



No Data <10% 10% – 14% 15% – 19% ≥20




No Data <10% 10% – 14%



1985 vs. 2001



No Data <10% 10% – 14% 15% – 19% 20% – 24% ≥25%




No Data <10% 10% – 14%



1985 vs. 2003


Obesity* Trends Among U.S. AdultsBRFSS, 2003


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)

Energy BalanceWeight Gain

Chemotherapy Weight Gain

Goodwin PJ, J Clin Oncol 1999; 17:120

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

Exercise

• 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

Mortality curves by exercise level

Mechanisms for Energy Balance Affecting Breast Cancer Survival

•Sex steroid hormones

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

Colon Cancer

• 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 &acute-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

Dietary Fat and Breast Cancer Survival

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%

Conclusions

• Advising weight maintenance and exercise after breast & colon cancer may help our patients as much as standard treatments.

• Important in our sedentary & obesigenic environment.

energy balance and cancer survival michelle d. holmes, md, drph november 11, 2005

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