1. Uni- & Multivariate Analysis Sponsored by GERCOR (www.canceronet.com)
Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II & III included in the MOSAIC study. Jean-François Flejou, Thierry André, Benoist Chibaudel, Aurelie Scriva, Tamas Hickish, Josep Tabernero, Jean-Luc Van Laethem, Maria Banzi, Eduard Maartense, Adi Shani, Göran Carlsson, Werner Scheithauer, Demetris Papamichael, Markus Moehler, Stefania Landolfi, Pieter Demetter, Alex Duval, Mark Lee, Soudhir Colote, Aimery de Gramont
Background
MMR availability
dMMR population
Uni- & Multivariate Analysis
Adding oxaliplatin to adjuvant 5FU and leucovorin improved 3-year Disease- Free Survival (DFS) and Overall Survival (OS) after resection of stage II and III colon cancer in the MOSAIC study. 1, 2
Prognosis of patients with stage II and III colon cancer is better in patients with dMMR (dMMR) tumors than in patients with proficient MMR (pMMR).
Data suggest that 5FU-based chemotherapy is less or ineffective in patients with stage II dMMR tumor.
Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study. 3 MMR status is an independent prognostic biomarker of DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy. 4  
In NSAP C07 and C08, MMR status seems not predictive for oxaliplatin benefit ?
Univariate analysis
Multivariate analysis N HR
95% CI
P value
Arm
LV5FU2
FOLFOX
491
513
0,84 0,
0.083
0.82
0.054
Age
<70
≥70
848
156
1.74
<0.0001
1.64
0.0001
Sex
Male
Female
541
463
0.74
0.004
0.73
0.003 PS 1
803
201
1.41
1.28
0.041
Stage II
III
365
639
1.76
0.76
0.196
MMR
pMMR
dMMR
909 95
0.65
0.036
0.67
0.056
Perforation No
Yes
933 71
1.54
0.013
1.42
0.066
T stage
T1-3 T4
805
199
0.0002
1.38
0.011
N stage N0 N1 N2
366
411
227
1.43
2.46
1.83 .
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
Stage
Endpoint
LV5FU2
FOLFOX HR
[95% CI]
P value
N=51
N=44
II-III
3-yr RFS, % (sd)
80.2 (5.6)
90.9 (4.3)
0.49
0.134
3-yr DFS, % (sd)
78.4 (5.8)
88.6 (4.8)
0.48
0.081
5-yr OS, % (sd)
82.3 (5.3)
0.42
0.060
N=29
N=18
III
69.0 (8.6)
83.3 (8.8)
0.55
0.302
0.50
0.499
72.2 (8.3)
88.9 (7.4)
0.43
0.190
N=22
N=26 II
95.2 (4.6)
96.2 (3.8)
0.58
0.542
90.9 (6.1)
92.3 (5.2)
0.53
0.324
95.5 (4.4)
0.46
0.273
MMR NA : MMR status not available; MMR OK : MMR status available
In patients with MMR available (N=1004), hazard ratios (HR) for comparing FOLFOX4 (N=513) with LV5FU2 (N= 591) were :
[ ] for 3-Year Relapse Free-Survival (RFS)
0.84 [ ] for 3-Year Disease Free Survival (DFS)
Methods
Of the 2246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1019 pts were obtained.
Twenty two samples with insufficient tumor tissue were excluded from this translational study.
MMR status was determined by immunohistochemistry (IHC) of the protein products of MLH1, MSH2, PMS2 and MSH6 genes.
In 11 pts with inconclusive IHC (negative staining of both tumor and internal control), MMR status was determined by pentaplex PCR with 5 mononucleotide repeats. 6
pMMR population
Stage II & III
Conclusions
RFS
DFS OS
Stage
Endpoint
LV5FU2
FOLFOX HR
[95% CI]
P value
N=440
N=469
II-III
3-yr RFS, % (sd)
74,8 (2.1)
78.9 (1.9)
0.81
0.076
3-yr DFS, % (sd)
73.9 (2.1)
77.6 (1.9)
0.86
0.170
5-yr OS, % (sd)
78.8 (2.0)
80.5 (1.8)
0.91
0.434
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
Flow-chart
MOSAIC study N=2246
MMR status available, N=1004
MMR status not available
N=1242
Tumor block not collected, N=1220
MMR not evaluable, N=22
pMMR, N=909
dMMR, N=95
Stage II & III - DFS
Stage III - DFS
Stage II - DFS
Stage III - DFS
References
1 André T et al, N Engl J Med 2004
2 André T et al, J Clin Oncol 2009
3 Zaanan A, Ann Oncol 2010;
4 Zaanan A, Clin Cancer Res 2011
5 Gavin P G et al. Clin Cancer Res 2012
6 Suraweera N et al, Gastroenterology 2002
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