Breast Cancer: Weight and Exercise. Anne McTiernan, MD, PhD. Fred Hutchinson Cancer Research Center Seattle, WA

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1 Breast Cancer: Weight and Exercise Anne McTiernan, MD, PhD Fred Hutchinson Cancer Research Center Seattle, WA

2 Associations of Obesity with Overall & Breast Cancer Specific Survival

3 Survival Obese vs. Non-obese Breast Cancer Patients by Hormone Receptor Niraula et al. BCRT 2012;134:769-81

4 Survival Obese vs. Non-obese Breast Cancer Patients by Menopausal Status Niraula et al. BCRT 2012;134:769-81

5 Breast Cancer Specific Survival Obese vs. Non-obese Breast Cancer Patients by Hormone Receptor Niraula et al. BCRT 2012;134:769-81

6 Breast Cancer Specific Survival Obese vs. Non-obese Breast Cancer Patients by Menopausal Status Niraula et al. BCRT 2012;134:769-81

7 BMI & Recurrence: Non-inflammatory Locally Advanced and Inflammatory: MD Anderson (N=602) Dawood S et al. Clin Cancer Res 2008;14: by American Association for Cancer Research

8 Obesity & Treatments

9 Obesity in N 0, ER+ Breast Cancer: Tamoxifen Efficacy

10 Survival by BMI: Neoadjuvant Breast Cancer Patients MD Anderson Series Litton, J. K. et al. J Clin Oncol; 26: Copyright American Society of Clinical Oncology

11 BMI in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: BIG trial, N=2,887 A: overall survival B: disease-free survival de Azambuja et al. Br Ca Res Treat 2009

12 Overweight/obese by Treatment (tamoxifen, anastrozole) & Survival: ABCSG-12 Trial (n=1803 Premenopausal Patients) Pfeiler G et al. JCO 2011;29: by American Society of Clinical Oncology

13 ATAC Trial Anastrozole vs Tamoxifen by BMI: All & Distant Recurrences Sestak I et al. JCO 2010;28: by American Society of Clinical Oncology

14 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: kg/m 2 : 1.35 > 2.0 kg/m 2 : 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): Kroenke et al. J. Clin Onc 2005;23(7): Caan B et al. Ca Causes Cont 2008:19:

15 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

16 Weight & Prognosis: Summary Overweight/obese/underweight prognosis Weight gain after diagnosis Purposeful weight loss after diagnosis???

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

18 Potential Mechanisms of Obesity- Prognosis Link Estrogens, androgens Hyper-insulinemia, insulin resistance, diabetes, pre-diabetes Inflammatory markers Diet/physical activity Inadequate chemotherapy dosing

19 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):

20 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

21 Hazard Ratio Risk of Breast Cancer Death by C-peptide (HEAL, 571 stage I-IIIa patients, followed up mean 4.1 years) C-peptide P trend = 0.03 < 1.7 ng/ml ng/ml > 2.5 ng/ml Diabetics Irwin et al. J Clin Oncol 2011; 29(1):47-53

22 Fasting Glucose and Breast Cancer Outcomes Population: 512 early stage breast cancer no known diabetes Results: Quartile DDFS OS Mean Range HR (adjusted)* (95% CI) HR (adjusted)* (95% CI) ( ) 1.26 ( ) ( ) 1.46 ( ) ( ) 1.81 ( ) 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

23 Hazard Ratio Risk of Death by C-Reactive Protein (HEAL, 734 stage I-IIIa patients, followed up mean 3.8 years) 2.5 P trend = < 1.2 mg/l mg/l > 3.9 mg/l Met-hr/wk Pierce et al. J Clin Oncol 2009; 27(21):

24 HEAL Study Weight Change (kg) in 2 Years after Diagnosis, by Stage P=0.004 Stage in situ Stage I Stage II-IIIa Irwin, M. L. et al. J Clin Oncol; 23:

25 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 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

26 High Vegetable/Lower Fat Diet: Multi-site clinical trial the WHEL Study 3088 women with early stage breast cancer 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 Jul 18;298(3):

27 Alcohol & Breast Cancer Prognosis Recent findings suggest alcohol use (> 1 drink/d) associated with: Increased recurrence Increased contralateral/2 nd primary breast cancer Moderate alcohol use may be associated with reduced mortality Li et al. JCO 2009;27: Kwan et al. JCO 2010;28(29): Barnett et al. JCO 2008; 26:

28 Physical Activity & Breast Cancer Survival Ballard-Barbash R, et al. JNCI Jun 6;104(11):815-40

29 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: (review). Schmitz K et al. N Engl J Med 2009;361: Courneya et al. JNCI 2013 Dec 4;105(23): Irwin ML et al. JCO (in press)

30 Hours/week Total Physical Activity Before and After Diagnosis in Breast Cancer Survivors by Treatment (HEAL) P<.05 Surgery Surgery + Radiation Treatment P<.05 Surgery + Chemo Irwin M. et al. Cancer 2003;97: Before Diagnosis After Diagnosis

31 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)

32 Implementing Lifestyle Change Reduced calorie (~ 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

33 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

Breast Cancer: Weight and Exercise. Anne McTiernan, MD, PhD. Fred Hutchinson Cancer Research Center Seattle, WA

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