1. Prof. Julien Taïeb Georges Pompidou European Hospital Paris, France
Should MSI be determined in all patients with stage II and III colon cancer?
Prof. Julien Taïeb
Georges Pompidou European Hospital Paris, France

2. Disclosure No disclosure to declare for this presentation

3. Mutation on target genes
Two major pathways for colorectal cancer carcinogenesis
Chromosomic
instability
(LOH, MSS)
Activation
-catenin et KRAS
Inactivation
SMAD4, p53 et E-cadherin
85%
Normal
Epithelium
Adenoma
Early Carcinoma
Late Cancer ? ? ?
15%
TGF-RII, Bax , IGFIIR, MSH3 MSH6, TCF-4, Axin-2, Caspase-5, PTEN, WISP-3, RAD50 , RIZ …
Genetic Instability
(MSI)
Deficient MMR
Mutation on target genes
Hamelin, Bull Cancer 2008
MSI : microsatellite instability; MSS : microsatellite stable; MMR : Mismatch Repair

4. (HMLH1 promoter methylation) Consitutional Mutation
MSI
COLORECTALCANCER
2/3
1/3
HEREDITARY
HNPCC (Lynch syndrome )
SPORADIC
Early
Late
BRAF
Mutation
50-60%
Somatic Inactivation
Of a MMR gene
(HMLH1 promoter methylation)
Consitutional Mutation
Of a MMR gene
(MLH1, MSH2, MSH6, PMS2)
MSI : microsatellite instability; MMR : Mismatch Repair
Parsons, J Med Genet 2012

5. Lack of protein expression
How to determine MSI status?
Immuno-histochemistry
Molécular Biology (PCR)
MMR Protein Expression
(MLH1, MSH2, MSH6 et PMS2)
→ microsatellite markers
(BAT25, BAT26, NR21, NR24, NR27)
=> MSI tumor
Lack of protein expression
=> MSI tumor
Protein Expression
=> MSS tumor
Anti MLH1 antibody
=> MSS tumor
96% concordancy

6. KRAS Mutation and Microsatellite Instability (dMMR) Incidence
532 resected CRC
Nash GM et al. Ann Surg Oncol Feb;17(2):416-24

7. Is MSI status determination useful?
Genetic disease screening
MSI
Prognostic role
(natural history of the disease)
Predictive role
(in relation with treatments)

8. Is MSI status determination useful?
Yes!
What for?
Screening lynch syndrome?
Prognostic impact for
stage II?
Stage III?
Predictive value for treatment efficacy
5FU?
Oxaliplatin?

9. Genetic disease screening

10. A proposed Lynch Synd diagnostic algorithm
Selective screening is currently debated More ¼ of cases will be missed
Universal IHC (+/- MSI)
altered IHC
or MSI +
Normal IHC
and no MSI
MLH1(-)
MSH2(-)
MSH6(-)
PMS2(-)
R Salazar
ESMO- WCGIC 2012
MLH1 hypermethylation or BRAF V600E
BRAF
V600E - +
Germline genetic testing
STOP
This is where all footnotes and references go.

11. Prognostic value

12. Risk of death decreased of 35% in MSI patients
MSI : prognostic value?
Popat et al, 2005 : OS and MSI
Meta-analysis of 32 studies , 7642 patients (1277 MSI)
All stages
HR=0,65 (95% CI; 0,59-0,71)
Stage II-III
HR=0,67 (95% CI; 0,58-0,78)
Risk of death decreased of 35% in MSI patients

13. MSI : OS for stage IIA (T3N0)
After surgery only
Parc Y et al, Gut 2004
5 year DFS : 90% versus 70%; p=0,02
Multivariate analysis (age, gender, location, VELIPI, MSI status) :
=> MSI = independent prognostic marker
VELIPI: vascular emboli, lymphatic invasion and perineural invasion

14. MSI in stage II and III patients treated with surgery alone
Sargent DJ et al. J Clin Oncol Jul 10;28(20):

15. Predictive value

16. MSI and adjuvant chemo with 5FU
Reférence
Type
N patients
(% MSI)
Stage
N patients with CT
comparison
Survival
Benefit
Elsaleh et al, 2000 R
656 (8.5)
III
272
CT adj : MSS vs MSI MSI: chir seule vs CT adj
5 year OS
Hemminki et al, 2000
P / NR
95 (12) 95
CT adj : MSS vs MSI
3 year DFS
Ribic et al, 2003 CR
570 (16.7)
II + III
283
5 year OS and DFS
Carethers et al, 2004
204 (17.6) 66
MSI: chir seule vs CT adj OS
De Vos Tot et al, 2004
92 (100) 28
Westra et al, 2005
ECR
273 (16)
273
5 year DFS
Lanza et al, 2006
718 (15.9)
193
6 year OS
Kim et al,
2007
542 (18)
369
Sargent et al, 2010 *
457 (15)
229
1027 (16)
512
Abréviations: Adj, adjuvant; CT, chimiothérapie par 5FU; NR, non randomisé; P, prospectif; R, rétrospectif; ECR, essai contrôlé randomisé;
SSM, survie sans maladie; SSR, survie sans récidive; SG, survie globale. * Analyse poolée des données des études de Ribic et al + Sargent et al.
BENEFIT
NO BENEFIT
Contradictory results
Zaanan A et al, La Lettre du Cancérologue 2011

17. MSI : resistance to adjuvant 5FU?
Meta-analysis , Des Guetz et al, EJC 2009
-> 3690 patients: stage III=75%, MSI=14%
HR = 0.96 (95% CI, 0.62–1.49)
NO BENEFIT

18. MSI : resistance to adjuvant 5FU?
MSS
NO BENEFIT of adjuvant 5FU for MSI patients stage III
MSS
MSI
DELETERIOUS EFFECT of adjuvant 5FU for MSI patients stage II
Sargent et al , JCO 2010

19. suspected germline mutations with suspected sporadic CRC
Effect of 5-FU-based therapy on DFS
dMMR colon cancer patients with:
suspected germline mutations with suspected sporadic CRC
5FU
No CT
5FU
No CT
99 stage II and III patients
245 stage II and III patients
5FU may be efficient in patient with lynch syndrome but not in patient with sporadic MSI
Sinicrope FA, Foster NR,Thibodeau SN, et al. DNA Mismatch Repair Status and Colon Cancer Recurrence and Survival in Clinical Trials of 5-Fluorouracil-Based Adjuvant Therapy. J Natl Cancer Inst 2011;103:863–875

20. Patients from the QUASAR trial
Value of dMMR in predicting recurrence and benefits from chemotherapy in colorectal cancer with stage II
Patients from the QUASAR trial
Stage II Colon
Hutchins G et al. J Clin Oncol Apr 1;29(10):

21. And with FOLFOX?

22. MSI and adjuvant FOLFOX?
HR 0.66, 95% CI 0.38 - 1.15; p=0.15
HR 0.17, 95% CI 0.04 - 0.68; p=0.01
MSS
MSI
100%
80.3%
57.9%
Disease-free survival probability
73.6%
FOLFOX, 97 patients, 19 recurrences
5FU, 104 patients, 32 recurrences
FOLFOX, 12 patients, 0 recurrence
5FU, 20 patients, 8 recurrences
Time after surgery (months)
Zaanan et al, Annals of Oncology 2010

23. MSI and adjuvant FOLFOX?
303 patients, Stage III, FOLFOX treatment
P = 0.037
MSI is an independent prognostic marker in multivariate analysis
DFS (%)
HR, 2.11; 95% CI,
MSI, 34 patients, 3 events
MSS, 269 patients, 74 events
Year
Zaanan et al, Clin Can Res 2012

24. C07 and C08: Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and oxaliplatin Predictive Value
Gavin P G et al. Clin Cancer Res 2012;18:

25. C07 and C08: Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and oxaliplatin Predictive Value
MSI : prognostic factor with HR 0.48 for RFS
MSI : non predictive for oxaliplatin (suggesting a similar benefit in pMMR and dMMR)
Gavin P G et al. Clin Cancer Res 2012;18:

26. Patients with or without blocks had equivalent RFS, DFS or OS!!!
MSI and adjuvant FOLFOX?
Results from the MOSAIC Trial
Stage
Endpoint
MMR NA
MMR OK HR
[95% CI]
P value
N=1242
N=1004
II-III
RFS, No of events
351
303
1.01
0.942
DFS, No of events
385
378
1.08
0.284
OS, No of events
322
309
0.97
0.740
MMR NA : MMR status not available; MMR OK : MMR status available
Patients with or without blocks had equivalent RFS, DFS or OS!!!
Fléjou JF, ASCO 2013

27. dMMR OS (Stage II and III)
Endpoint
LV5FU2
FOLFOX HR
[95% CI]
P value
5-yr OS, % (sd)
82.3 (5.3)
90.9 (4.3)
0.42
0.060
Fléjou JF, ASCO 2013

28. Stage II and III dMMR
Fléjou JF, ASCO 2013

29. Conclusions dMMR MOSAIC
Findings of these translational analyses in MOSAIC show Hazard Ratio in favor of FOLFOX4 vs LV5FU2 in dMMR colon cancer patients.  
Low dMMR prevalence in stage II & III colon cancer limits conclusive evidence for oxaliplatin benefit in this population, even in this large study. 
Analyses of colon cancer MMR status in patients included in the MOSAIC study support the use of FOLFOX4, in patients with dMMR stage III cancer ( but not in stage II?)
Fléjou JF, ASCO 2013

30. Take home messages (I)
MSI colon cancer is an heterogenous group Sporadic and LS-MSI may behave differently, BRAFmt and WT MSI also…
MSI studies are difficult because of the low incidence of this characteristic, in different stages of the disease, with different standard treatment over time
MSI is a genetic marker useful to screen out Lynch syndrome
MSI shall be determined in all patients under 60 year old with a colorectal cancer
MSI has a clear prognostic value for stage II colocrectal cancer patients
MSI shall be determined in all patients resected from a stage II colon cancer to help in adjuvant treatment decision

31. Take home messages (II)
MSI seems predictive of resistance to fluoropyrimidine in stage II and III patients (inconclusively) in exploratory analyses
FOLFOX seems as efficient in MSI or MSS patients in stage III tumors
Unanswered questions:
Stage II patients T4 MSI with other bad prognosis factors???
Stage III patients contraindicated for oxaliplatin???

32. Algorithm for chemotherapy decision
Colon cancer
Stage II
Stage III
MSI
MSS
NO MSI
Determination
needed
NO CT
Good prognosis, resistance to FU
CT may be discussed
Regarding other prognostic factors, age, patient wish...
FOLFOX

33. The Future
Develop worldwide collaborations to obtain sufficient number of patients to address unanswered questions
NSABP and MOSAIC will be pooled
PETACC8 and NCCTG N0147 also