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Unpublished data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

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24a

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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