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) 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
Adjuvant 5FU: QUASAR Lancet 2007;370:2020-2029
Quencher Reporter Forward Primer Probe Q R Polymerization Reverse Primer R Q Strand Displacement and Cleavage of Probe Q R Polymerization Completed RT-PCR for RNA Quantification from Fixed Paraffin-Embedded Tumor Tissue Clark-Langone, BMC Genomics: 2007; 8:279. Cronin et al. Am J Pathol. 2004;164:35-42.
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 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? 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) 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
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 COINCetuximab 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)
Biomarkers Total 1316 All WT 581 KRAS 565 BRAF 102 NRAS 50 KRAS & NRAS 11 JCO 28:15s, 2010 (suppl; abstr 3502)
COIN: Survival by Subgroup Median Overall Survival (Months) JCO 28:15s, 2010 (suppl; abstr 3502)
COIN: Response Rates JCO 28:15s, 2010 (suppl; abstr 3502)
???Front Line Chemotherapy Plus EGFR-Targeted Antibody - KRAS Wild Type CAUTION: CROSS TRIAL COMPARISONS!!
BRAF Mutation: Prognostic and/or Predictive? BRAF Mutated KRAS and BRAF Wild Type JCO 28:15s, 2010 (suppl; abstr 3506)
Predictors of Benefit from Bevacizumab in Colon Cancer ?? VEGF Pathway Polymorphisms
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