Download Where are we in the treatment of Metastatic Colorectal Cancer?

Progress towards an individualized
approach to therapy: colorectal cancer
Alan P. Venook, M.D.
University of California, SF
Breast Cancer Oncologist Envy
Alan P. Venook, M.D.
University of California, SF
Personalized decision-making: predicting risk:benefit
Personalized decision-making: predicting risk:benefit
Personalized decision-making: predicting risk:benefit
Personalized decision-making: predicting risk:benefit
Escalating cost of cancer care
Meropol, et al; JCO, 2007
“Predictive” vs. “Prognostic”
• Predictive: response to treatment
• Prognostic: independent of treatment
Variables:
host (germline)
tumor
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
CRC Stage at Diagnosis
21.2% Stage IV
13.7% Stage I
27.9% Stage II
37.2% Stage III
Treatment Algorithms: Colorectal Cancer 5th Edition. Datamonitor 2003.
Colorectal Cancer:
TNM Staging System
• Extent of invasion
through bowel wall
(T)
• Extent of LN
metastases (N)
• Presence of
distant metastases
(M)
Renouf et al, Clin Col Can, 2008
QASAR, Lancet, 2007
QASAR, Lancet, 2007
Colorectal Cancer, 2007
18Q deletion & outcome in untreated colorectal cancer
18Q +
18Q -
Jen, et al. NEJM, 1994
E5202 – Stage II Colon Cancer
Surgery
Tumor risk
assessed
based on
biology
(18q/MSI)
High-risk
(MSS and
18q LOH)
mFOLFOX6
v.
mFOLFOX6 +
Bevacizumab qow
Low-risk
(MSI + or
no loss 18q)
OBSERVATION
Accrual Goal: 3,125
Khambata-Ford, JCO, 2007
Towards Personalized Therapy:
Stage II Colon Cancer
•
•
•
•
MSI and del 18q
Microarrays
Composite of prognostic and predictive genes
Nodal analysis
Towards Personalized Therapy: Tumor
Genetics
• EGF-R antibodies: yes or no?
• KRAS
• BRAF
• PTEN
• VEGF antibody: yes or no?
Personalized Therapy: Tumor Genetics
• EGF-R antibodies
• KRAS
• BRAF
• PTEN
The Ras Oncogene
Kirsten and Harvey: 1964
Identification of a virus that
produced tumors in mice
HaMSV
KiMSV
• 100% of mice developed tumors in weeks
• Rapid development of sarcomas and erythroleukemias
Harvey (1964) Nature 204:1104; Somers and Kirsten Science 1967;40:1053
Ras Family of Proteins
• Monomeric G proteins (H-Ras, K-Ras and N-Ras)
• Cycle between GDP bound “off” state and GTP bound “on”
state
• Act as “molecular switches” linking extracellular signals
through membrane receptors to intracellular signals
• Respond to activation of membrane-associated receptors for
cell growth and survival
Ras: Downstream Signaling
Sebolt-Leopold, J. S. Clin Cancer Res 2008;14:3651-3656
Copyright ©2008 American Association for Cancer Research
Ras mutations: 30% of Human Cancers
Pancreatic carcinoma
Cholangiocarcinoma
Colon adenocarcinoma
Thyroid carcinoma
Seminoma
Embryonal rhabdomyosarcoma
Acute myelogenous leukemia
Myeloblastic syndromes
Lung carcinoma
72-90%
55%
32-57%
30%
40%
35%
35%
30%
15-50%
CRC: Adenoma-Carcinoma Sequence
32-57%
K-Ras mutant
Detecting tumor K-Ras mutations
Single base substitutions that
render GTPase domain insensitive
to inactivation by GAP
•
•
•
•
Gly 12 Asp
Gly 12 Ala
Gly 12 Val
Gly 12 Ser
• Gly 12 Arg
• Gly 12 Cys
• Gly 13 Asp
• 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
Prognostic implications: K-Ras
Probably NO
Smakman 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
Retrospective studies supporting K-ras and lack of antiEGFR response
Advanced CRC treated with
cetuximab: case series N=30
Most with prior
irinotecan exposure
97% irinotecan +
cetuximab
Lievre, A. et al. Cancer Res 2006;66:3992-3995
Single agent cetuximab: N=80
Khambata-Ford et al J Clin Oncol, 2007; 25: 3230-3237
Single agent panitumumab: N=208
K-Ras Mutation
Wild-Type K-Ras
Panitumumab registration trial
Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.
CRYSTAL
R
A
N
D
O
M
I
Z
E
FOLFIRI
n = 540
FOLFIRI + Cetuximab
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
Van Cutsem ASCO 2008; JCO 28: May 20 suppl; abstr 2.
CALGB/SWOG 80405 Study Design
Open-label Phase III Study
Bevacizumab
followed by
FOLFOX or FOLFIRI
q 2 wks
Register
Patient
Untreated
advanced
or mCRC
N = 2600
Screen
for
eligibility
Send
tumor
tissue
block to
SWOG
PCO
One cycle=8 weeks
mCRC=metastatic colorectal cancer
Randomize
Patients
w/
Wild type
K-ras
tumor
Cetuximab
followed by
FOLFOX or FOLFIRI
q 2 wks
Cetuximab
followed by
Bevacizumab
followed by FOLFOX
or FOLFIRI q 2 wks
Ras: Downstream Signaling
Sebolt-Leopold, J. S. Clin Cancer Res 2008;14:3651-3656
Copyright ©2008 American Association for Cancer Research
DiNicolantonio et al, JCO, 2008
DiNicolantonio et al, JCO, 2008
Ras: Downstream Signaling
Sebolt-Leopold, J. S. Clin Cancer Res 2008;14:3651-3656
Copyright ©2008 American Association for Cancer Research
44th ASCO Annual Meeting May 30-June 3, 2008
McCormick 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
PTEN
Ligands
EGF receptor
• 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
PIP2
PI3K
PTEN
PIP3
AKT
mTOR
PROTECTION FROM APOPTOSIS
Nucleus
CONCLUSIONS
 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.
PTEN: remaining challenges
• Reproducible assay
• Immunohistochemistry
• Gene copy number
• Sequence
• Proving predictive / prognostic value
Wong et al, JCO, 2008
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
Genetics and Pharmacokinetics / Pharmacodynamics
Dose
Compliance
Tumor
Response
Pharmacokinetics
-Absorption
-Distribution
-Metabolism
-Excretion
Pharmacodynamics
Pharmacogenetics
Host
Toxicity
Cellular transporter pharmacogenetics in metastatic
colorectal cancer: initial analysis of C80203
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
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
Irinotecan pathway
CPT-11
cell membrane
ABCB1
CPT-11
CES1
CES2
CPT-11
CES1
APC
CYP3A5
NPC
CES2
SN-38
SN-38
SN-38
CYP3A4
SN-38G
TOP1
ADPRT
XRCC1
TDP1
CDC45L
NFKB1
Cell Death
UGT1A1: promoter polymorphism and toxicity
UGT1A1 gene structure
Iyer et al 2002
% grade 4/5 neutropenia
50
45
P=0.007
40
35
35.7
30
25
16.3
20
15
10
8.6
5
0
6/6
6/7
7/7
UGT1A1 genotype
Objective response (%)
UGT1A1 TA repeat: irinotecan neutropenia/activity
45
40
35
30
25
20
15
10
5
0
41.9
P=0.045
33.8
14.3
6/6
6/7
7/7
UGT1A1 genotype
N=524
McLeod et al, ASCO 2003
Camptosar package insert, May 2005
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
• FCgR polymorphisms?
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
Genetic Polymorphism
of Drug Exposure
+
Genetic Polymorphism
of Drug Sensitivity
Drug Metabolism
Genotypes
Drug Receptor
Genotypes
=
Genetically Regulated
Heterogeneity in Drug Effects
Therapeutic
Effect (%)
Toxicity
(%)
Efficacy
Toxicity
A.
100
100
wt/wt
75
1
wt/m
35
1
m/m
10
1
wt/wt
85
<10
wt/m
45
<10
m/m
10
<10
wt/wt
95
>80
wt/m
50
>80
m/m
10
>80
wt/wt
50
50
30
0
0
B.
24 hr
100
0
0
50
100
100
wt/m
50
50
65
0
0
C.
24 hr
100
50
0
0
50
100
100
m/m
50
99
0
0
24 hr
Time
0
0
50
100
Drug Concentration
Evans WE and Relling MV, Science 286:487-91, 1999
Biochemical Pathways of 5-FU Metabolism
Reference
Au et al.,1982
Schedule, Tumor
PK variable, threshold
Leucopenia
Cpss > 1.5 µM
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
Trump et al., 1991
5D CVI, CRC
Toxicity
3D CVI, CRC
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
Studies Correlating Systemic Exposure
with Tumor Response for 5-FU Infusional Regimen
Reference
Schedule, Tumor
AUC
(mg/h.L)
AUC
(mg/h.L)
(Responder) (Non-Responder)
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
29.7
27.2
Vokes et al., 1996
5D CVI, HNC
27.5
21.0
AUC: Area under the curve; CCR: Colorectal cancer; CVI: Continuous venous infusion;
HNC: Head and Neck Cancer; LV: Leucovorin
Relationship between Systemic Exposure
and survival
Milano et al., J Clinical Oncology 1994; 12: 1291
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?
Opportunities for TDM
• Most oral chemotherapy drugs
• Imatinib
• Sorafenib
• Sunitinib
• Taxanes
• Biologics
GI Stromal Tumor Oncologist Envy
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
Joensuu et al. N Engl J Med. 2001;344:1052. Copyright  2001 Massachusetts Medical Society.
Overall Survival by Genotype
(Kaplan-Meier Estimate)
Von Mehren, ASCO, 2008
over all KIT mutation groups
Joensuu H et al. Eur J Cancer. 2007;5(suppl):404. Abstract 7506.
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?