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Individualizing Adjuvant Therapy on the Basis of Molecular Markers
Charles S. Fuchs, MDCharles S. Fuchs, MD
Dana-Farber Cancer InstituteDana-Farber Cancer Institute
Harvard Medical SchoolHarvard Medical School
Boston, MABoston, MA
Conflict of Interest Disclosure
Consultant or Advisory Role
Adolor
Alnylam
Amgen
Genentech
Imclone
Pfizer
Roche
Sanofi-Aventis
Adjuvant Therapy for Stage II/III Colon Cancer
Fluorouracil-based therapy significantly improves survival in stage III disease.
Optimal use of adjuvant therapy in stage II remains controversial.
Growing interest in biomarkers to tailor therapy for each patient.
Biomarkers in Colorectal Cancer Management
Predictive FactorPredicts the likelihood of response to therapy
Prognostic FactorCorrelates with clinical outcome regardless of treatment
Despite a growing list of biomarkers in CRC,
few have entered into clinical practice.
Biomarkers in Colorectal Cancer
Studies of Biomarkers in CRC: Potential Issues
Assay standardization & reproducibility
Small sample size
Inadequate data on patient, disease, and treatment characteristics
Lack of standardized statistical analysis
No adequate validation
Assessing a Predictive Marker
Statistical test for interaction: Assess whether the presence of a biomarker
significantly modifies the effect of a specific therapy
Prognostic Biomarkers
Cannot guide the choice of a specific therapy
Can place patients into distinct risk categories where different treatment options may be deemed appropriate
Potential Poor Prognostic Factors in Stage II Colon Cancer
Bowel perforationBowel perforation
Bowel obstructionBowel obstruction
Tumor adherence/invasion (TTumor adherence/invasion (T44))
Lymphatic vessel invasionLymphatic vessel invasion
Venous invasionVenous invasion
Poorly differentiated histologyPoorly differentiated histology
<10-12 lymph nodes examined<10-12 lymph nodes examined
Risk Stratification by Prognostic Markers: INT-0035
Survival at 7 years (%)Survival at 7 years (%)
CovariateCovariate ObservationObservation 5-FU/Levamisole5-FU/Levamisole
Adhesion to adjacent organsAdhesion to adjacent organs 7070 8282
Invasion to adjacent organsInvasion to adjacent organs 6464 8686
ObstructionObstruction 5858 7070
PerforationPerforation 5151 6767
Moertel et al J Clin Oncol 1995.Moertel et al J Clin Oncol 1995.
All stage II patients (N = 318)All stage II patients (N = 318) 7272 7272
Use of Prognostic Markers in Stage II: MOSIACDeGramont et al, ASCO 2007
5-year DFS (%)5-year DFS (%)
FOLFOX4FOLFOX4 LV5FU2LV5FU2 HRHR
[95% CI][95% CI]
All Stage II Pts.All Stage II Pts. 83.783.7 79.979.9 0.840.84[0.62-1.14][0.62-1.14]
High-risk Stage II* (N=576)High-risk Stage II* (N=576) 82.182.1 74.974.9 0.740.74[0.52-1.06][0.52-1.06]
Low-risk Stage II (N=323)Low-risk Stage II (N=323) 86.386.3 89.189.1 1.221.22[0.66-2.26][0.66-2.26]
*One of the following:*One of the following:
•T4, perforation, obstruction, poorly differentiated, venous invasion, T4, perforation, obstruction, poorly differentiated, venous invasion, <10 nodes examined.<10 nodes examined.
Microsatellite Instability in Colon Cancer
Measure of deficient DNA mismatch repair
Occurs in 10% to 18% of colon cancers
Predicted better prognosis --- but lack of benefit to 5-FU-based adjuvant therapy
– Ribic et al. NEJM 2003
– Sargent et al. ASCO 2008
S. Tejpar, F. Bosman, M. Delorenzi, R. Fiocca, P. Yan, D. Klingbiel, D. Dietrich, E. Van Cutsem, R. Labianca, A. Roth
Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial).
Abst. ID: 4001
PETACC 3: MSI in Colon Cancer
MSI conferred improved survival – most apparent in stage II vs. III pts (P for interaction = 0.058)
Benefit of MSI noted in both treatment arms
MSI did not predict a benefit for adding irinotecan
All patients received adjuvant chemotherapy
Stage II – MSI-H: cannot assess outcome for surgery alone
18q Loss of Heterozygosity
Associated with chromosomal instability, inversely associated with MSI.
Long arm of chromosome 18 contains several genes including: DCC, SMAD-4, SMAD-2, CABLES1.
18q LOH in Stage III Colon Cancer (N= 279)Watanabe et al. N Engl J Med. 2001;344:1196-206
18q LOH not associated with survival in stage II patients
Molecular markers in colon cancer have a stage specific prognostic value. Results of the translational study on
the PETACC 3 - EORTC 40993 -SAKK 60-00 trial..
A. D. Roth, S. Tejpar, P. Yan, R. Fiocca, D. Dietrich, M. Delorenzi, R. Labianca, D. Cunningham, E. Van Cutsem,
F. Bosman
18qLOH in PETACC3
0.381.37 [0.67 - 2.77]18qLOH
0.00890.28 [0.10 - 0.72]MSI-H v. MSS
0.000242.58 [1.56 - 4.28]T4 v. T3
•18q LOH was not associated with outcome in stage III patients
•Stage II patients:
Large Studies Assessing 18qLOH in CRC (N>250)
Author (Year)Author (Year) No. of PatientsNo. of Patients FindingFinding
Watanabe, 2001Watanabe, 2001 279279 HR=2.75 (P=0.006)HR=2.75 (P=0.006)
Halling, 1999Halling, 1999 508508 NullNull
Barratt, 2002Barratt, 2002 314314 NullNull
Roth, 2009Roth, 2009 14041404 NullNull
Ogino, 2009Ogino, 2009 555555 NullNull
ECOG 5202: Stage II Colon Cancer
RRAANNDDOOMMIIZZEE
High-riskHigh-risk::MSS andMSS and18q LOH18q LOH
Low-riskLow-risk::MSI orMSI orNo 18q LOHNo 18q LOH
observeobserve
FOLFOX + BevacizumabFOLFOX + Bevacizumab
FOLFOX + PlaceboFOLFOX + Placebo
Studies of 18q LOH
Could methodology explain discrepancy between studies?
Individual markers & criteria do differ
However, rates of 18q LOH are similar
18q LOH inversely associated with MSI
Do we have the right locus on 18q?
Need to identify specific gene(s) responsible
Predictive role for 18q LOH remains uncertain
Multi-gene expression assays to define cancer recurrence and therapy
Paik et al N Eng J Med 351:2817, 2004
Gene Expression and Recurrence in Node-Negative, ER-Positive Breast Cancer
7% 14% 31%
Paik, S. et al. J Clin Oncol; 24:3726-3734 2006
Gene Expression and Benefit from Chemotherapy in Node-Negative, ER-Positive Breast Cancer
P, interaction = 0.038
David Kerr1, Richard Gray2, Philip Quirke3, Drew Watson4, Greg Yothers5, Ian Lavery6, Mark Lee4, Michael O'Connell5, Steven Shak4, Norman Wolmark5 and the Genomic Health & QUASAR Colon Teams
A quantitative multi-gene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes
in 4 large studies and results of the independent, prospectively-designed QUASAR validation study
Colon Cancer Technical Feasibility
Development StudiesSurgery Alone
NSABP C-01/C-02 (n=270)
Cleveland Clinic (n = 765)
Selection of Final Gene List & Algorithm
Development Studies Surgery + 5FU/LV
NSABP C-04 (n=308)
NSABP C-06 (n=508)
Clinical Validation Study – Stage II Colon Cancer
QUASAR (n=1,436)
Test Prognosis and Treatment Benefit
Development and Validation of a Multi-Gene RT-PCR Colon Cancer Assay
Standardization and Validation of Analytical Methods
22% (16%-29%) 18% (13%-24%) 12% ( 9% -16%)
Kaplan-Meier Estimates (95% CI) of Recurrence Risk at 3 years
QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups (n=711)
Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046)
Years
Recurrence Risk Group
HighIntermediate
Low
Pro
por
tion
Eve
nt F
ree
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5
Recurrence Risk Group
Range of RS
Proportion of patients
Low <30 43.7%
Intermediate 30-40 30.7%
High ≥41 25.6%
Results
Recurrence Score significantly associated with DFS, OS
Recurrence and Treatment Scores did not predict benefit from FU/LV
Questions
How did FU/LV vs. control arms compare within each risk strata?
How did Recurrence and Treatment Scores perform in the development dataset?
Could heterogeneity between the development and validation datasets affected assay performance in validation?
3-year recurrence ranged from 12% (low risk) to 22% (high risk)
Is assay sufficiently discriminative?