progress towards an individualized approach to therapy: colorectal cancer alan p. venook, m.d....
TRANSCRIPT
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Progress towards an individualized approach to therapy: colorectal
cancerAlan P. Venook, M.D.
University of California, SF
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Breast Cancer Oncologist Envy
Alan P. Venook, M.D.University of California, SF
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Personalized decision-making: predicting risk:benefit
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Personalized decision-making: predicting risk:benefit
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Personalized decision-making: predicting risk:benefit
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Personalized decision-making: predicting risk:benefit
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Meropol, et al; JCO, 2007
Escalating cost of cancer care
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“Predictive” vs. “Prognostic”
• Predictive: response to treatment
• Prognostic: independent of treatment
Variables: host (germline) tumor
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Towards Personalized Therapy of Colon Cancer
• Tumor genetic profiling• Stage II colon cancer• Stage IV colorectal cancer
• Pharmacogenetics• Oxaliplatin efficacy• Irinotecan - UGT1A1
• Therapeutic Drug Monitoring
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CRC Stage at Diagnosis
13.7% Stage I
27.9% Stage II37.2% Stage III
21.2% Stage IV
Treatment Algorithms: Colorectal Cancer 5th Edition. Datamonitor 2003.
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Colorectal Cancer: TNM Staging System
• Extent of invasionthrough bowel wall (T)
• Extent of LN metastases (N)
• Presence of distant metastases (M)
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Renouf et al, Clin Col Can, 2008
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QASAR, Lancet, 2007
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QASAR, Lancet, 2007
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Colorectal Cancer, 2007
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18Q deletion & outcome in untreated colorectal cancer
18Q +
18Q -
Jen, et al. NEJM, 1994
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mFOLFOX6
v.
mFOLFOX6 +Bevacizumab qow
Accrual Goal: 3,125
Tumor risk assessed based on biology (18q/MSI)
High-risk (MSS and 18q LOH)
Low-risk (MSI + or no loss 18q) OBSERVATION
Surgery
E5202 – Stage II Colon Cancer
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Khambata-Ford, JCO, 2007
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Towards Personalized Therapy:
Stage II Colon Cancer• MSI and del 18q• Microarrays• Composite of prognostic and predictive genes• Nodal analysis
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Towards Personalized Therapy: Tumor Genetics
• EGF-R antibodies: yes or no?• KRAS• BRAF• PTEN
• VEGF antibody: yes or no?
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Personalized Therapy: Tumor Genetics
• EGF-R antibodies• KRAS• BRAF• PTEN
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The Ras Oncogene
• 100% of mice developed tumors in weeks• Rapid development of sarcomas and erythroleukemias
Kirsten and Harvey: 1964Identification of a virus that produced tumors in mice
HaMSVKiMSV
Harvey (1964) Nature 204:1104; Somers and Kirsten Science 1967;40:1053
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Ras Family of Proteins• Monomeric G proteins (H-Ras, K-Ras and N-Ras)
• Respond to activation of membrane-associated receptors for cell growth and survival
• Cycle between GDP bound “off” state and GTP bound “on” state
• Act as “molecular switches” linking extracellular signals through membrane receptors to intracellular signals
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Copyright ©2008 American Association for Cancer Research
Sebolt-Leopold, J. S. Clin Cancer Res 2008;14:3651-3656
Ras: Downstream Signaling
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Ras mutations: 30% of Human Cancers
Pancreatic carcinoma 72-90%Cholangiocarcinoma 55%Colon adenocarcinoma 32-57%Thyroid carcinoma 30%Seminoma 40%Embryonal rhabdomyosarcoma 35%Acute myelogenous leukemia 35%Myeloblastic syndromes 30%Lung carcinoma 15-50%
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CRC: Adenoma-Carcinoma Sequence
32-57%K-Ras mutant
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Detecting tumor K-Ras mutations
• DNA extracted from tumor (FFPE, cell-free DNA)
• Mutational analysis by sequencing (various methods) or mutant allele specific amplification
• Detection threshhold:
• 1% of mutant DNA in a background of wild-type genomic DNA
• Gly 12 Asp• Gly 12 Ala• Gly 12 Val• Gly 12 Ser
Single base substitutions thatrender GTPase domain insensitive to inactivation by GAP
• Gly 12 Arg• Gly 12 Cys• Gly 13 Asp
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Prognostic implications: K-Ras
Probably NOSmakman et al; Biochem Biophys Acta 2005; 1756:103
• Stage I-IV CRC; 24 studies with >100 patients (range 100-3439)• Mutation rate 24-69%
• Association between K-Ras status and stage:• Yes: 7; No: 13; N/A: 4
• Association between K-Ras status and DFS:• Yes: 3; No: 3; N/A: 18
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Retrospective studies supporting K-ras and lack of anti-EGFR response
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Advanced CRC treated with cetuximab: case series N=30
Lievre, A. et al. Cancer Res 2006;66:3992-3995
Most with prior irinotecan exposure
97% irinotecan + cetuximab
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Single agent cetuximab: N=80
Khambata-Ford et al J Clin Oncol, 2007; 25: 3230-3237
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Single agent panitumumab: N=208
K-Ras Mutation Wild-Type K-Ras
Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.
Panitumumab registration trial
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CRYSTAL
RANDOMI
Z E
FOLFIRIFOLFIRI
FOLFIRI + CetuximabFOLFIRI + Cetuximab
n = 540
Van Cutsem ASCO 2008; JCO 28: May 20 suppl; abstr 2.
FOLFIRI
FOLFIRI + Cetuximab
P value
K-ras wildtype K-ras mutant
HR 0.68 HR 1.07
(0.051-0.934)
0.017
(0.71-1.61)
0.75
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CALGB/SWOG 80405 Study Design
Untreatedadvancedor mCRCN = 2600
Bevacizumabfollowed by
FOLFOX or FOLFIRIq 2 wks
Cetuximabfollowed by
FOLFOX or FOLFIRIq 2 wks
Cetuximabfollowed by
Bevacizumabfollowed by FOLFOXor FOLFIRI q 2 wksOne cycle=8 weeks
mCRC=metastatic colorectal cancer
Open-label Phase III Study
Screenfor
eligibility
Sendtumortissue
block toSWOGPCO
RandomizePatients
w/Wild type
K-ras tumor
RegisterPatient
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Copyright ©2008 American Association for Cancer Research
Sebolt-Leopold, J. S. Clin Cancer Res 2008;14:3651-3656
Ras: Downstream Signaling
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DiNicolantonio et al, JCO, 2008
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DiNicolantonio et al, JCO, 2008
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Copyright ©2008 American Association for Cancer Research
Sebolt-Leopold, J. S. Clin Cancer Res 2008;14:3651-3656
Ras: Downstream Signaling
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44th ASCO Annual Meeting May 30-June 3, 2008McCormick Place, Chicago, Illinois
Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary
tumors as predictors of activity of cetuximab plus irinotecan
treatment
F. Loupakis1,6, L. Pollina2, I. Stasi1, G. Masi1, N. Funel2, M. Scartozzi3, I. Petrini4, D. Santini5, S. Cascinu3, A.
Falcone1,6.1Department of Oncology, Azienda USL 6 - Istituto Toscano Tumori Livorno, Italy,
2Division of Pathology, AOUP, Pisa, Italy, 3Division of Medical Oncology, Azienda Ospedaliera Ospedali Riuniti,
Università Politecnica delle Marche, Ancona, Italy,4Division of Medical Oncology, AOUP, Pisa, Italy,
5Division of Medical Oncology, Campus Biomedico University, Rome, Italy, 6Department of Oncology, Transplants and New Technologies in Medicine, University
of Pisa, Italy
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PTEN
PIP3
Ligands
AKT
Nucleus
EGF receptor
mTOR
PIP2
• PTEN (phoshatase and tensin homologue deleted on chromosome 10) gene encodes a phosphatase, whose major substrate is PIP-3
• Loss of PTEN (mono or bi-allelic inactivation, but also epigenetic silencing) results in increased PIP-3 concentration
• Increase of PIP-3 leads to AKT hyperactivation
PROTECTION FROM APOPTOSIS
PTENPI3K
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CONCLUSIONSCONCLUSIONS
Primaries and related mets from CRC differed in terms of PTEN immunoreactivity in 40% of cases.
KRAS mutations found on primaries are almost always (95% of cases) confirmed on mets. Such analysis may be ruled out on any available tumor sample.
Loss of PTEN tested on mets predicted lack of activity of cetuximab plus irinotecan combination treatment in metastatic CRC pts.
KRAS is confirmed to be a predictor of resistance to cetuximab plus irinotecan combination treatment in metastatic CRC pts.
The combination of PTEN IHC performed on mets and KRAS mutational analysis identified a subgroup of patients with higher chances of benefiting from cetuximab plus irinotecan treatment.
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PTEN: remaining challenges
• Reproducible assay• Immunohistochemistry • Gene copy number• Sequence
• Proving predictive / prognostic value
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Wong et al, JCO, 2008
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Towards Personalized Therapy of Colon Cancer
• Tumor genetic profiling• Stage II colon cancer• Stage IV colorectal cancer
• Pharmacogenetics• Oxaliplatin efficacy• Irinotecan - UGT1A1
• Therapeutic Drug Monitoring
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Genetics and Pharmacokinetics / Pharmacodynamics
Pharmacokinetics-Absorption-Distribution-Metabolism-Excretion
PharmacodynamicsTumor Host
Response Toxicity
DoseCompliance
Pharmacogenetics
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H. L. McLeod, K. Owzar, D. Kroetz, F. Innocenti, S. Das, P. Friedman, K. Giacomini, R. Goldberg, A. Venook, M. J. Ratain
Univ of North Carolina-Chapel Hill, Chapel Hill, NC; Duke, Durham, NC; UCSF, San Francisco, CA; University of Chicago, Chicago, IL; CALGB, Chicago, IL
Cellular transporter pharmacogenetics in metastatic colorectal cancer: initial analysis of C80203
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Predicting oxaliplatin efficacy?
• Genomic DNA from 180/238 patients on C80203 (FOLFOX vs. FOLFIRI +/- cetuximab)
• Genotype transporter genes involved in irinotecan and oxaliplatin clearance:• ABCC2, ABCC4, ABCG2, SLCO1B1, SLC22A1, SLC22A2
• Association of genotype with response and toxicity
• Result:• ABCG2 34 G>A associated with response to FOLFOX, resistance to FOLFIRI but not to toxicity
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Irinotecan pathwayCPT-11
cell membrane
CPT-11
CPT-11
SN-38
SN-38
SN-38TOP1
Cell Death
APC
SN-38G
ABCB1
CYP3A4
CYP3A5CES1
CES2
UGT1A1
CES1
CES2
ABCC2
ABCG2
ABCC1
ADPRT
TDP1
CDC45L
XRCC1
NFKB1
NPC
ABCB1
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UGT1A1: promoter polymorphism and toxicity
UGT1A1 gene structure Iyer et al 2002
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UGT1A1 TA repeat: irinotecan neutropenia/activity
35.7
16.3
8.6
0
5
10
15
20
25
30
35
40
45
50
6/6 6/7 7/7
P=0.007
UGT1A1 genotype
% g
rade
4/5
neu
trop
enia
McLeod et al, ASCO 2003
N=524
41.9
33.8
14.3
05
1015202530354045
6/6 6/7 7/7
UGT1A1 genotype
Obj
ectiv
e re
spon
se (
%)
P=0.045
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Camptosar package insert, May 2005
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Towards Personalized Therapy of Colon Cancer: Pharmacogenetics
• Oxaliplatin efficacy• Rare polymorphism• Small sample size
• Irinotecan toxicity• Regimen depednent• Not all or none
• VEGF antibody efficacy• Polymorphisms?
• Cetuximab efficacy• FCR polymorphisms?
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Towards Personalized Therapy of Colon Cancer
• Tumor genetic profiling• Stage II colon cancer• Stage IV colorectal cancer
• Pharmacogenetics• Oxaliplatin efficacy• Irinotecan - UGT1A1
• Therapeutic Drug Monitoring
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Drug ReceptorGenotypes
Drug MetabolismGenotypes
TherapeuticEffect (%)
Toxicity(%)
+ = Genetically RegulatedHeterogeneity in Drug Effects
Genetic Polymorphismof Drug Sensitivity
Genetic Polymorphismof Drug Exposure
E fficacyTox ic ity
1
1
1
100
50
00 50 100
wt/wt
wt/m
m/m
75
35
10
100
50
00 24 hr
30
A.wt/wt
>80
>80
>80
Drug Concentration
100
50
00 50 100
wt/wt
wt/m
m/m
100
50
00 24 hr
99
Time
m / mC. 95
50
10
<10
<10
<10
100
50
00 100
wt/wt
wt/m
m/m
100
50
00 24 hr 50
65
wt/mB.
85
45
10
Evans WE and Relling MV, Science 286:487-91, 1999
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Biochemical Pathways of 5-FU Metabolism
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Au et al.,1982 5D CVI, CRC Leucopenia Cpss > 1.5 µM
Trump et al., 1991 3D CVI, CRC Leucopenia Cpss
Yoshida et al.,1990 7D CVI, CRC Leucopenia AUC > 33
mg/h.L
Thyss et al.,1986 5D CVI, HNC Leucopenia AUC 30 mg/h.L
Vokes et al., 1996 3D CVI, HNC Leucopenia Cpss
Reference Schedule, Tumor Toxicity PK variable, threshold
AUC: Area under the curve; CCR: Colorectal cancer; Cpss: Steady state plasma concentration; CVI: Continuous venous infusion; HNC: Head and Neck Cancer IVB: Intravenous bolus
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Hillcoat et al., 1978 5D CVI, CRC 36.1 19.2
Yoshida et al.,1990 7D CVI, CRC 27.4 22.5
Milano et al.,1994 5D CVI, HNC 29.727.2
Vokes et al., 1996 5D CVI, HNC 27.5 21.0
Reference Schedule, Tumor AUC AUC
(mg/h.L) (mg/h.L)
(Responder) (Non-Responder)
AUC: Area under the curve; CCR: Colorectal cancer; CVI: Continuous venous infusion;
HNC: Head and Neck Cancer; LV: Leucovorin
Studies Correlating Systemic Exposure with Tumor Response for 5-FU Infusional
Regimen
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Relationship between Systemic Exposure Relationship between Systemic Exposure
and survivaland survival
Milano et al., J Clinical Oncology 1994; 12: 1291Milano et al., J Clinical Oncology 1994; 12: 1291
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Remaining questions include:
• What is the target therapeutic range?• For toxicity• For efficacy• With oxaliplatin
• When to sample?• Would clinicans do this?• Is this important?
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Opportunities for TDM
• Most oral chemotherapy drugs• Imatinib• Sorafenib• Sunitinib
• Taxanes• Biologics
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GI Stromal Tumor Oncologist Envy
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Joensuu et al. N Engl J Med. 2001;344:1052. Copyright 2001 Massachusetts Medical Society.
GIST: PET change after 4 weeks imatinib
Multiple liver and upper abdominal 18FDG-accumulating metastases
A marked decrease in 18FDG uptake 4 weeks after starting imatinib
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Overall Survival by Genotype (Kaplan-Meier Estimate)
Joensuu H et al. Eur J Cancer. 2007;5(suppl):404. Abstract 7506.
over all KIT mutation groups
Von Mehren, ASCO, 2008
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Towards Personalized Therapy of Colon Cancer
• Tumor genetic profiling• Nearing clinical reality for stage II patients• KRAS a standard; BRAF coming; others pending
• Pharmacogenetics• Complex
• Therapeutic Drug Monitoring• Is there enough benefit to justify the effort?
• Can we change the paradigm for clinical trials?