obesity, activity and breast cancer prognosis · 2006. 3. 20. · • meta-analysis of reports...
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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