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)
5 year OS
Gunderson et al, JCO 2009; Slide adapted from A. Grothey

4. MOSAIC Study: Modestly improved OS At 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…
feasible in 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:
15%
Risk with FOLFOX:
Conclusion:
No oxaliplatin
Recurrence Risk with 5FU:
45%
Risk with FOLFOX:
20%
Conclusion:
Oxaliplatin
Risk
5-FU
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 oxaliplatin can give greater absolute risk reduction for high risk patients
Recurrence Risk with 5FU:
15%
Risk with FOLFOX:
12%
Conclusion:
???
Recurrence Risk with 5FU:
35%
Risk with FOLFOX:
30%
Conclusion:
???
Risk
5-FU
FOLFOX
Low
Score
High
Score

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

9. Current Commercial Tests:
Oncotype DX Colon
ColoPrint
ColoPrint High Risk patients have a 1 in 5 risk of relapse within 3 yrs.
ColoPrint Low Risk patients have a 1 in 13 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…
feasible in clinical practice
easily communicated

13. ColoPrint Patient Result Report13

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

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