Obesity, Activity

and Breast Cancer Prognosis

Pamela J. Goodwin, M.D., M.Sc., F.R.C.P.C.

Samuel Lunenfeld Research Institute at

Mount Sinai Hospital, University of Toronto

Body Size at Breast Cancer Diagnosis

26 - 282000’s

25 - 261980’s to 1990’s

BMI (kg/m2)

HR (95% CI) for “Obese” vs. “Non -obese”

Distant Recurrence

Death

Obesity 1.91 (1.52 - 2.40) 1.60 (1.38 - 1.76)

Weight 1.78 (1.50 - 2.11) 1.36 (1.19 - 1.55)

• over 50 reports since Abe 1976

• meta-analysis of reports prior to 1990 (Goodwin 1995)

Obesity – Breast Cancer Prognosis

• of 51 published reports 1976-2004 (Goodwin 2005)

– 36 (35,103 women) significant adverse effects (73.1%)– 15 (12,949 women) no significant effects (26.9%)

• obesity associated with more advanced stage, higher grade, ER negativity, higher proliferation rates, but prognostic effects independent of these factors

Prognostic Effects of Obesity – Endpoints

65%1320Breast cancerrecurrence

40

25

27

# studies

70%28Any breast cancerspecific outcome

68%17Breast cancerspecific survival

63%16Overall survival

%# “significant”

studies

Prognostic Effect of Body Size in Operable Breast Cancer

BMI (kg/m2)

Est

imat

ed R

elat

ive

Ris

k o

f A

dve

rse

Eve

nt

20 30 40 50

05

1015

25 35 45 55

Distant Recurrence, p=0.0005

Death, p=0.0007

Weight Gain After Breast Cancer Diagnosis

• Reported in over 20 studies since the early 1980’s

• Very common - occurs in 50-75% of women in most recent reports

- averages 1.5-3.0 kg over one year in most recent reports; up to 10 kg or greater on average in earlier reports

Weight Gain in Breast Cancer

Camoriano et al JCO 1990

Overall Survival and Weight Gain in Breast Cancer

Camoriano et al JCO 1990

Prognostic Effects of Weight Gain

None1.21-5.556371988Goodwin

None1.64452001Goodwin

None4.2321991Levine

None< 10621986Chlebowski

None4.32371985Heasman

Adverse(premenopausal)

5.9(premenopausal)5451990Camoriano

Adverse>10621986Chlebowski

Adverse8.2671984Bonomi

Prognostic EffectWeight Gain (kg)n

Weight Change and Survival After Breast Cancer Diagnosis

• T1• T>1

• N0• N1

• <25• ≥25

• Never• Ever

BMI Change Post Diagnosis (kg/m2)

0.003 0.89

1.780.99

0.971.07

1.001.00

1.040.87T Stage

0.007 0.74

1.741.10

1.221.18

1.001.00

1.101.06N Stage

<0.01 0.18

1.900.75

1.630.78

1.001.00

1.410.81

BaselineBMI

0.030.84

1.641.05

1.351.10

1.001.00

1.011.18

Smoking

pGain >2.0Gain 0.5-2.0MaintainLoss

>0.5

Population - Nurses’ Health Study, 5204 non-metastatic breast cancer 1976-2000

Measurement - self-report weight before and ≥ 12 months post diagnosis- self-report vs. actual weight r=0.99

Results

Kroenke CM et al. JCO 2005;23:1370-1378

Breast Cancer Mortality (RR)

Factors Commonly Associated With Weight Gain After Breast Cancer Diagnosis

1. Age/Menopausal Status

• younger age > older age; pre > postmenopausal

• menopause onset / reduction in estradiol > no change

2. Baseline BMI

• low BMI > high BMI

3. Adjuvant Treatment

• chemotherapy > no chemotherapy

- 12 months > 6 months- non-anthracycline > anthracycline

• steroids

- component of adjuvant therapy > antiemetic use

Physical Activity

• inactive > active

What is the Nature of the Weight Gain in Breast Cancer?

pNo CXT(n=12)

CXT(n=36)

stable

stable

stable

-0.1 ± 0.4+0.1 ± 0.3+0.8 ± 0.2+0.5 ± 0.1

1.0kg

reduced

stable

stable

+2.2 ± 0.6%+2.3 ± 0.7-0.4 ± 0.3-0.2 ± 0.1

2.1 kg

0.01Physical activity (all times)

nsREE* (BMI adj – all times)

nsEnergy intake (all times)

0.0010.0020.020.01

Body Composition

% fatfat masslean body masslean leg mass

0.02Weight gain (one year)

Population - 53 premenopausal women with newly diagnosed breast cancer- 36 CXT, 17 no CXT

Measurement - 3 weeks, 2, 6, 12 months post diagnosis

Results

Demark-Wahnefried at al JCO 2001;19:2381-2389

* REE higher in CXT group at all timepoints

Conclusions - pattern of “sarcopenic” obesity (weight gain in presence of lean tissue loss)

- physical activity interventions, especially lower body resistance training recommended

Mean Energy Required for Physical Activity

Demark-Wahnefried et al JCO 2001;19:2381-2389

Health, Eating, Activity and Lifestyle Study(HEAL)

≤ 00.1-1.5≥ 1.5

< -270-270 to 100> 100

SurgerySurgery + XRTCXT (any)

40-4950-5960+

0.052.92.01.3

0.032.21.91.2

Δ Sports (hrs/wk)

0.49

1.03.51.90.08

1.03.02.1

Δ Caloric Intake

ns

1.91.63.2<0.05

1.51.13.0

Treatment**

0.06

3.41.91.30.0001

3.71.80.3

Age*

2.1±3.91.7±4.7All

p (trend)% Body FatChangep (trend)

WeightChange

(kg)

Population - 514 women with Stage 0-IIIA breast cancer- enrolled prior to, during or after adjuvant therapy- Washington, New Mexico

Measurement - baseline (first year post diagnosis); 2 years later (third year post diagnosis)

Results

Irwin ML et al JCO 2005;23:774-782

* highest in younger postmenopausal women (vs. pre, older post)** unadjusted

Physical Activity and Survival After Breast Cancer Diagnosis

Physical Activity Post Diagnosis (MET – hrs/wk)

0.050.740.660.570.831.0Recurrence

0.0040.600.560.500.801.0Breast Cancer Death

0.030.650.560.590.711.0Total Deaths

p (trend)≥2415-23.99-14.93-8.9<3

Population - Nurses’ Health Study, 2987 Breast Cancer Stage I-III 1984-1998

Measurement - self-report physical activity prior to diagnosis and ≥ 2 years (38 months median) after breast cancer diagnosis- one MET (metabolic equivalent task) = energy expenditure for sitting quietly- median follow-up 96 months

Results • greater physical activity - low BMI, low weight gain, non-smoker, ST II (vs. I)

Multivariate RR (RF, protein, stage, treatment)

Holmes MD et al JAMA 2005;293:2479-2456

* effects greater in ER/PgR+, BMI >30, Stage III (trends)* effects independent of pre-diagnosis physical activity

Conclusions - physical activity over 9 MET-hours/week (walking 3 hours/week) reduces risk of recurrence and death

- both walking and vigorous activity lowered risk

- no added benefit beyond 9 MET-hours/week (3 hours walking)

Mortality According to Physical Activity Level in Breast Cancer

Holmes MD et al JAMA 2005;293:2479-2486

Potential Mediators of a Prognostic Effectof Obesity in Breast Cancer

• estradiol

• insulin (IGF’s / BP’s)

• adipocytokines (e.g. leptin)

• immune factors

ESTRADIOL - PROGNOSTIC EFFECTS(unadjusted)

Distant Recurrence Death

Range pmol/L

HR HR

Q1 0 - 73.6 1.0 1.0

Q2 73.6 - 149 0.95 0.98

Q3 149 - 301 0.92 0.97

Q4 301 - 1257 0.88 0.95

p=0.65 p=0.90

BMI and Fasting InsulinF

asti

ng

Insu

lin

20 30

40

50

010

020

030

0 BMI Spearman R

< 2020-25> 25Overall

0.330.22

0.590.50

BMI (kg/m2)

p < 0.00001

Insulin and Breast Cancer Prognosis

0

0.5

1

1.5

2

2.5

3

3.5

< 27 27-35.3 35.3-51.9 > 51.9

HR

Insulin Quartiles (pmol/L)

Death p=0.001

Distant Recurrence p=0.007

Goodwin PJ et al. J Clin Oncol 2002;20:42-51

Insulin Effect According to ER / PgR

Insulin (pmol/L)

Haz

ard

rat

io (

rela

tive

to

insu

lin =

10)

50 100 150 200

02

46

810

ER/PgR=neg

p = 0.12

ER/PgR=poseq

• n=603 early stage breast cancer

• mean BMI 26.0

• 43% received tamoxifen, 36% chemotherapy

• correlation non-fasting insulin and BMI: 0.29

• prognostic effects insulin

Non-Fasting Insulin – Breast Cancer Prognosis

Odds Ratio

0.101.93.01.0Post

0.750.90.71.0Pre

0.691.31.41.0All

pTertile 3Tertile 2Tertile 1

Borugian Cancer Epidemiol Biomarkers Prev 2004

Prognostic Associations of Other Members of the Insulin-IGF Family(Unadjusted)

0.93

0.003

0.84

0.90

p(2-tail)

0.02

0.009

0.97

0.09

p(2-tail)

0.97 1.84**IGFBP-3

0.330.48IGFBP-1*

0.940.99IGF-II

1.041.55IGF-I

HR(Q4 vs. Q1)

HR(Q4 vs. Q1)

OSDDFS

* expression of IGFBP-1 gene is inhibited by insulin; IGFBP-1not significant when insulin included in model (p≥0.22)

** present in postmenopausal women only (HR 3.84, p=0.002),replication recommended

Obesity and Related Factors in Breast Cancer

• adipocytokine secreted by fat cells

• strongly correlated with BMI (r=0.81) and insulin (r=0.64)

• stimulates tumor cell growth, migration, invasion,angiogenesis and aromatase activity

• associated with breast cancer risk in one study

Leptin

Nutrition Related Factors in Breast Cancer

• Mean 15.21 ± 10.09 ng/ml• Univariate analysis DDFS → HR 1.6 (0.9-2.7) p=0.09

OS → HR 2.2 (1.1-4.4) p=0.02

• Adjusted for T, N, tumor grade, ER, PgR, adjuvant CXT and tamoxifen

DDFS → HR 1.5 (0.8-2.7) p=0.22OS → HR 1.7 (0.78-3.8) p=0.17

• No significant survival effects after adjustment for BMI or insulin(all p ≥ 0.42)

Leptin – DDFS, OS

* HR’s were calculated for the midpoint of the upper vs. lower quartile

Obesity – PrognosisInteraction of Estrogen and Insulin/IGF Mechanisms

AdiposeAdiposeTissueTissue

↑↑ estrogens estrogens ↑↑ insulin insulin ↓↓ IGFBP-1 IGFBP-1

↑↑ IGF-I IGF-I↓↓ SHBG SHBG

ER/PgR

ER/PgRIGF-IRIGF-IR

IR IR αα, , ββ

(free)++

++ ++

++

++

++

++

++++++

++

−−

−−

−−

*

*

GH GH

ProliferationProliferationAnchorage Independent GrowthAnchorage Independent Growth

Reduced ApoptosisReduced Apoptosis

* PI3K, ras-raf-MAP Kinase signalling pathways

++ ++

++++

Intervention Research

Diet Interventions and Weight Loss in Breast Cancer (RCT’s)

Yes (1.46kg loss intervention vs.1.80kg gain control)

↓ fat, ↑ CHOno change calories

2901993Chlebowski

No (+0.04kg intervention vs. 0.46controls at 1 year)

↑ fruit, fiber, vegetables,↓ fat

10102001Rock

48obese

107

102

240

n

Yes (-2.6kg vs. -8.0kg vs. -9.4kg vs.+0.85kg at 1 year)

Weight Watchers vs.individual vs. both vs. nil(↓ energy)

2002Djuric

No (+2.0kg vs. +3.5kg at 6 months)↓ calories1996Loprinzi

Yes (-6kg vs. +1kg at 1 year)↓ calories1993de Waard

Yes (-0.4kg vs. +1.3 kg at 2 years)↓ fat, ↑ CHO1990Nordevang

Weight LossInterventionCitation

Fat gram / day Weight Change

Intervention 33.3±16.7 -1.46 kg

Control 51.3±24.4 +1.80 kg

p value <0.001 <0.05

• RCT of dietary fat reduction in postmenopausal women with primary breast cancer

• n=2437 age 48-79

• At 12 months

Womens’ Intervention Nutrition Study (WINS)

Relapse Free Survival(60 months)

0.0180.58 (0.37-0.91)59/27328/205ER-

0.2770.85 (0.63-1.14)122/118968/770ER+

0.0340.76 (0.60-0.98)181/146296/975All

p(2 tail)HRControlDiet

Chlebowski R et al ASCO 2005

Exercise Interventions and Weight Loss in Breast Cancer (RCT’s)

Non significant ↑ lean mass, ↓ body fat % in intervention (+0.32kg vs. +0.20kg)

Supervised weighttraining x 6 months

852005Schmitz

not reportedSelf-directed walking1192005Mock

53

123

24

42

n

No [(+0.1kg vs. +0.7kg (ns)](n/s ↓ skinfold in intervention)

Supervised cyclingx 15 weeks

2003Courneya

No (-1.4 kg supervised vs. +0.6 kg control)(significant in those not receiving CXT)

Supervised vs. self-directed walking

x 26 weeks

2001Segal

No [+0.82kg vs. +1.99 kg (ns)](↑ lean, ↓ fat)

Supervised cyclingx 10-12 weeks

1989Winningham

not reportedSupervised cyclingx 10-weeks

1988Winningham

Weight LossInterventionCitation

Multimodality Approach to Weight Management in Breast Cancer

• n=61 women with locoregional breast cancer• BMI 20-35 kg/m2 – 59% received CXT

Intervention

• One year group (weekly x 10, monthly x 10)

Individual Goals - avoid weight gain if BMI < 25- lose weight to BMI 25 or max 10 kg if BMI >25

Individual diet - Canada’s Food Guide - ↓ fat, ↑ CHO, ↑ fibre Individual exercise - self-directed – walking > 95% Group psychosocial - ↓ distress, ↑ QOL, ↑ adjustment

Results

• 70.9% successfully reached weight goal

• Greatest weight loss if - loss (vs. maintain) the goal- no CXT (vs. CXT)

• Strongest predictor of success - physical activity(OR 1.73 for each 30 minutes walking / week)

• Other predictors: ↓ disinhibited eating, ↑ psychosocial adjustment

Goodwin PJ et al Br Ca Res Treat 1998;48:53-64

Target Groups for a Weight ManagementIntervention in Breast Cancer

1)* BMI - all- > 25 kg/m2

- > 30 kg/m2

2)* Menopausal status - all- pre- post

3)* ER/PgR - all- ER and/or PgR negative

4) Biomarker - insulin > 45 pmol/L- estradiol, estrone

5) Adjuvant therapy - anthracyclines, AI’s, tamoxifen

Prognostic Effect of Body Size in Operable Breast Cancer

BMI (kg/m2)

Est

imat

ed R

elat

ive

Ris

k o

f A

dve

rse

Eve

nt

20 30 40 50

05

1015

25 35 45 55

Distant Recurrence, p=0.0005

Death, p=0.0007

Menopausal Status

14

13

# studies

42.96Postmenopausal

61.58Premenopausal

%# identifying adverse

prognostic effectof obesity

Subgroup

Adverse effect seen in both pre- and postmenopausal women.

Goodwin 2006

ER / PgR

1. Early Studies (prior to widespread use of adjuvant tamoxifen)

• greatest adverse effect in ER/PgR positive tumors

• no adverse effect in ER negative tumors

(McNee 1987, Maehle 1996)

2. Later Studies (after widespread use of adjuvant tamoxifen)

• little or no effect on breast cancer events in ER/PgR positive

• greater adverse effect in ER negative tumors

(Dignam 2003, Enger 2004)

Obesity Studies - Prognosis

ER / PgR

1. Fasting Insulin (majority of ER positive received tamoxifen)

• greater adverse effect in ER/PgR negative than ER or PgR positive

(HR 6.7 vs. 3.5 Q5 vs. Q1)(Goodwin 2001)

2. Waist-Hip Ratio/Non-Fasting Insulin (50% received tamoxifen)

• WHR: greater adverse effect in ER/PgR positive/postmenopausal

• non-fasting insulin – greatest effect in postmenopausal

(Borugian 2003, 2004)

• protective effect of exercise greatest in ER/PgR positive vs. negative

(HR 0.50 vs. 0.91)

• breast cancer diagnosed 1984-1998 – both before/after widespread use ofadjuvant tamoxifen

(Holmes 2005)

Insulin Resistance Studies - Prognosis

Exercise Studies - Prognosis

ER / PgR

1. WINS - Prognosis (ER positive received tamoxifen)

• greatest effect in ER negative

(HR 0.76 overall, 0.85 ER positive, 0.58 ER negative)

(Chlebowski 2005)

2. WHI - Prevention

• greatest effect in ER or PgR negative

HR 0.91 overall

HR 0.64 ER+ PgR-

HR 0.67 ER- PgR+

HR 0.89 ER- PgR-

(Prentice 2006)

Dietary Fat Reduction – RCT’s

ER / PgR

Synthesis

• Obesity - pre-tamoxifen → greatest effect in ER+

- post tamoxifen → greatest effect in ER-

• Insulin - post tamoxifen → greatest effect in ER-

• WHR/Exercise - pre/post tamoxifen → greatest effect in ER+

• Dietary fat reduction - post tamoxifen → greatest effect in ER or PgR-

May indicate that these lifestyle factors signal via at least two pathways:

1) Estrogen - ER blocked by tamoxifen

2) Insulin/IGF

Obesity – PrognosisInteraction of Estrogen and Insulin/IGF Mechanisms

AdiposeAdiposeTissueTissue

↑↑ estrogens estrogens ↑↑ insulin insulin ↓↓ IGFBP-1 IGFBP-1

↑↑ IGF-I IGF-I↓↓ SHBG SHBG

ER/PgR

ER/PgRIGF-IRIGF-IR

IR IR αα, , ββ

(free)++

++ ++

++

++

++

++

++++++

++

−−

−−

−−

*

*

GH GH

ProliferationProliferationAnchorage Independent GrowthAnchorage Independent Growth

Reduced ApoptosisReduced Apoptosis

* PI3K, ras-raf-MAP Kinase signalling pathways

++ ++

++++

Target Groups for a Weight ManagementIntervention in Breast Cancer

1)* BMI - all- > 25 kg/m2

- > 30 kg/m2

2)* Menopausal status - all- pre- post

3)* ER/PgR - all- ER and/or PgR negative

4) Biomarker - insulin > 45 pmol/L- estradiol, estrone

5) Adjuvant therapy - anthracyclines, AI’s, tamoxifen

RCT – Lifestyle – Early Stage Breast Cancer

Preliminary Sample Size Calculations

Assumptions: α = 0.05 (2 tail)

β = 0.80

Three years accrual, five years follow-up

2,829631247

10,9472,5611,056

0.900.800.70

25%

2,829631247

15,5403,6431,505

0.900.800.70

15%

2,829631247

23,1455,4342,427

0.900.800.70

10%

# events# subjectsHR

Risk of Recurrence @ 5 years (controls)

Sample Size