Transcript Identification, molecular characterization, clinical

Individualizing Therapy for
Gastrointestinal Malignancies
2010 Update
Thomas J. Semrad MD, MAS
Assistant Professor of Medicine
UC Davis Cancer Center
Disclosure
• Consulting or Advisory: Genomic Health, Inc
Individualizing Therapy in Colorectal
Cancer
• Tumor
– MSI
– KRAS, BRAF, and others
• Host
– Pharmacogenetics
Colon Cancer Is More Than One Disease
Chromosome Instability: 85%
Microsatellite
Instability: 15%
KRAS Mutation: 40%
BRAF
Mutation:
10%
CIMP
Watch this Space!!!
Microsatellite Instability (MSI)
• Defective DNA Mismatch
Repair (dMMR)
Nature Reviews Cancer 2004;4,769-780.
MSI Identifies a Subset of Stage II and III
Colon Cancer with a Lower Risk of Relapse
MSI
MSS
Untreated Patients
JCO 2010;28:3219-3226
MSI Predicts for Lack of Benefit from
Adjuvant 5FU
Stage II
Stage III
MSI
MSS
JCO 2010;28:3219-3226
E5202
mFOLFOX6
High Risk
(MSS and
18qLOH)
Surgery
R
mFOLFOX6 +
bevacizumab
Tumor Block Risk
Assessed Based
on MSI / 18q LOH
Low Risk
(MSI or no loss
18q)
Observation
Accrual Goal 3,125
Adjuvant 5FU: QUASAR
Lancet 2007;370:2020-2029
RT-PCR for RNA Quantification from Fixed
Paraffin-Embedded Tumor Tissue
Reporter
Forward
Primer
R
Probe
Quencher
Q
Polymerization
Reverse
Primer
R
Q
Strand Displacement
and Cleavage of Probe
Q
R
Polymerization
Completed
Clark-Langone, BMC Genomics: 2007; 8:279.
Cronin et al. Am J Pathol. 2004;164:35-42.
QUASAR: Pre-Specified Primary Endpoint:
Recurrence Risk
Is there a significant relationship
between the risk of recurrence
and the pre-specified continuous
Recurrence Score in stage II colon
cancer patients randomized to
surgery alone?
RECURRENCE SCORE
Calculated from Tumor
Gene Expression
STROMAL
FAP
INHBA
BGN
CELL CYCLE
Ki-67
C-MYC
MYBL2
GADD45B
REFERENCE
ATP5E
GPX1
PGK1
UBB
VDAC2
Kerr et al., ASCO 2009, #4000
QUASAR Results: Colon Cancer Recurrence Score
Predicts Recurrence Following Surgery
Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711)
35%
Risk of Recurrence at 3 years
30%
25%
20%
15%
10%
p=0.004
5%
0%
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0
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10
20
30
40
50
60
|
70
Recurrence Score
Kerr et al., ASCO 2009, #4000
QUASAR Results: Recurrence Score, T Stage, and MMR
Deficiency are Key Independent Predictors of Recurrence in
Stage II Colon Cancer
Kerr et al., ASCO 2009, #4000
Nature Reviews Cancer 2009; 9, 489-499
Mutated KRAS Predicts Absence of
Benefit From EGFR-Targeted Antibodies
Mutated KRAS
Wild-type KRAS
N Engl J Med 2008;359:1757-65
What We Thought We Knew: CRYSTAL
N Engl J Med 2009;360:1408-17
Cetuximab Does Not Improve DFS
in Stage III CRC
JCO 28:15s, 2010 (suppl; abstr 3508)
MRC COIN
Cetuximab and Oxaliplatin
• Advanced
Colorectal Cancer,
first line therapy
• No Prior
Chemotherapy for
Metastatic Disease
• PS 0-2
• Good Organ
Function
• No prior EGFR IHC
A
5FU or capecitabine
Oxaliplatin
Second Line Therapy:
Irinotecan based
Primary Endpoint:
B
C
5FU or capecitabine
Oxaliplatin
Cetuximab
5FU or cap
Oxaliplatin
5FU or cap
Oxaliplatin
Overall Survival in KRAS
wild-type
Secondary Endpoints:
OS in KRAS mutant
OS in “all wild-type”
PFS, RR
QOL
Health Economics
12 Weeks
OxMdG: mFOLFOX6 with slightly different LV
CapOx: Oxaliplatin 130mg/m2 D1; Capecitabine 1000mg/m2 D1-14 every 21 days, reduced to
850mg/m2 July 2007 due to toxicity
CapOx or OxMdG chosen before randomization; N=815 per arm
JCO 28:15s, 2010 (suppl; abstr 3502)
JCO 28:15s, 2010 (suppl; abstr 3502)
Biomarkers
Total
1316
Population
N
Arm A
Arm B
1630
815
815
Assessed for
mutation
1316 (81%)
648
668
KRAS mutated
565 (43%)
268
297
BRAF mutated
102 (8%)
57
45
NRAS mutated
50 (4%)
18
32
KRAS wild-type
729 (55%)
367
362
“All wild-type”
581 (44%)
289
292
ITT
All WT
581
KRAS
565
BRAF
102
NRAS
50
KRAS & NRAS
11
JCO 28:15s, 2010 (suppl; abstr 3502)
Median Overall Survival (Months)
COIN: Survival by Subgroup
JCO 28:15s, 2010 (suppl; abstr 3502)
COIN: Response Rates
KRAS WT
KRAS Mutated
Arm A
Arm B
Arm A
Arm B
N
367
362
268
297
ORR at 12 weeks
50%
59%
41%
40%
Odds Ratio (B vs. A)
Overall Response
Odds Ratio (B vs. A)
OR 1.44
P = 0.015
57%
64%
OR 1.35
P = 0.049
OR 0.97
P = 0.877
46%
43%
OR 0.88
P = 0.449
JCO 28:15s, 2010 (suppl; abstr 3502)
???
Front Line Chemotherapy Plus EGFRTargeted Antibody - KRAS Wild Type
P-value
PFS
(months)
P-value
OS
(months)
P-value
57
1.44
8.6
0.959
17.9
1.037
+ cetuximab
64
0.015
8.6
0.60
17.0
0.68
CRYSTAL
FOLFIRI
40
2.07
8.4
0.696
20.0
ASCO GI 2010
N = 1198
0.796
+ cetuximab
57
<0.0001
9.9
0.0012
23.5
0.0093
OPUS
FOLFOX4
37
2.544
7.2
0.570
NR
7.7
0.0163
NR
Trial
Arm
RR (%)
MRC COIN
OxFdG / XELOX
ASCO 2010
N = 1630
OR
HR
HR
NA
JCO 2009
N = 337
+ cetuximab
61
0.011
PRIME
FOLFOX4
48
8.0
0.80
19.7
ASCO GI 2010
N = 1183
NR
0.83
+ panitumumab
55
0.07
9.6
0.02
23.9
0.07
CAUTION: CROSS TRIAL
COMPARISONS!!
BRAF Mutation:
Prognostic and/or Predictive?
BRAF Mutated
Trial
CRYSTAL
Combined
CRYSTAL &
OPUS
Arm
RR (%)
FOLFIRI
15
+ cetuximab
19
Chemotherapy
13
+ cetuximab
22
OR
P-value
NR
0.9136
1.6
0.4606
PFS
(months)
P-value
OS
(months)
P-value
5.6
0.934
10.3
0.908
8.0
0.8656
14.1
0.7440
3.7
7.1
HR
0.69
0.267
9.9
14.1
HR
0.63
0.079
KRAS and BRAF Wild Type
Combined
CRYSTAL &
OPUS
Chemotherapy
49
+ cetuximab
61
2.27
<0.001
7.7
10.9
0.64
<0.001
21.1
24.8
0.84
0.041
JCO 28:15s, 2010 (suppl; abstr 3506)
www.abcam.com
Predictors of Benefit from
Bevacizumab in Colon Cancer
?? VEGF Pathway Polymorphisms
JCO 2005; 23: 7342-7349
JCO 2009; 27: 5519-5528
N9741
JCO 2010; 28: 3227-3233
Pharmacogenetic Hypotheses Can Be
Tested in Cooperative Group Trials
JCO 2010; 28: 3227-3233
Conclusions: I
• MSI
– Prognostic in Stage II and III
– Predicts lack of benefit from 5FU in Stage II
• KRAS mutations
– Predict lack of benefit from cetuximab
• BRAF mutation
– May NOT be a good predictor for lack of benefit from
cetuximab
– Suggests an awful prognosis
Conclusions: II
• No evidence for benefit of either bevacizumab
or cetuximab in adjuvant setting
• Does cetuximab combine better with
irinotecan than oxaliplatin?
• Pharmacogenetic data is needed from
cooperative group trials