Utilizing Gene Expression Profiles to Define Benefit of Oxaliplatin in Stage III Colon Cancer
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Transcript of 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, PhDDepartment of Gastrointestinal Medical OncologyThe University of Texas, MD Anderson Cancer Center, Houston, TX.
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
Stage III Risks are Variable (AJCC v7)
0102030405060708090
100
Gunderson et al, JCO 2009; Slide adapted from A. Grothey
Stage II Stage III
5 ye
ar O
S
0.1%
4.4%
Andre JCO 2009
MOSAIC Study: Modestly improved OS At Increased Cost
Who are the 4%?
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
Refresher: Predictive/PrognosticWhat we want:
A test to tell us who will benefit from the addition of oxaliplatin to 5-FU in stage III
Risk
LowScore
HighScore
Predictive
Recurrence Risk with 5FU:
15%Risk with FOLFOX:
15%Conclusion:
No oxaliplatin
Recurrence Risk with 5FU:
45%Risk with FOLFOX:
20%Conclusion:
Oxaliplatin
5-FU
FOLFOX
Refresher: Predictive/PrognosticWhat we have:
A test to tell us who is at highest risk of recurrence with Stage III
Risk
LowScore
HighScore
Prognostic
Recurrence Risk with 5FU:
15%Risk with FOLFOX:
12%Conclusion:
???
Recurrence Risk with 5FU:
35%Risk with FOLFOX:
30%Conclusion:
???
5-FU
FOLFOX
Same relative risk reduction with oxaliplatin can give greater absolute risk reduction for high risk patients
Gene Signature Development: A Long Road
1. Whole genome microarray profiling
2. Identification of genes correlated with CRC recurrence
Time
Gen
e Ex
pres
sion
4. Train a classification algorithm to predict status of new samples
3. Compile signature and evaluate separation of cohort
Recurrence No recurrence
6. Evaluate performance (+/- clinical variables)
5. Apply to independent cohorts
Training Validation
Current Commercial Tests:• Oncotype DX Colon • ColoPrint
0 10 20 30 40 50 60 700%5%
10%15%20%25%30%35%40%45%
Recurrence Score
3-ye
ar R
ecur
renc
e Ri
sk
Can be performed from FFPE sample
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.
Requires fresh frozen tissue for now
0%
10%
20%
30%
40%
50%
60%
70%
80%
0 10 20 30 40 50 60 70Recurrence Score
Example: Oncotype DX Colon Case #1
Solid: 5FU Dashed: 5FU+Ox
Stage III C
Stage III A/B
O’Connell MJ, et al. ASCO 2012, abstract 3512.
For RS = 30, 5 yr recurrence risk = 25% Absolute benefit from adding oxaliplatin to 5FU = 4%
Based on ValidationIn NSABP C-07
Below average
0%
10%
20%
30%
40%
50%
60%
70%
80%
0 10 20 30 40 50 60 70Recurrence Score
Example: Oncotype DX Colon Case #2
Solid: 5FU Dashed: 5FU+Ox
Stage III C
Stage III A/B
O’Connell MJ, et al. ASCO 2012, abstract 3512.
For RS = 41, 5 yr recurrence risk = 32% Absolute benefit from adding oxaliplatin to 5FU = 7%
Top 25% highest risk
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
ColoPrint Patient Result Report
Oncotype DX® Report Page 4
Stage IIIC5FU/LV5FU/LV + Oxaliplatin Stage IIIA/B 5FU/LV5FU/LV + OxaliplatinStage II(30% of study patients)5FU/LV5FU/LV + Oxaliplatin
OncotypeDX Colon Patient Result Report
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
Near future*: Molecular Subtypes Based on Gene Expression
Predictive Biomarkers of Chemotherapy Response
*ASCO ’14 Consensus Subtypes