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Individualizing Therapy for Gastrointestinal Malignancies 2010 Update

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

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Individualizing Therapy for Gastrointestinal Malignancies 2010 Update

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  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

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

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

  5. Microsatellite Instability (MSI) • Defective DNA Mismatch Repair (dMMR) Nature Reviews Cancer 2004;4,769-780.

  6. 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

  7. MSI Predicts for Lack of Benefit from Adjuvant 5FU Stage II Stage III MSI MSS JCO 2010;28:3219-3226

  8. 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

  9. Adjuvant 5FU: QUASAR Lancet 2007;370:2020-2029

  10. 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.

  11. 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

  12. 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

  13. 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

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

  15. Mutated KRAS Predicts Absence of Benefit From EGFR-Targeted Antibodies Mutated KRAS Wild-type KRAS N Engl J Med 2008;359:1757-65

  16. What We Thought We Knew: CRYSTAL N Engl J Med 2009;360:1408-17

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

  18. 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)

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

  20. Biomarkers Total 1316 All WT 581 KRAS 565 BRAF 102 NRAS 50 KRAS & NRAS 11 JCO 28:15s, 2010 (suppl; abstr 3502)

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

  22. COIN: Response Rates JCO 28:15s, 2010 (suppl; abstr 3502)

  23. ???Front Line Chemotherapy Plus EGFR-Targeted Antibody - KRAS Wild Type CAUTION: CROSS TRIAL COMPARISONS!!

  24. BRAF Mutation: Prognostic and/or Predictive? BRAF Mutated KRAS and BRAF Wild Type JCO 28:15s, 2010 (suppl; abstr 3506)

  25. www.abcam.com

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

  27. JCO 2005; 23: 7342-7349

  28. JCO 2009; 27: 5519-5528

  29. N9741 JCO 2010; 28: 3227-3233

  30. Pharmacogenetic Hypotheses Can Be Tested in Cooperative Group Trials JCO 2010; 28: 3227-3233

  31. 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

  32. 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

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