1. Individualizing Therapy for Gastrointestinal Malignancies 2010 Update
Thomas J. Semrad MD, MAS
Assistant Professor of Medicine
UC Davis Cancer Center

2. Disclosure
Consulting or Advisory: Genomic Health, Inc

4. Individualizing Therapy in Colorectal Cancer
Tumor
MSI
KRAS, BRAF, and others
Host
Pharmacogenetics

5. Colon Cancer Is More Than One Disease
Chromosome Instability: 85%
Microsatellite Instability: 15%
KRAS Mutation: 40%
BRAF Mutation:
10%
CIMP
Watch this Space!!!

6. Microsatellite Instability (MSI)
Defective DNA Mismatch Repair (dMMR)
Nature Reviews Cancer 2004;4,

7. MSI Identifies a Subset of Stage II and III Colon Cancer with a Lower Risk of Relapse
MSS
Untreated Patients
JCO 2010;28:

8. MSI Predicts for Lack of Benefit from Adjuvant 5FU
Stage II
Stage III
MSI
MSS
JCO 2010;28:

9. Tumor Block Risk Assessed Based on MSI / 18q LOH
mFOLFOX6
High Risk
(MSS and 18qLOH) R
Tumor Block Risk Assessed Based on MSI / 18q LOH
mFOLFOX6 + bevacizumab
Surgery
Low Risk
(MSI or no loss 18q)
Observation
Accrual Goal 3,125

10. Adjuvant 5FU: QUASAR
Lancet 2007;370:

11. RT-PCR for RNA Quantification from Fixed Paraffin-Embedded Tumor Tissue
Strand Displacement
and Cleavage of Probe
Polymerization
Completed R Q
Forward
Primer
Reverse
Probe
Reporter
Quencher
Clark-Langone, BMC Genomics: 2007; 8:279.
Cronin et al. Am J Pathol. 2004;164:35-42.

12. 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?
STROMAL
FAP
INHBA
BGN
CELL CYCLE
Ki-67
C-MYC
MYBL2
REFERENCE
ATP5E
GPX1
PGK1
UBB
VDAC2
GADD45B
RECURRENCE SCORE
Calculated from Tumor Gene Expression
Kerr et al., ASCO 2009, #4000

13. QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery
Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711)
Kerr et al., ASCO 2009, #4000

14. 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

15. Nature Reviews Cancer 2009; 9, 489-499

16. Mutated KRAS Predicts Absence of Benefit From EGFR-Targeted Antibodies
Wild-type KRAS
N Engl J Med 2008;359:

17. What We Thought We Knew: CRYSTAL
N Engl J Med 2009;360:

18. Cetuximab Does Not Improve DFS in Stage III CRC
JCO 28:15s, 2010 (suppl; abstr 3508)

19. MRC COIN Cetuximab and Oxaliplatin
5FU or capecitabine
Oxaliplatin
Second Line Therapy: Irinotecan based
Primary Endpoint:
Overall Survival in KRAS wild-type
Secondary Endpoints:
OS in KRAS mutant
OS in “all wild-type”
PFS, RR
QOL
Health Economics
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
Cetuximab B
5FU or cap
Oxaliplatin
5FU or cap
Oxaliplatin C
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)

20. JCO 28:15s, 2010 (suppl; abstr 3502)

21. Biomarkers Total 1316 Population N Arm A Arm B ITT 1630 815
All WT
581
KRAS
565
Population N
Arm A
Arm B
ITT
1630
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
BRAF
102
NRAS 50
KRAS & NRAS 11
JCO 28:15s, 2010 (suppl; abstr 3502)

22. COIN: Survival by Subgroup
Median Overall Survival (Months)
JCO 28:15s, 2010 (suppl; abstr 3502)

23. COIN: Response Rates KRAS WT KRAS Mutated Arm A Arm B N 367 362 268
297
ORR at 12 weeks
50%
59%
41%
40%
Odds Ratio (B vs. A)
OR 1.44
P = 0.015
OR 0.97
P = 0.877
Overall Response
57%
64%
46%
43%
OR 1.35
P = 0.049
OR 0.88
P = 0.449
JCO 28:15s, 2010 (suppl; abstr 3502)

24. CAUTION: CROSS TRIAL COMPARISONS!!
??? Front Line Chemotherapy Plus EGFR-Targeted Antibody - KRAS Wild Type
Trial
Arm
RR (%) OR
P-value
PFS (months) HR
OS (months)
MRC COIN
ASCO 2010
N = 1630
OxFdG / XELOX 57
1.44
0.015
8.6
0.959
0.60
17.9
1.037
0.68
+ cetuximab 64
17.0
CRYSTAL
ASCO GI 2010
N = 1198
FOLFIRI 40
2.07
<0.0001
8.4
0.696
0.0012
20.0
0.796
0.0093
9.9
23.5
OPUS
JCO 2009
N = 337
FOLFOX4 37
2.544
0.011
7.2
0.570
0.0163 NR NA 61
7.7
PRIME
N = 1183 48
0.07
8.0
0.80
0.02
19.7
0.83
+ panitumumab 55
9.6
23.9
CAUTION: CROSS TRIAL COMPARISONS!!

25. BRAF Mutation: Prognostic and/or Predictive?
BRAF Mutated
Trial
Arm
RR (%) OR
P-value
PFS (months) HR
OS (months)
CRYSTAL
FOLFIRI 15 NR
0.9136
5.6
0.934
0.8656
10.3
0.908
0.7440
+ cetuximab 19
8.0
14.1
Combined CRYSTAL & OPUS
Chemotherapy 13
1.6
0.4606
3.7
0.69
0.267
9.9
0.63
0.079 22
7.1
KRAS and BRAF Wild Type
Combined CRYSTAL & OPUS
Chemotherapy 49
2.27
<0.001
7.7
0.64
21.1
0.84
0.041
+ cetuximab 61
10.9
24.8
JCO 28:15s, 2010 (suppl; abstr 3506)

28. Predictors of Benefit from Bevacizumab in Colon Cancer
?? VEGF Pathway Polymorphisms

29. JCO 2005; 23:

30. JCO 2009; 27:

32. N9741
JCO 2010; 28:

33. Pharmacogenetic Hypotheses Can Be Tested in Cooperative Group Trials
JCO 2010; 28:

34. Conclusions: I MSI KRAS mutations BRAF mutation
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

35. 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