Nutrition and Breast Cancer Prognosis: the HEAL Cohort

Marian L. Neuhouser, PhD, RD

Anne McTiernan, MD, PhD

Fred Hutchinson Cancer Research Center October 21, 2010

Why Study Nutrition in Breast Cancer Survivor Cohorts?

• Survival numbers and duration increasing• Long-term treatment effects increasing• Excess or deficit of body mass are associated

with poorer prognosis• Survivors want to know what they can do• Nutritional effects on biology of

cure/stabilization/progression not established• Few adequately powered randomized trials

have been funded

5 year relative survival rates – 1999-2005

CA; Cancer J Clin2010

Prognostic Effect of Body Size in Early Stage Breast Cancer

BMI (kg/m2)

Estim

ated

Rel

ativ

e R

isk

of A

dver

se E

vent

20 30 40 50

05

1015

25 35 45 55

Distant Recurrence, p=0.0005

Death, p=0.0007

Goodwin JCO 2002

Contralateral Breast Cancer & Overweight/Obesity (n=15,000)

Majed et al. Br Ca Res Treat 2010 [epub Sept]

BMI and Recurrences: ATAC Trial BMI and Recurrences: ATAC Trial

.

Eligibility Criteria:

Postmenopausal women

Early breast cancer

ER+ or PR+

R A N D O M I Z E

R A N D O M I Z E

Anastrazole 1 mgAnastrazole 1 mg

Anastrazole 1 mg +Tamoxifen 20 mgAnastrazole 1 mg +Tamoxifen 20 mg

(n = 4,939 with baseline BMI data)

Tamoxifen 20 mgTamoxifen 20 mg

100

MONTHS

100

MONTHS

Sestak et al. JCO 2010; 28(21):3411-5.

All Breast Cancer Recurrences According to BMI (ATAC Trial Participants, N~5000)

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

©2010 by American Society of Clinical Oncology

Hazard Plots for Anastrozole vs Tamoxifen by BMI: All & Distant Recurrences

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

©2010 by American Society of Clinical Oncology

HEAL: Health, Eating, Activity and Lifestyle StudyCollaboration between National Cancer

Institute and three SEER Registries

Western WashingtonNew MexicoLos Angeles

HEAL: Health, Eating, Activity and Lifestyle StudyExamine associations between health

behaviors, clinical characteristics and a variety of potential mechanisms

sex hormones, C-peptide, IGFs, vitamin D, inflammatory markers

Examine longitudinal relationships of weight, diet and physical activity with breast cancer survivorship

HEAL Design and Data CollectionBaseline 6-8 months post diagnosis

Survey and ExamN = 1,183, Stg 0-IIIa, 1997-99- 615 New Mexico, Hispanic & non-Hispanic White- 202 Washington, primarily White- 366 Los Angeles, African-American

30 months post diagnosis Survey, Exam, & Follow-Up

Diet, dietary supplements, blood drawN = 944

Five Year Survey & Follow-upN = 817

Ten Year Survey & Follow-upN = 647

QOL Assessment~3 years post diagnosis

N = 858

Regular SEER updates: survival, recurrence, 2nd

breast primaries

HEAL – Dietary Exposures and Mechanisms

Set of exposures Set of mechanisms

Fiber Hormones

Diet Quality Inflammatory Factors

Dietary Supplements IGFs

Alcohol Insulin Resistance

BMI

Survival, recurrence, 2nd primaries

Dietary fiber and serum sex hormones in postmenopausal breast cancer survivors

Wayne et al. Br Cancer Res Treat 2008

Ptrend < 0.05

Dietary fiber and serum sex hormones in postmenopausal breast cancer survivors

Wayne et al. Br Cancer Res Treat 2008

Ptrend < 0.05

Dietary fiber, C-peptide and insulin-related peptides in HEAL

Wayne et al. Br Cancer Res Treat 2008

95100105110115120125

< 8.05 8.05 -10.03

10.03 -12.96

> 12.96

Dietary Fiber Intake (g/cal)

IGF-

1 (n

g/m

L)

3.83.853.9

3.954

4.054.1

4.15

< 8.05 8.05 - 10.03 10.03 -12.96

> 12.96

Dietary Fiber Intake (g/cal)

IGFB

P3

22.12.22.32.42.52.6

< 8.05 8.05 - 10.03 10.03 -12.96

> 12.96

Dietary Fiber Intake (g/cal)

C-p

eptid

e (n

g/m

L)

Ptrend = 0.01 Ptrend = NS

Ptrend = 0.01

Alcohol and Sex Hormones• < ½ were alcohol users • In drinkers vs. nondrinkers:

– androgens were higher (p=0.01)– leptin was lower (p=0.06)

• No association with estrogens• Some evidence for effect modification by

tamoxifen use

S Wayne et al CEBP 2008

Estrogen Levels by BMI in 505 Postmenopausal Patients (HEAL)

0

5

10

15

20

25

30

< 22 22-25 25-27.5 27.5-30 > 30

kg/m2

pg/m

l

EstroneEstradiol

P trend < 0.005

McTiernan et al. JCO 2003;21:1961-66

Testosterone Levels by BMI in 505 Postmenopausal Patients (HEAL)

020406080

100120140160180200

< 22 22-25 25-27.5 27.5-30 > 30

kg/m2

pg/m

l

Testosterone

P trend = 0.0001

McTiernan et al. JCO 2003;21:1961-66

Healthy Eating Index Scores in HEAL

S George et al CEBP 2009

SM George et al CEBP 2009

Dietary fiber, C-peptide, and insulin-related peptides and CRP in HEAL

• High vs. low dietary fiber intake was significantly associated with low serum levels of C-peptide (p = 0.01) and low estradiol (p< 0.05)

• Women in highest quartile of dietary fiber had C-peptide levels that were lower by 28% compared to women in lowest three quartiles

• Better quality diet was associated with lower C- reactive protein

Dietary fiber, C-peptide, and insulin-related peptides and CRP in HEAL

• High vs. low dietary fiber is associated with lower circulating C-reactive protein (p<0.01)

• The odds of having elevated CRP was halved among those with high fiber intake

Are these fiber-biomarker relationships associated with outcomes/survivorship?

Insulin Resistance & Prognosis

• Calculated HOMA score – (Insulin mU/mLxGlucose mmol/L)/22.5

• Explored association with survival• Followed median 76.9 months after 30-

month blood draw• Hazard ratio for breast cancer mortality

with each unit HOMA increase:– 1.12 (95% CI 1.05-1.20, p trend=0.001)

• Similar results for all-cause mortality

Duggan et al. JCO 2010 (in press)

C-Peptide and Breast Cancer Mortality

00.5

11.5

22.5

33.5

44.5

5

< 1.7 1.7-2.5 > 2.5 T2DM

C-Peptide Tertiles (ng/mL)

Haz

ard

Rat

io

Breast Cancer Death

p = 0.0048

Irwin ML, et al. (in press) 2010. N = 571 women; 32 Breast Cancer deaths

C-peptide (continuous) and Breast Cancer Mortality by Prognostic Characteristics

Multivariable-Adjusted Model*# Events / Total

N HR 95% CI P-value

Age < 55 yrs** 15 / 238 1.56 1.02 - 2.39 0.039Age > 55 yrs 12 / 277 1.44 0.83 - 2.50 0.19 BMI < 25 16 / 221 2.86 1.52 - 5.31 0.0009BMI > 25 11 / 294 1.01 0.57 - 1.79 0.97Stage I 12 / 371 1.01 0.55 - 1.85 0.97Stage II-III 15 / 144 1.96 1.20 - 3.20 0.0069 ER+ 15 / 371 1.70 1.14 - 2.54 0.0094 ER - 10 / 100 0.94 0.40 - 2.25 0.90

Irwin ML, et al. (in press 2010)

* Adjusted for age, menopausal status, race/ethnicity, education, BMI, physical activity, smoking status, radiation and chemotherapy, estrogen receptor status, and family history of breast cancer** C-peptide (continuous) excludes women with type 2 diabetes. Range of C-peptide is 0.25 to 9.70 ng/mL

Adiponectin and Breast Cancer Mortality

0

0.2

0.4

0.6

0.8

1

1.2

0.85 –15.45

15.55 –74.45

Adiponectin (microgram/ml)

Haz

ard

Rat

io

Breast Cancer Death

p = 0.04

Duggan C, et al. JCO (in press) 2010.

C-Reactive Protein (CRP) and Breast Cancer Mortality

(HEAL, 734 Stage I-IIIa patients, follow up mean of 6 years)

0

0.5

1

1.5

2

2.5

Haz

ard

Rat

io

<1.2 mg/L1.3-3.8 mg/L> 3.8 mg/L

Pierce, et al. JCO, 2009

Ptrend = 0.01

CRP tertiles

Inflammation Biomarkers and Survival Among Breast Cancer Patients

Elevated CRP and SAA were associated with reduced survival regardless of adjustment for age, tumor stage, race, and BMI (SAA Ptrend < 0.0001; CRP Ptrend = 0.002)

Hazard ratios for SAA and CRP (highest vs. lowest tertiles) suggested a threshold rather than a dose- response relationship:• SAA HR = 3.15 (95% CI 1.73–5.65)• CRP HR = 2.27 (95% CI 1.27–4.08)

Associations were similar and still significant after adjusting for self-reported history of cardiovascular events and censoring cardiovascular disease deaths.

Pierce et al., JCO 2009

Serum [25(OH)D] Deficiency in Breast Cancer Survivors

Neuhouser et al AJCN 2008

Serum [25(OH)D] by Stage of Disease in Breast Cancer Survivors

Neuhouser, et al AJCN 2008

Serum [25(OH)D] by Tamoxifen Use and Estrogen Receptor Status in Breast

Cancer Survivors

* p = 0.008 vs. no tamoxifen currently ** p = 0.005 vs. no tamoxifen ever^ NS vs. negative estrogen receptor status

Dietary Supplements Use by Cancer Survivors

Review: 64-81% of cancer survivors used dietary supplements vs. 50% of general US population

Velicer et al. J Clin Oncol 2008

HEAL Supplement Inventory: “Since the breast cancer diagnosis have you taken any herbal or alternative remedies?”

• Alfalfa• Bee Pollen• Black Cohosh• Blue Cohosh• Cat’s Claw• Chaste Berries• Dong Quai• Echinacea• Evening Primrose

Oil• False unicorn• Flax seed oil• Fo ti tieng

• Garlic• Ginko biloba• Ginseng• Green tea• Gotukola• Licorice Root• Motherwort• Nux vomica• Pulsatilla• Red clover • Red raspberry• Royal jelly• Sage tea

• Sarsaparilla• Saw palmetto• Sephia• Shark cartilage• Soy supplement• St John’s wort• Valerian• Wild yam/

Mexican yam • Yerba buena• Other – over 200

write-ins

Determining Estrogenicity128 supplements were reviewed (34

listed & 94 write-ins)Sources

– PDR for Herbal Medicines – Herb-Drug Interactions in Oncology– Natural Medicines Comprehensive

DatabaseDefined as estrogenic if any indication

that supplement had estrogenic properties (in vitro, animals, humans)

0 10 20 30 40 50 60 70 80

Yam

Turmeric

Soy

Saw Palmetto

Red Clover

Nettles

Licorice

Ginseng

Fo ti tieng

Flax

Dong Quai

DHEA

Combination supp

Cat's Claw

Burdock Root

Boron

Black Cohosh

Astragalus

Alfalfa

Number of people reporting use

Use of estrogenic-type supplements in HEAL at 24 month interview

Estrogenic Supplements & Mean Hormone Concentrations in Breast Cancer Survivors (postmenopausal)Hormones£ Users Non-Users

(n=174) (n=328)

Estrone (pg/ml) 20.8 23.6*Estradiol (pg/ml) 12.8 14.7*Free Estradiol (pg/ml) 0.29 0.35**Testosterone (ng/ml) 167.9 183.3DHEAS (ng/dl) 47.7 56.2*SHBG (nmol/L) 52.2 49.1*p<0.05, ** p<0.01£Adjusted for age, race, physical activity, BMI, stage of disease at

diagnosis, dietary genestein, tamoxifen use, educationS Wayne et al Br Can Res Treat, 2008

Soy Supplements & Mean Hormone Concentrations in Breast Cancer SurvivorsHormones£ Soy Users Non-Users

(n=26) (n=328)

Estrone (pg/ml) 20.5 23.4Estradiol (pg/ml) 11.8 14.9Free Estradiol (pg/ml) 0.27 0.36Testosterone (ng/ml) 180.3 180.6DHEAS (ng/dl) 48.6 53.9SHBG (nmol/L) 60.1 48.8No statistically significant differences£Adjusted for age, race, physical activity, BMI, stage of disease

at diagnosis, dietary genestein, tamoxifen use, education

S Wayne et al Br Can Res Treat, 2008

Estrogenic Supplements & Mean Hormone Concentrations in Breast Cancer SurvivorsHormones£ Non-users 1 supp > 2 supp p, trend

(n=328) (n=85) (n=89)Estrone (pg/ml) 23.7 21.6 19.7 0.01Estradiol (pg/ml) 14.7 12.2 13.2 0.08Free Estradiol (pg/ml) 0.35 0.27 0.30 0.02Testosterone (ng/ml) 184.0 177.4 157.1 0.09DHEAS (ng/dl) 56.1 47.5 48.2 0.04SHBG (nmol/L) 48.8 58.3 47.4 0.79£Adjusted for age, race, physical activity, BMI, stage of disease

at diagnosis, dietary genestein, tamoxifen use, education

S Wayne et al BR Can Res Treat 2008

Dietary Supplements and Cancer Survivors in HEALUse of botanical supplements by breast

cancer survivors is commonMany of these supplements have estrogenic

propertiesIn the HEAL study, use of estrogenic

botanical supplements was associated with lower estrone, estradiol, free estradiol and DHEAS – analyses to examine survival and quality of life are in progress

Dietary Supplements and Cancer Survivors in HEALCAVEATS Variety of botanical supplements were used

by HEAL participants

We cannot guarantee content or purity

Difficulties in “estrogenic” classification

Observational study – possible that breast cancer patients who had more estrogen withdrawal symptoms/lower estrogen used the supplements

Nutrition and Breast Cancer Prognosis: HEAL

• A cancer diagnosis can be a “teachable moment” for making diet/activity changes, but accurate data are needed on effects of changes

• Evidence from HEAL that these lifestyle changes can influence hormones, insulin-like growth factors, inflammatory factors and subsequently, mortality

• New opportunities for interventions

HEAL INVESTIGATOR TEAM

FHCRC

Anne McTiernan

Marian Neuhouser

Catherine Duggan

CY Wang

City of Hope/USC

Leslie Bernstein

Roberta McKean-Cowdin

Kathy Meeske

UNM/ U Louisville

Charles Wiggins

Rick Baumgartner

Kathy Baumgartner

NCI

Rachel Ballard-Barbash

Lynne Harlan

Ashley Wilder-Smith

Catherine Alfano

Yale

Melinda Irwin

** Plus numerous outstanding students, fellows, staff, and former investigators