Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know June 7, 2010 Neal J. Meropol, M.D. Chief, Division of Hematology and Oncology University Hospitals Case Medical Center Associate Director for Clinical Research Case Comprehensive Cancer Center Case Western Reserve University Cleveland, Ohio
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Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know
Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know. Neal J. Meropol, M.D. Chief, Division of Hematology and Oncology University Hospitals Case Medical Center Associate Director for Clinical Research Case Comprehensive Cancer Center - PowerPoint PPT Presentation
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Biomarker-driven treatment decisions in stage II colon cancer -
making sense of what we know
June 7, 2010
Neal J. Meropol, M.D.Chief, Division of Hematology and Oncology
University Hospitals Case Medical CenterAssociate Director for Clinical Research
Case Comprehensive Cancer CenterCase Western Reserve University
Cleveland, Ohio
QUASARSurvival – Stage II (92% of patients enrolled, N=2963)
QUASAR Collaborative Group, Lancet, 2007
RR=0.84P=0.05
Sargent, D. et al. J Clin Oncol; 2009
N = ~70005% benefit at 8
years
ACCENT pooled analysis: benefit of adjuvant therapy in stage II colon cancer
The Data
• Not all patients with stage II colon cancer have the same risk
• In unselected patients– 5-FU improves survival by a few percent– Oxaliplatin does not improve survival– Capecitabine as effective as 5-FU
Prospect Theory: People Care More About Outcomes Close to Their
Reference Point
Weinfurt, K. P. J Clin Oncol; 25:223-227 2007
Prospect Theory: People Care More About Loss Than Gain
Shifting Reference
Point
People weight probabilities differently depending on where they fall on the probability curve
• The “Russian Roulette” experiment (Zeckhauser; Kahneman and Tversky)– You’d pay more to remove 1 bullet if the chamber
is full, than if it only has 3 or 4 bullets to begin– You’d pay more to remove the final bullet, than to
remove 1 bullet from a chamber with 3 or 4 bullets
Do patients with stage II colon cancer weight absolute benefits of adjuvant therapy differently based upon their
baseline underlying risk of recurrence?
Age may be an appropriate consideration
%AC85%52%35%
Earle et al. J Surg Oncol, 2009
Should age matter?ACCENT: No benefit for combinations on
survival in elderly (stage II/III)
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2
Hazard Ratio
Age < 70
Age >= 70
Oxaliplatin
Oral
Irinotecan
Overall
McCleary et al. ASCO 2009
Molecular Risk Stratification• Mismatch repair is ready for clinical use
– MSI vs. IHC– Prognostic and ?predictive– Implications for hereditary predisposition
• Oncotype DX is a validated platform – Establishes prognosis– Relative benefit of 5-FU is consistent
across risk spectrum– Does not address benefit of oxaliplatin– Peer-reviewed publication is awaited
• ?Other molecular risk classifiers
Classifier discovery and validation
Discovery Validation
• assay technology• patient population
characterized• samples representative• training and validation sets
• Prospective randomized trial is gold standard
• Retrospective randomized trial may be acceptable if:– a priori hypothesis and
statistical design– samples available from
vast majority of patients– adequate follow up and
annotation
Adapted from D. Sargent, ISGIO 9/07
QUASAR Recurrence Score
• 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
• The relative risk reduction with 5-FU is consistent across Recurrence Score risk levels
STROMALFAP
INHBABGN
CELL CYCLEKi-67
C-MYCMYBL2
REFERENCEATP5EGPX1PGK1UBB
VDAC2
GADD45B
RECURRENCE SCORECalculated from Tumor
Gene Expression
Kerr et al. ASCO 2009
QUASAR : Clinical/Pathological Covariates and Recurrence
Recurrence Score, T Stage, and MMR Deficiency are Independent Predictors of Recurrence in Stage II Colon Cancer
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
0 10 20 30 40 50 60 70
Recurrence Score
Ris
k of
recu
rren
ce a
t 3 y
ears
MMR deficient (11%)
T4 stage (13%)
T3 and MMR proficient (76%)
Kerr et al. ASCO 2009
E5202: Stage II Colon Cancer
Accrual Goal: 3438
Arm A:FOLFOX
Arm B:FOLFOX + Bevacizumab
Tumor block risk
assessment based on biology
(18q/MSI)
High-risk (MSS and 18q LOH)
Low-risk (MSI + or no
loss 18q)Observation
Surgery
NCCN Recommendations 2010
• Ask the patient how much they’d like to know• Discuss risks and benefits• Consider clinical features that confer risk• Consider comorbidities and life expectancy• If considering fluoropyrimidine alone, MMR
testing recommended
Proposed Stage II Algorithm Today
MMR
Clinical Risk
No Adjuvant
Deficient Intact
Not HighHigh
No AdjuvantOr
Adjuvant
Adjuvant
*all decisions require discussion with patient
Proposed Stage II Algorithm Soon
MMR
Clinical & Molecular
Risk
No Adjuvant
Deficient
Intact
Very small benefit from adjuvant
therapy?<3%
No AdjuvantOr
Adjuvant
No Adjuvant
*all decisions require discussion with patient
More than very small benefit from adjuvant therapy
?3+%
What we need• Models that integrate clinical and molecular risk
assessment• Improved methods of communicating risk (and
risk reduction) to patients• Formal modeling of impact of molecular vs.
clinical tools on adjuvant therapy use, recurrence, survival, QOL, and cost
• Decision tools that go beyond simple calculations of 3 or 5 year clinical endpoints, and integrate comorbidities and life expectancy, i.e. will I gain or lose QALYs by taking adjuvant therapy?