Breast Cancer:

Weight and Exercise

Anne McTiernan, MD, PhD

Fred Hutchinson Cancer Research Center

Seattle, WA

Associations of Obesity with

Overall & Breast Cancer Specific

Survival

Survival Obese vs. Non-obese Breast Cancer Patients by Hormone

Receptor

Niraula et al. BCRT

2012;134:769-81

Survival Obese vs. Non-obese Breast Cancer Patients

by Menopausal Status

Niraula et al. BCRT 2012;134:769-81

Breast Cancer Specific Survival Obese vs. Non-obese Breast

Cancer Patients by Hormone Receptor

Niraula et al. BCRT 2012;134:769-81

Breast Cancer Specific Survival Obese vs. Non-obese Breast

Cancer Patients by Menopausal Status

Niraula et al. BCRT 2012;134:769-81

BMI & Recurrence: Non-inflammatory Locally

Advanced and Inflammatory: MD Anderson (N=602)

Dawood S et al. Clin Cancer Res 2008;14:1718-1725

©2008 by American Association for Cancer Research

Obesity & Treatments

Obesity in N0, ER+ Breast Cancer:

Tamoxifen Efficacy

Copyright © American Society of Clinical Oncology

Litton, J. K. et al. J Clin Oncol; 26:4072-4077 2008

Survival by BMI: Neoadjuvant Breast Cancer Patients MD Anderson Series

de Azambuja et al. Br Ca Res Treat 2009

BMI in node-positive breast cancer

patients treated with docetaxel and

doxorubicin-containing adjuvant

chemotherapy: BIG 02-98 trial,

N=2,887

A: overall survival

B: disease-free survival

Overweight/obese by Treatment (tamoxifen, anastrozole) & Survival:

ABCSG-12 Trial (n=1803 Premenopausal Patients)

Pfeiler G et al. JCO 2011;29:2653-2659

©2011 by American Society of Clinical Oncology

ATAC Trial Anastrozole vs Tamoxifen by BMI: All & Distant Recurrences

Sestak I et al. JCO 2010;28:3411-3415

©2010 by American Society of Clinical Oncology

Weight Change after Diagnosis and

Breast Cancer Prognosis

• 4/8 studies: significant decreased survival/ increased recurrence with weight gain

• Nurses Health Study, n=5204, followed ~ 9 years, risk or death for BMI gain in non-smokers: – 0.5 -2.0 kg/m2: 1.35

– > 2.0 kg/m2: 1.64

• LACE cohort, stage 1-3, n=1689, followed ~ 7 years – Weight loss > 10%: 2.5 x increased risk of death in ER-

/PR- patients

Chlebowski, Aiello, McTiernan JCO 2002;20(4):1128-1143

Kroenke et al. J. Clin Onc 2005;23(7):1370-8.

Caan B et al. Ca Causes Cont 2008:19:1319–1328

Other Potential Adverse Effects of

Obesity in Breast Cancer

• Wound complications

• Lymphedema

• Radiation therapy challenges?

• Endometrial cancer in tamoxifen users

• Congestive heart failure in patients treated with doxorubicin

• Increased risk for coronary disease, diabetes, stroke, hypertension, osteoarthritis, several cancers, decreased quality of life

Weight & Prognosis: Summary

• Overweight/obese/underweight ↓ prognosis

• Weight gain after diagnosis ↔

• Purposeful weight loss after diagnosis ???

Weight & Prognosis: Summary

• Associations seen in: – Pre-menopausal

– Postmenopausal

– All stages

– Hormone receptor positive & negative

– Varied treatments including surgery, chemotherapy, hormonal agents

– Population & clinical trial cohorts

Chlebowski, Aiello, McTiernan JCO 2002;20(4):1128-1143

Niraula et al. BCRT 2012;134:769-81

Potential Mechanisms of Obesity-

Prognosis Link

• Estrogens, androgens

• Hyper-insulinemia, insulin resistance,

diabetes, pre-diabetes

• Inflammatory markers

• Diet/physical activity

• Inadequate chemotherapy dosing

Chemotherapy Dosing:

ASCO Guidelines • Up to 40% of obese patients receive limited

chemotherapy doses that are not based on

actual body weight.

• Full weight–based cytotoxic chemotherapy

doses should be used to treat obese patients

with cancer.

• No evidence that short or long-term toxicity

is increased among obese patients receiving

full weight–based doses.

Griggs et al. JCO 2012; 30(13):1553-61

HEAL Cohort

• 1183 newly diagnosed breast cancer patients

• 3 centers: FHCRC, New Mexico, Los Angeles

• Population-based (registries)

• Multi-ethnic

• Followed for ~ 10 years post-diagnosis

• Assessing effect on prognosis of:

– weight, physical activity, metabolic hormones, inflammation, sex hormones, nutrition, vitamin D

Risk of Breast Cancer Death by C-peptide

(HEAL, 571 stage I-IIIa patients,

followed up mean 4.1 years)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

C-peptide

Ha

za

rd

Ra

tio

< 1.7 ng/mL

1.7-2.5 ng/mL

> 2.5 ng/mL

Diabetics

P trend = 0.03

Irwin et al. J Clin Oncol 2011; 29(1):47-53

• 512 early stage breast cancer

• no known diabetes

Fasting Glucose and Breast Cancer Outcomes

Quartile DDFS OS

Mean Range HR

(adjusted)*

(95% CI) HR

(adjusted)*

(95% CI)

4.5 3.5-4.7 1 1

4.9

5.2

5.7

4.7-5.1

5.1-5.4

5.4-11.6

1.28

1.50

1.88

(1.02-1.60)

(1.04-2.17)

(1.06-3.35)

1.26

1.46

1.81

(0.93-1.70)

(0.89-2.40)

(0.83-3.93)

p=0.027 unadjusted

p=0.034 adjusted

p=0.036 unadjusted

p=0.014 adjusted

* adjusted for age, T, N, grade, hormone receptor, chemotherapy, hormone

therapy

Goodwin PJ et al. J Clin Oncol 2012

Results:

Population:

Risk of Death by C-Reactive Protein (HEAL, 734

stage I-IIIa patients, followed up mean 3.8 years)

0

0.5

1

1.5

2

2.5

Met-hr/wk

Ha

za

rd

Ra

tio

< 1.2 mg/L

1.3-3.8 mg/L

> 3.9 mg/L

Pierce et al. J Clin Oncol 2009; 27(21):3437-44.

P trend =0.01

HEAL Study Weight Change (kg) in 2 Years

after Diagnosis, by Stage

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Stage

in situ

Stage I

Stage II-IIIa

Irwin, M. L. et al. J Clin Oncol; 23:774-782 2005

P=0.004

Low-Fat Diet and Breast Cancer

Prognosis: the WINS Study

• Clinical trial

• 2,437 women with early stage breast cancer

• Recruited from 37 U.S. sites

• 48-79 years old

• Randomly assigned to low-fat diet or control

group

• 6 lb. greater weight loss at 12 mos. in intervention

vs. control women

• Followed for up to 5 years

• Risk of death was significantly reduced by 24

percent in diet patients vs. controls

High Vegetable/Lower Fat Diet:

the WHEL Study

• Multi-site clinical trial

• 3088 women with early stage breast cancer

• 18-70 years old

• Randomly assigned to high vegetable/fruit/fiber,

low-fat diet or control group

• Followed for a mean 7.3 years

• Little change in diet vs. control diets

• No effect of diet on prognosis

Pierce et al. JAMA. 2007 Jul 18;298(3):289-98.

Alcohol & Breast Cancer Prognosis

• Recent findings suggest alcohol use (> 1 drink/d)

associated with:

– Increased recurrence

– Increased contralateral/2nd primary breast cancer

• Moderate alcohol use may be associated with

reduced mortality

Li et al. JCO 2009;27:5312-5318.

Kwan et al. JCO 2010;28(29):4410-6.

Barnett et al. JCO 2008; 26:3310-6.

Physical Activity

& Breast Cancer Survival

Ballard-Barbash R, et al. JNCI Jun 6;104(11):815-40

Exercise Effects in Breast Cancer Survivors

• Aerobic exercise:

– Improves fitness, mood, overall quality of life

– Reduces weight (moderately) and fatigue

– Increases lean mass

• Resistance (strength) training:

– Decreases lymphedema episodes & symptoms

– Increases strength

• Combined aerobic + resistance:

– Decreases arthralgia in aromatase inhibitor users

Galvao et al. JCO 2005;23:899-909 (review).

Schmitz K et al. N Engl J Med 2009;361:664-73.

Courneya et al. JNCI 2013 Dec 4;105(23):1821-32.

Irwin ML et al. JCO (in press)

Total Physical Activity Before and After

Diagnosis in Breast Cancer Survivors by

Treatment (HEAL)

1515.5

16

16.517

17.518

18.5

1919.5

20

Surgery Surgery +

Radiation

Surgery +

Chemo

Treatment

Hou

rs/w

eek

Before Diagnosis

After Diagnosis

P<.05

P<.05

Irwin M. et al. Cancer 2003;97:1746-57

Treatments Available for Conditions

(None FDA Approved for Breast Cancer)

• Reduce/treat obesity:

– Reduced calorie diet

– Physical activity

– Weight loss therapies (extreme obesity or co-morbidities)

• Xenical/Alli (orlistat, blocks fat absorption – prescription & OTC)

• Qsymia (topiramate, an anti-convulsant & phentermine, an appetite

suppressant)

• Belviq (lorcaserin hydrochloride, activates serotonin 2C receptor)

• Bariatric surgery

• Note: all for adding to diet & exercise weight loss program

• Medications to treat obesity mediators:

– Excess insulin (Metformin - NCIC trial ongoing)

– Inflammation (Statins, NSAIDS)

Implementing Lifestyle Change

• Reduced calorie (~ 1200-1800 kcal/day)

• Increased physical activity (>150 minutes/week moderate intensity)

• Strength training does not increase lymphedema (progress slowly)

• Weekly meetings with counselor

• Self-monitoring:

– Daily diet logs – all foods and drinks

– Weighing at least weekly

– Daily exercise logs - recreational/walking activity

• Goal 7%-10% weight loss in 6 months

• Studies in breast cancer survivors show lower weight loss than in persons without cancer

Conclusions: Clinical Guidelines • During chemo/radiation:

– Avoid weight gain unless underweight

– Exercise as tolerated: start slowly, increase slowly

• After or no chemo/radiation:

– Lose weight if BMI > 25.0 through calorie reduction +

increased physical activity

– Aerobic exercise at least 30 min/day, 5 days/wk

– Gradually increase to moderate intensity (e.g. brisk

walking, biking, fast dancing)

• Long-term survivors: weight loss may lower

adverse prognosis biomarkers

• Keep alcohol to 1 drink/day or less