Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): Results.
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Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): Results of the
intergroup phase III trial ACOSOG Z9001
C. L. Corless, K. V. Ballman, C. Antonescu, C. Blanke, M. E. Blackstein, G. D. Demetri, M. von Mehren, R. G. Maki, P. W. T. Pisters, R. P. DeMatteo
American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team
Oregon Health & Science Univ, Portland, OR; University of Toronto, Toronto, ON; Mayo Clinic, Rochester, MN; University of British Columbia/British Columbia Cancer Agency, Vancouver, BC; Dana Farber Cancer Inst, Boston, MA; Fox Chase Cancer Ctr, Philadelphia, PA; UT MD Anderson Cancer Ctr, Houston, TX; Memorial Sloan-Kettering Cancer Center, New York, NY
Primary GIST > 3 cm
Complete Gross ResectionTumor KIT +
Recurrence/Survival
Imatinibx 1 yr
Placebox 1 yr
Double-blindCross-over if recur
713 evaluable patientsTrial halted early
ACOSOG Phase III Z9001 Adjuvant Trial
Recurrence-Free Survival
Lancet 2009; 373:1097
ACOSOG Z9001 Cases Genotyped For KIT & PDGFRA
Placebo(n=261)
Imatinib(n=252)
All Patients(n=513)
Tumor Size
<5 cm 107 102 209 (40.7%)
5-10 cm 89 83 172 (33.5%)
>10 cm 65 67 132 (25.7%)
Mitotic Rate
<5/50 149 150 299 (61.3%)
≥5/50 101 88 189 (38.7%)
Mitotic Index: Inter-Observer Comparison (45 Cases)
r=0.94
Pathologist #1:65% of cases
Pathologist #2:35% of cases
No statisticaldifferencebetween observers
p=.4851 by Wilcoxon signed rank test
Multivariate Analyses For Recurrence RiskPlacebo Group
p value Hazard Ratio (95% CI)
Mitotic rate
<5/50 hpf
<0.0001 17.07 (6.620, 44.043)≥5/50 hpf
Genotype
WT ---- ----
Exon 9 0.45 1.74 (0.413, 7.359)
Exon 11 0.042 2.97 (1.307, 8.537)
PDGFRA 0.255 2.30 (0.547, 9.722)
Tumor location
Stomach ---- ----
Small intestine 0.0267 2.08 (1.089, 4.001)
Rectum 0.7895 1.31 (0.178, 9.681)
Tumor size
<5 cm
0.0026 1.70 (1.203, 2.402)>5-10 cm
>10 cm
Mitotic Index Vs Tumor Size & Location
0
20
40
60
80
<5 cm 5-10 cm > 10 cm
Tumor Size
Per
cen
t o
f C
ases
<5/50 hpf ≥5/50 hpf
0
10
20
30
40
50
60
70
Stomach Small intestine Rectum/other
Tumor Location
Per
cen
t o
f C
ases
PDGFRA (n=28)Wild-type (n=32)
Exon 9 (n=22)
RFS For Placebo Cases By Genotype
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
an
d A
liv
e
Exon 11 Deletion (n=93)
Exon 11 PM (n=55)Exon 11 Insertion (n=25)
p=0.0240 vs WTHR 3.45
(95% CI 1.177 -10.137)
RFS For PDGFRA-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=29)
Placebo (n=28)
p<0.01
Treatment
RFS For PDGFRA D842V-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54
Time in Months
% R
ec
urr
en
ce
-Fre
e a
nd
Ali
ve
Imatinib (n=15)
Placebo (n=13)
Treatment
RFS For PDGFRA-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
All PDGFRA (n=29) - imatinib
All PDGFRA (n=28) - placebo
Treatment
D842V (n=13) - placebo
RFS For Exon 11-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ec
urr
en
ce
-Fre
e a
nd
Ali
ve
Imatinib (n=173)
Placebo (n=173)
Treatment
p<0.0001
HR 3.42 (95% CI 1.93 - 6.06)
RFS for Exon 11 Deletion 557-558 by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=52)
Placebo (n=57)
p=0.0013HR 4.07 (95% CI 1.73 - 9.57)Treatment
RFS for Exon 11 Other Deletion by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=42)
Placebo (n=36)
p=0.0087HR 4.85 (95% CI 1.49 -15.76)
Treatment
RFS For Wild-type Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=32)
Placebo (n=32)
Treatment
p=0.6126
RFS For Exon 9-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=13)
Placebo (n=22)
Treatment
p=0.8443
SizeGastric
(n=1055)
Jejunum/Ileum
(n=629)
Duodenum
(n=144)
Rectum
(n=111)
Mitotic ≤ 2 cm 0% 0% 0% 0%
Index > 2 ≤ 5 cm 1.9% 4.3% 8.3% 8.5%
≤5 per 50 hpf> 5 ≤ 10 cm 3.6% 24% Insuff. data Insuff. data
> 10 cm 10% 52% 34% 57%
Mitotic ≤ 2 cm (None) (High) Insuff. data 54%
Index > 2 ≤ 5 cm 16% 73% 50% 52%
>5 per 50 hpf> 5 ≤ 10 cm 55% 85% Insuff. data Insuff. data
> 10 cm 86% 90% 86% 71%
Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70-83
Miettinen et al.Older model microscope
Area of50 highpower fields
5.3 mm2
11.87 mm2 Newer microscope
in this study Is 5/50 hpfstill valid?
Risk of Recurrence In Placebo GroupBy Miettinen Risk Assessment Criteria
Mitoses Size
Gastric ≤5/50 ≤10 cm
LowNon-gastric ≤5/50 ≤5 cm
Gastric ≤5/50 >10 cm
Moderate >5/50 ≤5 cm
Non-gastric ≤5/50 5 - 10 cm
Gastric >5/50 >5 cm
High Non-gastric >5/50 Any
Any >10 cm
Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70-83.
2%
9%
44%
2%
24%
59%
0%
10%
20%
30%
40%
50%
60%
70%
Low Moderate High
Risk Assessment (Miettinen)
1 Year
2 Years
• Low risk (n=270)• Moderate risk (n=148)• High risk (n= 201)
Summary & Conclusions• The Z9001 trial represents the largest cohort of adjuvant
GIST patients followed to date• Risk of recurrence in untreated patients is related to:
– Mitotic index (HR 17.1)– KIT exon 11 mutation (vs WT; HR 3.0)– Small bowel primary (vs gastric; HR 2.1)– Tumor size (HR 1.7)
• 12 months of adjuvant imatinib significantly delays recurrence of:– KIT exon 11-mutant tumors– PDGFRA-mutant tumors (primarily non-D842V) – but not wild-type tumors
• More data are needed to define the impact of adjuvant imatinib on recurrence of exon 9-mutant tumors
• Miettinen criteria for risk stratification remain valid using a newer microscope with a larger field of view
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