1. No category

ESMO Preceptorship Program 27.-28. March Singapore
Adjuvant treatment of stage II: Which
patients to treat?
Claus-Henning K öhne
Klinik für Onkologie und Hämatologie
Oldenburg, Germany
AJCC v7
5yr rel OS (%)
100
90
80
70
60
50
40
30
20
10
0
Stage II
Stage III
Gunderson et al, JCO 2009
Stage II
Small survival benefit (3%) with 5-FU
No further improvement with FOLFOX
?? Does a Clinically defined high risk
group benefit from FOLFOX (PFS) ??
Clinical Data in Stage II Colon Cancer
• Randomized trials: Stage II subsets
Study
N
Arms
5y OS
Intergroup 0035
935
5FU/LV vs. Obs.
72% vs. 72%
QUASAR
3238
FU vs. Obs.
80% vs. 77%
IMPACT B2
1016
5FU vs. Obs.
82% vs. 80%
• QUASAR-1:superior OS with adjuvant therapy for stage II disease
100
80
Chemo
60
No chemo
92% Dukes’ B, 71% colon cancer
40
n
Deaths 5y survival
Chemo 1622 281
80.3
None
1617 328
77.4
20
Diff. 2.9%
p
0.02
0
0
1
2
3
4
5
6
Years of follow-up
7
8
9
0
Gray et al. Lancet 2007
SEER (Medicare) Database
Patients > 65y
Stage II and III
n=43032 1992-2005
Stage II
No risk factor
Stage III
Stage II
Any risk factor
O‘Connor et al. JCO 2011
0.6
0.8
NSABP experience: 4 trials
5-FU
2009 Pts, 483 Deaths
5-FU+Oxali
991 Pts, 100 Deaths
HR = 0.95, 95% CI 0.75 - 1.21
P = 0.67
0.2
0.4
Overall Survival
1.0
Adjusted* Kaplan Meier Es
1851
893
0.0
Number
at-risk
0
1
2
3
1710
339
4
5
1571
247
6
7
Time in Years
*Adjusted for age, gender, race, nodes examined, and T-stage
Yothers ASCO 2011
MOSAIK FOLFOX vs. FU/LV
Overall survival all stage II patients
1.0
p=0.996
0.9
0.1%
0.8
Probability
0.7
0.6
0.5
0.4
FOLFOX4 stage II
HR [95% CI]
0.3
0.2
0.1
Stage II
1.00 [0.71–1.42]
Stage III
0.80 [0.66–0.98]
LV5FU2 stage II
0
0
6
12
Data cut-off: January 2007
18
24
30
36
42
48
54
60
66
Overall survival (months)
72
78
84
90
96
De Gramont et al. ASCO 2007
MOSAIK: disease free survival
High-risk Stage II Patients
1.0
0.9
0.8
Probability
0.7
7.2%
FOLFOX4 n=286
0.6
LV5FU2
n=290
0.5
0.4
FOLFOX4
LV5FU2
0.3
0.2
3-year 5-year
85.4% 82.1%
80.4% 74.9%
High-risk stage II- defined as at least one
of the following:
T4, tumor perforation, bowel obstruction,
poorly differentiated tumor, venous
invasion , <10 lymph nodes examined;
Data cut-off: June 2006
HR [95% CI]: 0.74 [0.52–1.06]
0.1
0
0
6
Exploratory analysis
12
18
24
30
36
42
48
54
60
66
72
Disease-free survival (months)De Gramont et al. ASCO 2007
Updated MOSAIK data High Risk Stage II
FOLFOX vs. FU/LV
OS
PFS
Age
high risk
N Pat
569
5 y DFS
HR
P-value
0.72
.062
0.51-1.01
low risk
330
1.36
0.76-2.45
6y OS
HR
P-value
0.91
.648
0.66-.97
1.01
1.36
.399
0.67-2.5
Tournigant et al. JCO 2012
Patient groups in adjuvant Therapy
100
No benefit
80
60
40
Cured by
surgery already
20
0
0
1
2
Jahre
3
4
5
TOXICITY
cured
Stage II Colon Cancer
Are there subgroups that might
benefit from adjuvant
chemotherapy ?
Mismatch Repair Deficiency (MMR-D):
Unique Biological Subgroup of Colon Cancer
IHC for MMR
protein status
MLH1+
MSH2-
MLH1-
MSH2+
Thus, IHC for MMR proteins and PCR for MSI detect two
PCR on
tumor tumor biology:
manifestations of the
same
DNA for MSI
• MMR-D is synonymous
with MSI-H
(microsatellite
• MMR-P is synonymous
with MSI-L/MSS
instability)
Imai K, et al. Carcinogenesis. 2008;29:673-680.
Umetani N, et al. Ann Surg Oncol. 2000;7:276-280.
Rosen DG, et al. Mod Pathol. 2006;19:1414-1420.
MMR-Deficiency (MSI-H) is a Favorable Prognostic Marker
The ~15% of stage II colon cancer patients with MMR-deficient (MSI-H) tumors have
been found consistently to have a lower risk of recurrence and/or death
Source
Stage /
Treatment
Endpoint
MMR-D vs MMR-P
HR (95% CI); p-value
Ribic et al1
II/III
Surgery alone
Overall survival
0.31 (0.14-0.72)
p=0.004
Sargent et al2
II/III
Surgery alone
Disease-free survival
Overall survival
0.46 (0.22-0.95); p=0.03
0.51 (0.24-1.10); p=0.06
Gray et al3
(QUASAR)
II
Surgery alone
Recurrence-free interval
0.31 (0.15-0.63)
p<0.001
Roth et al4
(PETACC-3)
II
5FU ± irinotecan
Relapse-free survival
0.30
p=0.004
Ribic et al. NEJM2003 Sargent et al. JCO. 2010; Gray R, et al. JCO 2011 Roth AD, et al. JCO 2010
Stage II and III
MSI is prognostic and predictive
DFS by MMR status
dMMR
(MSI-H)
pMMR
(MSI-L/MSS)
Untreated
5Y DFS; p=.009
dMMR 80%
pMMR 56%
dMMR: deficient MMR
pMMR: proficient MMR
Treated
5Y DFS; p=.30
dMMR 70%
pMMR 67%
Sargent D J et al. JCO 2010;28:3219
Are stage II and Stage III different diseases?
Prognostic Value (RFS)
Multivariate Analysis in whole population
Markers
Stage II
Stage III
HR§
p value*
HR§
p value*
T Stage (T4 vs T3)
2.8
0.0001
1.6
0.0006
N Stage (N2 vs N1)
N/A
N/A
2.2
<0.0001
Histologic Grade (3-4 vs 1-2)
0.6
0.55
1.4
0.07
Age (>60 vs ≤60)
1.8
0.026
1.1
0.3
MSI (High vs Stable)
0.3
0.027
0.7
0.12
p53 (High)
0.7
0.27
1.3
0.015
SMAD4 (any loss)
1.0
0.9
1.6
0.0002
Treatment, Sex, Site, KRAS, BRAF,TS, 18qLOH (Stage II: HR 1.4, p=0.33), hTERT:
not significant
* p values from the Wald test in a multiivariate Cox regression
§ HR = hazard ratio
PETACC 3 ASCO 2009
Gene expression signatures
Almac Diagnostics
Formalin-fixed paraffin-emmedded
N=144 stage II Colon Cancer
Relaps free survival
ColoPrint / Agendia
Fresh frozen tumor tissue
N=188 stage I-IV CRC
Salazar et al. JCO 2011
Kennedy et al. JCO 2011
Prediction of recurrence in Stage II Colon Cancer
Clinical vs. ColoPrint assessment
Clinical
assessment
All stage II
N=416
ColoPrint assessment
All stage II
N=416
stage II MSI-S/L
N=301
High risk
Low risk
Kopetz et al. The Oncologist 2015
Prediction of recurrence in Stage II Colon Cancer
Clinical vs. ColoPrint assessment
Multivariate Analysis for ris of
recurrence:
all pts
untreated ptst
ColoPrint
2.16
2.65
MSI vs. MSS n.sn.s.
Other variables:
Age, Localisation (r/l), grade (1/2 vs.
3), gender, LN, pT (3 vs. 4), Tx
(y/n), NCCN clinical factors
Kopetz et al. The Oncologist 2015
Gen-Expression Assay (OncoType Dx)
CRC Stage II
Gray et al. JCO 2011
Breast Cancer
N- HR +
Paik et al. NEJM 2004
25
Recurrence Score® Guideposts for Clinical Decisions:
T3, MMR-P Patients with RS ≥ 41
45%
T4 and MMR proficient (13%) (MSI-L/MSS)
Risk of Recurrence at 3 years
40%
35%
30%
25%
T3 and MMR proficient (74%) (MSI-L/MSS)
20%
15%
10%
5%
T3 and MMR deficient (11%) (MSI-H)
0%
0
10
20
30
40
50
60
70
Recurrence Score
This population of patients with high Recurrence Score disease
(~25% of total) has recurrence risk that overlaps with T4 patients and would be
expected to have >3% benefit with adjuvant 5FU.
Gen-Expression assay not predictive for adjuvant
chemotherapy
low
intermediate
high
Gray et al. JCO 2011
Gene expression platforms in stage II colon cancer
all describing prognosis
Platform
Oncotype
ColDx
ColoPrint
Previstage
Training set
Stage II / III
Stage II
Stage II / III
Stage II
Validation set
Stage II
n=1436
Stage II
n=144
Stage II / III
n=114
-
Tissue source
FFPE
FFPE
Fresh frozen
FFPE LN
Type of study
Prospective
retrospective
Prosspective
Retrospective
Adj Ctx inclued
Yes
No
Yes
No
MMR data
Available
Not available
Available
Available
Technology
RT-PCR
Microarry
Microarray
qRT-PCR
Type of gene
signiture
12-genesignature
634-transcript
signature
18-gene
classifier
GCC gene
expression
RR high risk group
22%
60%
26%
27%
RR reduction to
acheive absolute
RR of 5%
23%
8%
19%
19%
Chee & Meropol The Oncologist 2014
Different intentions to use
Gen-Expression Assays in
Breast or Colon Cancer
Tumor
Stage
Aim
Breast
N- (N1-3) HR+
Not to use chemo
Colon
N- (pMSI?)
To use chemo
Prognostic and predictive value of a microRNA signature in
stage II colon cancer: a microRNA expression analysis
Zhang et al. Lancet Oncol 2013
Prognostic and predictive value of a microRNA signature in
stage II colon cancer: a microRNA expression analysis
IOP internal obstraction or perforation
Zhang et al. Lancet Oncol 2013
Prognostic and predictive value of a microRNA signature in
stage II colon cancer: a microRNA expression analysis
Poor prognostic factors: T4, high grade,
intestinal obstraction or perforation,
exsamination < 12 LN
Zhang et al. Lancet Oncol 2013
Prognostic and predictive value of a microRNA signature in
stage II colon cancer: a microRNA expression analysis
Zhang et al. Lancet Oncol 2013
Adjuvant! Online Prediction:
Cancer and non-cancer related 5-year-Mortality
Inprovement of cancer specific survival by 1.7% (FU) and 2.3% (FOLFOX)
T3 NO MO
T4 NO MO
Assumption of Gill model
Algorithm for treatment decison in stage II colon cancer
The decision for adjuvant therapy has to balances the risk of cancer and other competing risks
Stage II colon cancer
Advanced age or
comorbidities
Age < 60y
pT3
pT4
pMMR / MSI-H
dMMR / MSS
Additional marker ?
Gen signature / miRNA ?
Consider adj. CTx
No adj. CTx