Post on 27-Jul-2020
The gist of GIST
Ronald P. DeMatteo MDPerelman School of Medicine
University of Pennsylvania
Gastrointestinal Stromal Tumor (GIST)
• Most common sarcoma
• Incidence ~12 per million
• Ages 40-80
• Stomach and small intestine most common sites
• Originates from the interstitial cells of Cajal
Spectrum of Primary GISTIncidental Gastric GIST
Jejunal GISTExophytic Gastric GIST
Endoscopic GIST
Outcome after Resection of Primary GIST Before the era of tyrosine kinase inhibitors
Years1614121086420
Frac
tion
Sur
vivi
ng1.0
.8
.6
.4
.2
0.0
5 yr 54%
Ann Surg 2000; 231:51
N=80
KIT Receptor
NH2
Extracellular
MembraneJuxtamembrane
Tyrosine kinase 1
Tyrosine kinase 2
COOH
KIT
S6
PI3K
AKT
mTOR
SRC
ERK
RAS
RAF
MEK
STATs
Kitamura Science 1998; 279:577-80
GIST Subsets
PDGFRA other
Wild type*
KIT exon 11
PMINS
KIT exon 9
PDGFRA D842V
J Clin Oncol 2014; 32:1563
ImatinibKITPDGFRα
SunitinibKITPDGFRαVEGFR
RegorafenibKITPDGFRβVEGFRTie2
DEL
Chart1
11 del
PM
INS
9
not 842
842
WT
Sales
184
111
46
35
30
27
64
Sheet1
Sales
11 del184
PM111
INS46
935
not 84230
84227
WT64
GIST is mutationally “quiet”
Unpublished data
amplificationdeep deletionmissense mutationinframe mutationtruncating mutation
p53
PDGFR
α
Kit
NF1
Ros
1
45 primary GISTs~400 cancer genes sequenced
Imatinib Efficacy in Advanced GIST (N=694)
Blanke, J Clin Oncol 2008; 26.626
Overall SurvivalProgression-Free Survival
Pre-treatment6 months
on imatinib 10 monthson imatinib
Focal Imatinib Resistance
Exon 11 Exon 13 Exon 14 Exon 17
Primary mutation Secondary mutation 560 570 580 650 670 820
WT Q W K V V E E I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I V - - - T E Y C C - - - D S N Y V
25 Q W K D V E E I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I V - - - T E Y C C - - - Y S N Y V
24a Q W K V - E E I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I V - - - T E Y C C - - - D S K Y V
24b Q W K V - E E I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I A - - - T E Y C C - - - D S N Y V
19 Q - - V V E E I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I V - - - I E Y C C - - - D S N Y V
22 Q W N P V V E E I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I V - - - T E Y C C - - - D S K Y V
15 Q W - - - - - I N G N N Y V Y I D P T Q L P Y D H - - - - H M N I V - - - T E Y C C - - - D S N D V
14 Q W K V V E E I N G N N Y - - - - - - - - P Y D H - - - - H M N I V - - - T E Y C C - - - Y S N Y V
27 Q W K V V E E I - - - - - - - - - - - - - - - D H - - - - H M N I V - - - T E Y C C - - - D S K Y V
Clin Cancer Res 2005; 11:4182
Mechanism of Resistance2nd KIT mutation in 7 patients
Primary mutation
Secondary mutation
560
570
580
650
670
820
WT
Q
W
K
V
V
E
E
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y
D
H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
D
S
N
Y
V
25
Q
W
K
D
V
E
E
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y
D
H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
Y
S
N
Y
V
24a
Q
W
K
V
-
E
E
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y
D
H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
D
S
K
Y
V
24b
Q
W
K
V
-
E
E
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y
D
H
- -
- -
H
M
N
I
A
- - -
T
E
Y
C
C
- - -
D
S
N
Y
V
19
Q
-
-
V
V
E
E
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y
D
H
- -
- -
H
M
N
I
V
- - -
I
E
Y
C
C
- - -
D
S
N
Y
V
22
Q
W
N
P
V V
V EE
E
E
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y D
D H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
D
S
K
Y
V
15
Q
W
-
-
-
-
-
I
N
G
N
N
Y
V
Y
I
D
P
T
Q
L
P
Y
D
H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
D
S
N
D
V
14
Q
W
K
V
V
E
E
I
N
G
N
N
Y
-
-
-
-
-
-
-
-
P
Y
D
H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
Y
S
N
Y
V
27
Q
W
K
V
V
E
E
I
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
D
H
- -
- -
H
M
N
I
V
- - -
T
E
Y
C
C
- - -
D
S
K
Y
V
Diagnosis
Only one is a GIST – Which one?
Leiomyoma GIST
SchwannomaEctopic Pancreas
Primary Disease
45 yo F with incidental mass on CT scan
4 cm jejunal GIST with 7 mitoses/50 HPFs
The patient now should be:1. Followed for symptoms.2. Undergo radiologic surveillance.3. Treated with 1 year of imatinib.4. Treated with >1 year of imatinib.
How do we assess recurrence risk?
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%
Semin Diagn Pathol 2006; 23:70
Miettinen Risk Criteria
GIST NomogramGIST Nomogram for Recurrence-free Survival
Lancet Oncol 2009; 10:1045
GIST 4 cm, 7 mitoses, small intestine = 145 points
What are the results of adjuvant imatinib?
Primary GIST > 3 cm
Complete Gross ResectionTumor Kit +
Recurrence/Survival
Imatinibx 1 yr
Placebox 1 yr
Double-blindCross-over if recur
Does adjuvant imatinib improve outcome?ACOSOG Z9001 Phase III Trial (6/2002 – 4/2007)
Imatinib
Placebo
P=0.0002
Lancet 2009; 373:1097J Clin Oncol 2014; 32:1563
Adjuvant imatinib is not curative (N=713)
Median f/u 74 months
70% cured by surgery
Treatment period
Overall Survival
Placebo
P=0.19
(Imatinib)
J Clin Oncol 2014; 32:1563
December 19, 2008
Approval for adjuvant therapy (no patient criteria or time restrictions).
March 19, 2009
Approval for adult patients with KIT+ GIST at significantrisk of relapse. Patients at low or very low risk of recurrence should not be treated.
Approval of Adjuvant Imatinib
http://www.fda.gov/default.htm
Is tumor mutation status important in adjuvant therapy?
Natural History and Mutation (N=252)
P=0.098
Exon 11
Exon 9Wild typePDGFRA
J Clin Oncol 2014; 32:1563
Natural History and KIT Exon 11 Deletion
P=0.0004
Wild type
Exon 11 INSExon 11 PM
Exon 11 DEL other
Exon 11 DEL 557/8
J Clin Oncol 2014; 32:1563
5-10 cm>10 cm
Small bowelRectumOther5-10>10
Exon 9Exon 11 DEL
Exon 11 no DELPDGFRA
Size
Location
Mitoses
Mutation
3.32.0
7.8
Mutation is not independently prognostic
Better WorseJ Clin Oncol 2014; 32:1563
Which patients do not need adjuvant therapy?
Miettinen 2 yr RFSrisk score % Imatinib Placebo p valueLow 45 98 98 0.92Moderate 24 98 76 0.05High 31 77 41
Who should receive adjuvant imatinib?GIST Nomogram for Recurrence-free Survival
Lancet Oncol 2009; 10:1045
GIST 5 cm, 7 mitoses, stomach = 110 points
https://www.mskcc.org/nomograms/gastrointestinal
All Exon 11 Exon 9 WT PDGFRA
Exon 11 PMExon 11 insExon 11 - other delExon 11 del557/8
Imatinib 170
Placebo 171
Imatinib 13
Placebo 22
Imatinib 32
Placebo 32
Imatinib 30
Placebo 27
Imatinib 51
Placebo 56
Imatinib 41
Placebo 36
Imatinib 21
Placebo 25
Imatinib 57
Placebo 54
J Clin Oncol 2014; 32:1563
Effect of Imatinib by Mutation
What is the optimal duration of adjuvant therapy?
Joensuu, JAMA 2012; 307:1265
SSG XVIII – 1 vs. 3 years
Rel
apse
Fre
e Su
rviv
al
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.0
Patients still at risk1.0
0
91
6
89
12
85
18
84
24
80
30
71
36
67
42
64
48
61
54
56
60
53
66
46
72
26
78
19
84
7
90
0
Months
PERSIST5 Trial
ASCO 2017in submission
Locally Advanced Primary Disease
50 y.o. male with abdominal discomfort.Palpable mass on exam.CT scan performed.
The patient should:
1. Begin imatinib 400 mg/day.2. Begin imatinib 800 mg/day.2. Undergo percutaneous biopsy. 3. Undergo surgery.4. Undergo colonoscopy.
The patient gets a biopsy which shows GIST.Imatinib 400 mg/day is started. 1 month later a CT is performed.
Baseline
1 month
The patient should now:
1. Undergo surgery.2. Increase the dose to 800 mg/day.3. Undergo a PET scan.4. Continue imatinib 400 mg/day.
A repeat CT scan is done 4 months later.
The patient should now:
1. Undergo surgery.2. Increase the dose to 800 mg/day.3. Undergo a PET scan.4. Continue imatinib 400 mg/day.
Verweij, Lancet 2004; 364:1127
Time to imatinib discontinuation
Time to imatinib response
Imatinib then Surgery: When to operate
When to Consider Neoadjuvant Therapy
Primary GIST
Resectable Unresectable/extensive surgery
Surgery
Moderate/high risk
Imatinib*
* If not WT or PDGFRA D842V
Metastatic GIST
Residual Primary and Metastatic GIST
50 y.o. maleGastric GIST + liver mets
Stomach partially removedImatinib stable disease x1 year
The patient should now:
1. Continue imatinib 400 mg/day.2. Increase the dose to 800 mg/day.3. Undergo surgery.4. Undergo liver RFA.
Rationale for Surgery in TKI-Stable GIST
• Responsive tumors have viable cells and active KIT signaling
• Possibility for cure?
• Reduce/delay chance of imatinib resistance
• Time to resistance = ƒ (tumor load)?
J Clin Oncol 2008; 26.626
Progression-free survival in U.S. M1 Trial (n=694)
Outcome of TKIs + Surgery for Metastatic GIST
Ann Surg 2007; 245:347
0 12 24 36 48Months since operation
0.0
0.2
0.4
0.6
0.8
1.0
Responsive diseasen=20
Focal resistancen=13
Multifocalresistancen=7 p < 0.001
0 12 24 36 48Months since operation
0.0
0.2
0.4
0.6
0.8
1.0
Responsive diseasen=20
Focal resistancen=13
Multifocalresistancen=7 p < 0.001
0 12 24 36 48Months since operation
Responsive diseasen=20
Focal resistancen=13
Multifocalresistancen=7
p < 0.0010.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48Months since operation
0 12 24 36 48Months since operation
Responsive diseasen=20
Focal resistancen=13
Multifocalresistancen=7
p < 0.001
J Clin Oncol 2006; 24:2325
PFS OS
Multimodality Therapy for Metastatic GIST
Imatinib
Responsive/stable
Surgery Ablation
Observation
Multifocal progression
Dose escalationSunitinib
Clinical trial
Dose escalationSunitinibSurgery
Clinical trial
Focal progression
Summary
• Adjuvant imatinib prolongs recurrence-free survival
• Risk of recurrence depends mostly on mitotic rate
• Patients with low risk tumors do not benefit from adjuvant imatinib
• Adjuvant therapy is beneficial for KIT exon 11 mutations
• Surgery for responsive metastatic GIST may be useful
Murine model of GIST
Deletion mutation in KIT exon 11
Sommer, PNAS 2003; 100:6706
% S
urvi
val
Weeks
You are whom you teach
The gist of GISTGastrointestinal Stromal Tumor (GIST)Spectrum of Primary GISTSlide Number 4KIT ReceptorGIST SubsetsGIST is mutationally “quiet”Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Miettinen Risk CriteriaSlide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31SSG XVIII – 1 vs. 3 yearsSlide Number 33Slide Number 3450 y.o. male with abdominal discomfort.�Palpable mass on exam.�CT scan performed.Slide Number 36The patient gets a biopsy which shows GIST.�Imatinib 400 mg/day is started. �1 month later a CT is performed. �Slide Number 38A repeat CT scan is done 4 months later. �Slide Number 40When to Consider Neoadjuvant TherapySlide Number 42Slide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47Slide Number 48Slide Number 49SummarySlide Number 51You are whom you teach