obesity, activity and breast cancer prognosis · 2006. 3. 20. · • meta-analysis of reports...
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![Page 1: Obesity, Activity and Breast Cancer Prognosis · 2006. 3. 20. · • meta-analysis of reports prior to 1990 (Goodwin 1995) Obesity – Breast Cancer Prognosis • of 51 published](https://reader033.vdocuments.site/reader033/viewer/2022051912/60035bb257535309053f5a3e/html5/thumbnails/1.jpg)
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
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Body Size at Breast Cancer Diagnosis
26 - 282000’s
25 - 261980’s to 1990’s
BMI (kg/m2)
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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
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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
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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
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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
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Weight Gain in Breast Cancer
Camoriano et al JCO 1990
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Overall Survival and Weight Gain in Breast Cancer
Camoriano et al JCO 1990
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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
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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)
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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
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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
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Mean Energy Required for Physical Activity
Demark-Wahnefried et al JCO 2001;19:2381-2389
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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
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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)
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Mortality According to Physical Activity Level in Breast Cancer
Holmes MD et al JAMA 2005;293:2479-2486
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Potential Mediators of a Prognostic Effectof Obesity in Breast Cancer
• estradiol
• insulin (IGF’s / BP’s)
• adipocytokines (e.g. leptin)
• immune factors
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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
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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
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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
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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
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• 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
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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
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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
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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
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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
++ ++
++++
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Intervention Research
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
++ ++
++++
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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
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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