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?