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