1
The Role of Exercise as a The Role of Exercise as a
Prevention and Prevention and
Treatment Strategy for Treatment Strategy for
CancerCancer
Lee W. Jones, PhDLee W. Jones, PhDLee W. Jones, PhDLee W. Jones, PhD
‘Adults should engage in ≥ 150 min/wk of moderate‐
Kushi et al. CA Cancer J Clin, 2012
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• Adults should engage in ≥ 150 min/wk of moderate‐intensity exercise or ≥ 75 min/wk of vigorous exercise, evenly spread throughout the week ’
• ‘…may reduce the risk of several types of cancer, including cancers of the breast, colon, and endometrium, as well as advanced prostate cancer & possibly, pancreatic cancer’
• ‘Exercise is a safe & feasible intervention for cancer patients both during & after therapy’
Rock et al. CA Cancer J Clin, 2012
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patients both during & after therapy
• ‘…associated with significant improvements in physical functioning, fatigue, and multiple aspects of QOL’
• Strong evidence for exercise as an adjunct to improve symptom controlDo the effects of exercise extend beyond symptom Do the effects of exercise extend beyond symptom
control to impact tumor biology & clinical outcomes?control to impact tumor biology & clinical outcomes?
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
2
Hawk et al. Clin Cancer Res, 2008
TRWGTRWG DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
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2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
4. Creation of modality Development and refinement of a promising lifestyle alteration intervention
5. Preclinical development Initial animal models to define biological plausibility & mechanisms of action
6. Phase II trials Preliminary human studies
7. Phase III trials Definitive phase III testing
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
3
• Holmes et al. JAMA, 2005
• N=2987 Nurses Health Study
DiscoveryDiscovery
70
80
90
100
y reduction
Padjusted <0.01
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0
10
20
30
40
50
60
<3 3‐8.9 9‐14.9 15‐23.9 >24
Percent cancer mortalit
Self‐reported physical activity category (MET‐hrs/wk)
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
HR from cancer‐specific death, 95% CI
Exercise & breast cancer‐specific mortality
CredentialingCredentialing
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0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0
Adapted from BallardAdapted from Ballard‐‐BarbashBarbash et al. et al. JNCIJNCI, 2012; , 2012; BetofBetof et al. et al. Brain Brain BehavBehav ImmunImmun, 2012 , 2012
Lower mortality Higher mortality
SuggestiveSuggestive evidence that exercise is associated with evidence that exercise is associated with improved breast cancerimproved breast cancer‐‐specific outcome specific outcome
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
4
HR from cancer‐specific death, 95% CI
Breast cancer
Exercise & cancer‐specific mortality
CredentialingCredentialing
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0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0Lower mortality Higher mortality
GI
prostate
Adapted from BallardAdapted from Ballard‐‐BarbashBarbash et al. et al. JNCIJNCI, 2012; , 2012; BetofBetof et al. et al. Brain Brain BehavBehav ImmunImmun, 2012 , 2012
SuggestiveSuggestive evidenceevidence
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
Differences by molecular features
p27p27‐‐ p27+p27+
Meyerhardt et al. CCR, 2009
<18 MET‐hrs.wk‐1 1.00 1.00
≥18 MET‐hrs.wk‐1 1.40 0.33
Molecular modifiers of the exercise – colorectal cancer prognosis relationship
Tools: discoveryTools: discovery
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CTNNB1CTNNB1‐‐ CTNNB1+CTNNB1+
Morikawa et al. JAMA, 2011
<18 MET‐hrs.wk‐1 0.89 1.00
≥18 MET‐hrs.wk‐1 0.33 1.07
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
5
Molecular modifiers of the exercise – breast cancer prognosis relationship
Differences by ER status
ERER++ ERER‐‐
Holmes et al. JAMA, 2005
<9 MET‐hrs.wk‐1 1.00 1.00
Tools: discoveryTools: discovery
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<9 MET hrs.wk 1.00 1.00
≥9 MET‐hrs.wk‐1 0.50 0.91
Irwin et al. JCO, 2008
0 MET‐hrs.wk‐1 1.00 1.00
>0 MET‐hrs.wk‐1 0.20 1.26
Secondary analyses, limited statistical powerSecondary analyses, limited statistical power
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
E07716
Voluntary wheel running
3 days
Effects of exercise in an orthotopic model of murine breast cancer (E0771; ER+)
Tools: preclinical developmentTools: preclinical development
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C57/Bl‐6 female mice
(1 x106)
Sedentary control
1,500mm3
Nelson et al. in progress
1,500mm3
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
6
Voluntary wheel running
~2 weeks
8 weeks
Effects of exercise in GEM model of murine breast cancer (PyMT; ER+)
Tools: preclinical developmentTools: preclinical development
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PyMT Sedentary control
Nelson et al. in progress
~2 weeks
4T1( 6)
Voluntary wheel running
3
3 days
Effects of exercise in an orthotopic model of murine breast cancer (4T1; ER‐)
Tools: preclinical developmentTools: preclinical development
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BALB/C
(1 x106)
Sedentary control
1,500mm3
Betof et al. submitted
1,500mm3
Effects of exercise on tumor growth in PyMT (ovxd) GEMM of murine breast cancer
Tools: preclinical developmentTools: preclinical development
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Nelson et al. in progress
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
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Effect of exercise on circulating levels of select growth factors (RTK ligands; PyMT)
IFN Collective
Control Runner0.0
0.5
1.0
1.5
2.0
IFN
pg
/mL
IL10 Collective
Control Runner0
25
50
75
IL10
(p
g/m
L)
IL12 collecitve
Control Runner0
50
100
150
IL12
(p
g/m
L)
P=0.0285P=0.3423
P=0.0009
Tools: preclinical developmentTools: preclinical development
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Control Runner Control Runner Control Runner
IL1bCollective
Control Runner0.0
2.5
5.0
7.5
10.0
IL6 Collective
Control Runner0
25
50
75
100
IL6
(pg
/mL
)
KC/GRO Collective
Control Runner0
10
20
30
40
50
60
70
80K
C/G
RO
(p
g/m
L)
P=0.0009
P=0.4209
P=0.8509
Effect of exercise on select growth factors in tumor microenvironment (PyMT)
TNFa
N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3
P value 0.0926
mR
NA
CXCL12
N R0.00
0.25
0.50
0.75
1.00
1.25
P value 0.0087
(mann whitney)
mR
NA
RANKL
N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3
P value 0.0519
(mann whitney)
mR
NA
Tools: preclinical developmentTools: preclinical development
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N R N R
IL6
N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3
P value 0.0303
(mann whitney)
mR
NA
IL7
N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.31.4
P value 0.2293
mR
NA
N R
CSF1
N R0.00.10.20.30.40.50.60.70.80.91.01.11.21.3
P value 0.0430mR
NA
Nelson et al. in progress
Clinical translation (EXTRA trial)
HHistologically istologically confirmed solid confirmed solid
tumortumor
ildild
RRAANNDDOOMM
Darbepoetin Alfa (Control
EENND D
OOF F
MulitplexMulitplexELISA ELISA ––
LuminexLuminex ArrayArray
Tools: preclinical developmentTools: preclinical development
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MildMild‐‐toto‐‐moderate moderate anemiaanemia
Baseline Baseline AssessmentAssessment
N=44N=44
MMIIZZAATTIIOONN
Darbepoetin Alfa + Aerobic Training (cycle ergometry, 60‐100% VO2peak for
12 weeks)
TTHHEERRAAPPYY
12 weeks
35 cytokines, 35 cytokines, chemokineschemokines, & , & angiogenicangiogenicfactorsfactors
44 44 –– paired paired prepre‐‐post post samplessamples
Glass et al. Cancer Res, submitted
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
8
FactorFactor MedianMedian MinMin MaxMax MedianMedian MinMin MaxMax PP
HGF ‐54.73 ‐775.55 294.68 96.74 ‐296.93 475.43 0.008
IL‐4 ‐3.36 ‐155.81 72.58 3.79 ‐50.72 211.16 0.012
MIP1‐β ‐19.21 ‐1086.53 39.47 9.75 ‐1033.08 138.63 0.034
ExerciseExercise ControlControl
Tools: preclinical developmentTools: preclinical development
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VEGF ‐0.96 ‐22.38 12.27 0.00 ‐15.31 32.70 0.043
TNF‐α 0.00 ‐11.29 12.02 0.00 ‐1.45 10.33 0.046
IFNα ‐8.79 ‐364.18 57.22 ‐4.69 ‐159.88 78.61 0.188
EGF ‐3.00 ‐8720.21 42.30 1.16 ‐1879.26 435.56 0.196
MCP1 ‐108.58 ‐2228.35 549.36 42.89 ‐1266.63 983.37 0.240
MIP1‐α ‐4.89 ‐710.65 53.61 ‐1.44 ‐246.03 45.17 0.240
Glass et al. Cancer Res, submitted
MCF‐7 (ER+) MDA‐MB‐231 (ER‐)
12000
14000
16000
18000
20000
10000
12000
14000
*
**
Apoptosis (*serum from n=20 breast cancer pts)
Tools: preclinical developmentTools: preclinical development
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0
2000
4000
6000
8000
10000
Day2 Day4 Day6
0
2000
4000
6000
8000
Day2 Day 4
Exercise Control
Glass et al. Cancer Res, submitted
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
9
Working modelWorking model
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Working modelWorking model
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Exercise modulation of host Exercise modulation of host –– tumor interactiontumor interaction
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© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
10
Exercise & triple negative breast cancer: translational
AIM 1 (PRE‐CLINICAL)• Mouse models of Trip Negative Bca
• C3Tag / 4T1
• ‘Dose‐response’ of aerobic training• Low / Moderate / High
AIM 3 (MECHANISTIC)• Utilizing tissue samples from animals (Aim 1) and clinical trial (Aim 2)
• Mechanistic identification and inhibition
Procurement of plasma & tumor tissue
Creation of modalityCreation of modality
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AIM 2 (CLINICAL TRIAL – PHASE I)
• ‘Proof‐of‐Concept’ phase II ‘window of opportunity’ RCT
• Supervised aerobic training @ ‘firstin man dosing’ (informed by Aim 1)
Mechanistic Identification Plasma: Effects on circulating growth factors using ‘omics’ platforms
Tumor tissue: Effects on growth factors; cell survival pathways; Next Generation Sequencing
tumor tissue
Procurement of plasma & tumor tissue
StepStep DescriptionDescription
1. Discovery Association between exposure (exercise) and clinical events
2. Credentialing Consensus of indicative findings across studies
3. Supporting tools Omic‐based approaches to provide mechanistic insight
3i. Discovery data Findings derived from epidemiological data
3ii. Preclinical development Biological plausibility of the exercise response modifier using a combination of in vitro & in vivo platforms
Modified Translational Research Pathway for Exercise Modified Translational Research Pathway for Exercise –– Oncology ResearchOncology Research
All Rights Reserved, Duke Medicine 2011
using a combination of in vitro & in vivo platforms
4. Creation of modality Exercise ‘dose’ (freq, duration, intensity, length) to modulate identified pathway / tumor phenotype
4i. Preclinical development Clinically‐relevant in vivomodels (based on discovery data)
4ii. ‘First time in man’ (phase I) studies
Use of animal data to inform phase I‐type studies with correlative science endpoints
5. Phase II trials ‘Smart’ phase II trials on surrogate markers & preliminary data on DFS
6. Phase III trials Adequately‐powered phase III trial on DFS & overall survival
HHistologically istologically confirmed confirmed triple triple negneg
breast cancerbreast cancer
RRAANNDDOOMM
Standard of Care (Control)(neo / adjuvant chemotherapy)
EENND D
OOF F
Tumor tissue Tumor tissue outcomes (if outcomes (if appropriate)appropriate)
Potential phase II / III RCTPotential phase II / III RCT
Pre‐operative or adjuvant setting
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‘Enriched’ ‘Enriched’ patient cohortpatient cohort
Physically Physically inactive / inactive / exercise exercise
intoleranceintolerance
MMIIZZAATTIIOONN
Std of Crae + Adjuvant Aerobic Training (dose informed by translational study)
TTHHEERRAAPPYY
~4 – 24 weeks
BloodBlood‐‐based based biomarkersbiomarkers
SignalSignal for DFSfor DFS
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
11
Current paradigm for exercise – oncology research
Cancer survivorCancer survivor•• CancerCancer TypeType
CC ThTh
Sub‐set / Eligibility Criteria
Exercise Px
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population(s)population(s) •• CancerCancer TherapyTherapy
•• YearsYears from from DiagnosisDiagnosis Control
Approach does not take into account expected (tumor) heterogeneity – exercise relationship
Proposed future paradigm for exercise – oncology research??
Clinical TestClinical Test toto
HostHostDNA mutation DNA mutation
(BRCA1)(BRCA1)Exercise Px A
Exercise Px B HostHost
BiomarkerBiomarker++
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Clinical TestClinical Test to to SubSub‐‐Categorize Categorize
PatientsPatientsExercise Px A + Drug Px B
Exercise Px A +Drug Px C or unresponsive
(IL(IL‐‐6, TNF6, TNF‐‐α)α)
TumorTumorReceptor Receptor
status(ERstatus(ER++, HER2, HER2++))
TumorTumorMutant pathway Mutant pathway (PI3K, EGFR)(PI3K, EGFR)
Opportunities
1. Optimize efficacy (dose) of exercise therapy
2. Improved mechanistic understanding
3. Novel combinational approaches
1. Exercise – diet combinations
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2. Exercise – drug combinations
4. Increased credence of lifestyle interventions in the oncology setting
Facilitate shift to matching right treatment to the right patient to optimize disease and health outcomes following a cancer diagnosis
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
12
Jones Lab
Miranda West, MSWhitney Hornsby, PhDAmy Lane, MSCaroline Bishop, MSBeth Fowler, BSAarti Kenjale, MDLauren Valera, MS
il S h i S
AcknowledgementsAcknowledgementsBreast Tumor GroupJeff Peppercorn, MDKelly Marcom, MDKimberley Blackwell, MDGretchen Kimmick, MDNeil Spector, MD
PRT‐BTCHenry Friedman, MDAllan Friedman, MD
Dewhirst Laboratory
Allison Betof, MD, PhD (c)
Lascola Laboratory
Nixon Laboratory
Poss Laboratory
O’Donnell LaboratoryErik Nelson, PhD
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Emily Schwitzer, BSKaitlin Ray, BSGraeme Koelwyn, BSMichael Peace, DVMOliver Glass, BS
CardiologyPamela Douglas, MDBill Kraus, MDJason Allen, PhD
Katy Peters, MD, PhDDavid Reardon, MD
GU Tumor GroupDan George, MDAndy Armstrong, MDSteve Freedland, MDBrant Inman, MD
Thoracic Tumor GroupJeff Crawford, MDJennifer Garst, MD
BiostatisticsJames Herndon, PhDApril Coan, MPHBill Barry, PhDGloria Broadwater, MS
© 2013 Memorial Sloan-Kettering Cancer Center, All Rights Reserved.
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