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Utilizing Gene Expression Profiles to Define Benefit of Oxaliplatin in Stage III Colon Cancer

Utilizing Gene Expression Profiles to Define Benefit of Oxaliplatin in Stage III Colon Cancer. Scott Kopetz, MD, PhD Department of Gastrointestinal Medical Oncology The University of Texas, MD Anderson Cancer Center, Houston, TX. . Big picture….

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Utilizing Gene Expression Profiles to Define Benefit of Oxaliplatin in Stage III Colon Cancer

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  1. Utilizing Gene Expression Profiles to Define Benefit of Oxaliplatin in Stage III Colon Cancer Scott Kopetz, MD, PhD Department of Gastrointestinal Medical Oncology The University of Texas, MD Anderson Cancer Center, Houston, TX.

  2. Big picture…. • Adjuvant therapy is a risk/benefit decision, regardless of the stage of therapy • The incremental benefit for oxaliplatin is small in many stage III patients • What is needed is information to improve understanding of individualized risk and benefit

  3. Stage III Risks are Variable (AJCC v7) Stage III Stage II 5 year OS Gunderson et al, JCO 2009; Slide adapted from A. Grothey

  4. MOSAIC Study: Modestly improved OSAt Increased Cost 0.1% 4.4% Who are the 4%? Andre JCO 2009

  5. Why gene expression signatures? • Aside from stage, clinical and pathologic factors are poor predictors of outcomes • Gene expression has the potential to better interrogate biology, if… • aligned with clinical need • validated, re-validated… • feasiblein clinical practice • easily communicated

  6. Refresher: Predictive/Prognostic What we want: A test to tell us who will benefit from the addition of oxaliplatin to 5-FU in stage III Predictive Recurrence Risk with 5FU: 45% Risk with FOLFOX: 20% Conclusion: Oxaliplatin Recurrence Risk with 5FU: 15% Risk with FOLFOX: 15% Conclusion: No oxaliplatin 5-FU Risk FOLFOX Low Score High Score

  7. Refresher: Predictive/Prognostic What we have: A test to tell us who is at highest risk of recurrence with Stage III Prognostic Same relative risk reduction with oxaliplatincan give greater absolute risk reduction for high risk patients Recurrence Risk with 5FU: 35% Risk with FOLFOX: 30% Conclusion: ??? Recurrence Risk with 5FU: 15% Risk with FOLFOX: 12% Conclusion: ??? 5-FU Risk FOLFOX Low Score High Score

  8. Gene Signature Development: A Long Road 2. Identification of genes correlated with CRC recurrence 1. Whole genome microarray profiling Gene Expression Time 3. Compile signature and evaluate separation of cohort Training Validation Recurrence No recurrence 4. Train a classification algorithm to predict status of new samples 5. Apply to independent cohorts 6. Evaluate performance (+/- clinical variables)

  9. Current Commercial Tests: • Oncotype DX Colon • ColoPrint ColoPrint Low Risk patients have a 1 in 13 risk of relapse within 3 yrs. ColoPrint High Risk patients have a 1 in 5 risk of relapse within 3 yrs. Can be performed from FFPE sample Requires fresh frozen tissue for now

  10. Example: Oncotype DX Colon Case #1 Below average Solid: 5FU Dashed: 5FU+Ox Stage III C Stage III A/B Based on Validation In NSABP C-07 For RS = 30, 5 yr recurrence risk = 25% Absolute benefit from adding oxaliplatin to 5FU = 4% • O’Connell MJ, et al. ASCO 2012, abstract 3512.

  11. Example: Oncotype DX Colon Case #2 Top 25% highest risk Solid: 5FU Dashed: 5FU+Ox Stage III C Stage III A/B For RS = 41, 5 yr recurrence risk = 32% Absolute benefit from adding oxaliplatin to 5FU = 7% • O’Connell MJ, et al. ASCO 2012, abstract 3512.

  12. Why gene expression signatures? • Aside from stage, clinical and pathologic factors are poor predictors of outcomes • Gene expression has the potential to better interrogate biology, if… • aligned with clinical need • validated, re-validated… • feasiblein clinical practice • easily communicated

  13. ColoPrint Patient Result Report

  14. OncotypeDX Colon Patient Result Report Oncotype DX® Report Page 4 Stage IIIC 5FU/LV 5FU/LV + Oxaliplatin Stage IIIA/B 5FU/LV 5FU/LV + Oxaliplatin Stage II (30% of study patients) 5FU/LV 5FU/LV + Oxaliplatin

  15. Conclusions • Ultimately, use of oxaliplatin requires a discussion of the risks/benefits • Patient aids, education material are needed • Gene expression profiles represent additional tools to facilitate this discussion • Promise of gene expression profiles are not yet realized: Lack of truly predictive tests

  16. Near future*: Molecular Subtypes Based on Gene Expression Predictive Biomarkers of Chemotherapy Response *ASCO ’14 Consensus Subtypes

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