al b. benson iii, md, facp professor of medicine associate director for clinical investigations...

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer Centerof Northwestern University

To Treat or Not to Treat Stage II Colon Cancer = Yes (sometimes)

Disclosures

Research = Genentech, Amgen, Astellas, Gilead, Bayer, Novartis

Consultant = Sanofi, Bayer, Genentech, Lilly/ImClone, Bristol-Myers Squibb

Genomic Health (Uncompensated)

The Stage II Colon Cancer Controversies/Dilemmas

Imperfect risk factors/assessments are not linked to

treatment efficiency

Growing list of risk factors and tools to define risk

Overall good prognosis but subsets clearly recur


Proof of principle: chemotherapy reduces risk but for

whom?

Choice extrapolated from Stage III benefits – is this

correct?

Role of oxaliplatin: Stage T4, MSI-H


Complicated discussion with patients

Patient perceptions of risk (and MD’s)

Cannot predict absolute risk for individual

Cannot link risk and treatment benefit

Cannot define which factors are most important

AJCC v7

Gunderson et al, JCO 2009

Stage II Stage III

QUASAR: 5FU/LV Chemotherapy Benefit in the 1,436 Evaluable Stage II Colon Cancer Patients

RFI

Treatment Surgery Chemo

Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

0.6

0.8

1.0

Years

0 1 2 3 4 5

OS


Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

0.6

0.8

1.0

Years

0 1 2 3 4 5

DFS


Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

0.6

0.8

1.0

Years

0 1 2 3 4 5

Kerr et al., ASCO 2009, #4000

RFI (recurrence-free interval) DFS (disease-free survival)

OS (Overall Survival)

Kaplan-Meier estimates of disease-free survival (A) by treatment arm and (B) by treatment arm and by stage

(intent-to-treat population).

André T et al. JCO 2009;27:3109-3116

©2009 by American Society of Clinical Oncology

Kaplan-Meier estimates of overall survival (A) by treatment arm and (B) by treatment arm and by stage

(intent-to-treat population).

André T et al. JCO 2009;27:3109-3116


Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients with high-risk stage II colon cancer

treated with leucovorin and fluorouracil with oxaliplatin (FOLFOX4) or without (FL).

Tournigand C et al. JCO 2012;30:3353-3360


Oxaliplatin trials with censoring analyses of different time points.

McCleary N J et al. JCO 2013;31:2600-2606


Recurrence RiskBowel obstruction or perforationT-Stage# of nodes assessedTumor gradeLymphatic/vascular invasionMargin status

Treatment Benefit None

* NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.

Numeracy calculator www.adjuvantonline.com: · three choices for lymph nodes (none, 1–4, 5+ lymph nodes),· three choices for tumor stage (T1/T2, T3, T4),· two choices for grade (low, high),· four choices for age (49 years or younger, 50–59, 60–69, 70 or older). Adjuvant! tool www.mayoclinic.com/calcs has three additional options:gender (male, female), comorbidity (perfect health, minor problems, average for age, or major problems), and the number of examined lymph nodes (0, 1–3, 4–10, >10).

Overall survival by stage group (Kaplan-Meier).

O'Connor E S et al. JCO 2011;29:3381-3388


Similar Coexpression of 48 Recurrence Risk Genes Stage II vs Stage III Colon Cancer

Stage II Stage III

UMPSMYBL2CSEL1CMYCNME1HNRPDSKP2RRM1MCM2RRM2KI_67CDC20P16_INK4P14ARFKLK6GRB10TGFBILAMC2P21CDC42BPAHSPA1AS100A4

OPN__OSTEOPONTINPAI1GADD45BEGR1STMY3DLC1IGFBP3SFRP4PDGFCIGFBP7CALD1TIMP3TGFB3SFRP2INHBAFAPCTHRC1LOXL2SPARCCOL1A1BGNTIMP2ANTXR1ITGB1AKT3AKAP12

Average Distance Between Clusters

0.0 0.2 0.4 0.6 0.8 1.0 1.2

HNRPDUMPSNME1MYBL2CSEL1CMYCSKP2RRM1MCM2RRM2KI_67CDC20P16_INK4P14ARFGRB10HSPA1ASTMY3LAMC2S100A4KLK6TGFBIP21CDC42BPA

OPN__OSTEOPONTINPAI1GADD45BEGR1IGFBP3IGFBP7TIMP3LOXL2SFRP4PDGFCTGFB3SFRP2INHBACTHRC1FAPSPARCCOL1A1BGNTIMP2ANTXR1ITGB1DLC1CALD1AKT3AKAP12

Average Distance Between Clusters

0.0 0.2 0.4 0.6 0.8 1.0 1.2

Stromal Genes

Cell CycleGenes

p=0.004

0%

5%

10%

15%

20%

25%

30%

35%

0 10 20 30 40 50 60 70

Recurrence Score

Ris

k o

f re

cu

rre

nc

e a

t 3

ye

ars

QUASAR RESULTS: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery

STROMALFAP

INHBABGN

CELL CYCLEKi-67

c-MYCMYBL2

REFERENCEATP5EGPX1PGK1UBB

VDAC2

GADD45B

RECURRENCE SCORECalculated from Tumor

Gene Expression

Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711)

Group Risk (by Kaplan-Meier) 12% 18% 22%

QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer

Multivariate Analysis

QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups

Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046)

Recurrence Risk Group

Range of RS

Proportion of patients

Low <30 43.7%

Intermediate 30-40 30.7%

High ≥41 25.6%

22% (16%-29%)

18% (13%-24%)

12% ( 9% -16%)

Kaplan-Meier Estimates (95% CI) of Recurrence Risk at 3 years

Years

Recurrence Risk Group

High

Intermediate

Low

Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

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0.8

1.0

0 1 2 3 4 5

n=711Kerr et al., ASCO 2009, #4000

Relationship between the continuous Recurrence Score (RS) and 5-year recurrence risk by stage and treatment in

National Surgical Adjuvant Breast and Bowel Project C-07.

Yothers G et al. JCO 2013;31:4512-4519©2013 by American Society of Clinical Oncology

Recurrence-free interval for (A) all patients and (B) stage II, (C) stage IIIA/B, and (D) stage IIIC patients by Recurrence Score (RS) groups and treatment in National Surgical Adjuvant

Breast and Bowel Project C-07.

Yothers G et al. JCO 2013;31:4512-4519


Overall Survival by Treatment, Stage II dMMR patients

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8Years

% A

live

HR: 3.15 (1.07-9.29)p=0.03

N = 55

N = 47

Untreated 93%Treated 75%

5 yr OS

P-value = 0.014 for treatment by MMR status interaction

Kaplan–Meier estimates of disease-free survival (DFS) in the groups of patients given 5-fluorouracil and leucovorin (FL) or FOLFOX according to tumour p53 expression and

microsatellite instability (MSI) phenotype.

Zaanan A et al. Ann Oncol 2009;21:772-780

© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

REMARK diagram of mutation profiling of NSABP trials C-07 and C-08.

Gavin P G et al. Clin Cancer Res 2012;18:6531-6541

©2012 by American Association for Cancer Research

Overlap of mutations in the BRAF, KRAS, NRAS, and PIK3CA are shown.



Kaplan–Meier plots of BRAF and MMR status cases.



Kaplan–Meier survival plots for colorectal cancer according to combined MSI/BRAF subgroup.

Lochhead P et al. JNCI J Natl Cancer Inst 2013;105:1151-1156

© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

The phosphatidylinositol 3-kinase (PI3K) signaling pathway and its potential interaction with the influence of aspirin on colorectal

cancer (CRC) and the tumor microenvironment.

Fuchs C S , and Ogino S JCO 2013;31:4358-4361


Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA

Mutation Status.

Liao X et al. N Engl J Med 2012;367:1596-1606

Biomarkers Indicating Aspirin Efficiency

COX - 2 over expressing tumors

PIK3CA - mutant tumors

BRAF - wild type tumors

Nurses’ Health and Health Professional follow-up studyFrom Tougeron et. al. Clin Cancer Res 2013

Colorectal Cancer: Diet and Lifestyle Impact on Cancer Patients

Many studies on diet / lifestyle and risk of DEVELOPING colorectal cancer

Few studies show whether these factors affect patients with colorectal cancerDisease recurrenceSurvivalTolerance to chemotherapy

Forest plots of hazard ratios (black divided by white) for death (overall survival [OS]), recurrence or death (recurrence-free survival [RFS]), and recurrence

(recurrence-free interval [RFI]).

Yothers G et al. JNCI J Natl Cancer Inst 2011;103:1498-1506

© The Author 2011. Published by Oxford University Press.

Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy

CancerVolume 119, Issue 8, pages 1528-1536, 10 JAN 2013 DOI: 10.1002/cncr.27938http://onlinelibrary.wiley.com/doi/10.1002/cncr.27938/full#fig1

CALGB 89803: DFS By Dietary Pattern

11 1.1 10.7

1.3

0

0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5Quintiles of Dietary Pattern

Haz

ard

Ratio

for C

ance

r Rec

urre

nce

or D

eath

Prudent diet

1.2

22.2

3.9

Western diet

P, trend < 0.001P, trend < 0.001

Meyerhardt, J. et al. JAMA 2007298(7):754-764.

Plasma Vitamin D and Survival in Colorectal Cancer Patients: NHS/HPFS (N = 304)

1

0.890.83

0.49

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

<22.8 22.8-27.1 27.2-33.1 >33.1

Quintiles of plasma Vitamin D ng/mL

Haz

ard

Ratio

for D

eath

(0.28-0.86)

P, trend = 0.01

People with highest level of vitamin D have 50% improvement in outcome

Ng et al J Clin Oncol. 2008 Jun 20;26(18):2984-91

Clinical potential of prognostic gene expression–based tests for colon cancer stage II and III. According to standard protocols, adjuvant treatment of patients

with colon cancer stage II and III is decided by assessment of risk of relapse after surgical res...

Sveen A et al. Clin Cancer Res 2013;19:6669-6677


E5202 Trial Schema

Low-Risk PatientsMSS or MSI-L with

retention of 18q allelesMSI-H

Arm A:mFOLFOX6q2w × 12

Arm B:mFOLFOX6 + bevacizumab* q2w × 12

Arm C:Observation only

High-Risk PatientsMSS/18q LOH orMSI-L/18q LOH

areRANDOMIZED

MSI-L = low-level microsatellite instabilityMSI-H = high-level microsatellite instability*Bevacizumab continued for an additional 6 months

Stratify:Disease stage

(IIA or IIB)Microsatellite stability

(stable vs MSI)18q LOH

Stage II CRC Treatment Summary:

Discuss risks with patients including potential link between risk

and lifestyle factors and race

MSI testing for Stage II patients

Acknowledge risk is not associated with treatment efficiency (T3

MSS)

Stage II CRC Treatment Summary:

5FU/capecitabine remains an appropriate consideration

(T3 MSS, elderly)

Discuss lifestyle changes = diet, exercise

MSI-H T3 – no treatment

Oxaliplatin + 5FU/capecitabine (T4b MSI-H and high risk, MSS

BRAF mutated)

Role of ASA for patients with mutated – PIK3CA evolving

Observed Survival Rates for 28,491 Cases with Adenocarcinoma of the Colon

Reproduced with permission from Springer.Edge SB, et al (eds.) AJCC Cancer Staging Manual and Handbook,

7th edition. New York, NY: Springer; 2009.

Recurrence-free interval by stage and treatment in National Surgical Adjuvant Breast and Bowel Project C-07.

Yothers G et al. JCO 2013;31:4512-4519


Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients older than 70 years treated with leucovorin and fluorouracil with oxaliplatin

(FOLFOX4) or without (FL).

Tournigand C et al. JCO 2012;30:3353-3360


K-M plot of recurrence-free survival in C-07 according to treatment and MMR status.

Gavin P G et al. Clin Cancer Res 2013;19:1301


The effect of bevacizumab (Bev) treatment on overall survival by mismatch repair (MMR) status for colon cancer: NSABP C-08.

Pogue-Geile K et al. JNCI J Natl Cancer Inst 2013;105:989-992

© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

al b. benson iii, md, facp professor of medicine associate director for clinical investigations...

Documents

stage t4

stage intent

evaluable stage

highrisk stage

colon cancer v3

colon cancer patientskerr

tumor stage t1t2

treatment arm