Update on GIST

1
Update on GIST

• George Ansstas, MD
• 6/19/09

2
Overview

• Background
• Epidemiology
• Pathologic Diagnosis
• Molecular Changes
• Treatment

3
Background

• Derived from ICC
• - Cells of Auerbachs plexus with both
  neural and stromal features by EM
• - GIST and ICC may arise from a common
  mesenchymal stem cell
• Previously misclassified as leiomyosarcoma/other
  spindle cell cancers
• Standard sarcoma adjuvant therapy is
  ineffective
• Chemo RR 5, no impact on
  survival
• RT morbidity due to location
  limits use-? role for rectal tumors
• Classic IHC (positive for c-KIT 95, CD34
  60-70, negative for S-100 and desmin)
• Well described mutations in KIT, PDGFR tyrosine
  kinase receptors

4
Epidemiology

• GIST about equal male to female ratio.
• Reported in people of all ages, most patients are
  between 40-80 years. Median age is 60.
• Incidence is estimated around 5000 cases per year
  in the US.
• May occur anywhere in the GI tract.
• Stomach (65)
• Small intestine (25)
• Colon or rectum (5-10)
• Esophagus (5)
• Rarely may originate in the omentum, mesentery or
  retroperitoneum.

5
More Epidemiology of GIST

• The vast majority of GIST cases are sporadic
• Familial GIST
• About a dozen families have been identified with
  germline mutations leading to GIST
  predisposition.
• Multiple members of each family develop numerous
  GISTs in a background of ICC hyperplasia.
• This is inherited in an autosomal dominant
  fashion, since KIT and PDGRFA are located on the
  long arm of chromosome 4.
• Familial GIST syndrome families have been
  identified with mutations in KIT exon 11, exon
  13, exon 17, and PDGFRA, exon 18.

6
More Epidemiology of GIST

• Patients with Neurofibromatosis type 1 (NF1)
• This usually presents in the setting of ICC
  hyperplasia.
• Incidence of GIST is about 7.
• GISTs develop most frequently in the small
  intestine in these patients.
• The reported incidence of point mutations in the
  KIT and PDGFRA genes are 8 and 6 respectively.
• Carney Triad
• Small cohort of patients identified with a tumor
  syndrome consisting of multicentric functioning
  extra-adrenal paraganglioma, pulmonary chrondroma
  and multifocal epitheliod GIST of the stomach.
• Female predominance (85).
• Most patients are lt30.
• KIT and PDGFRA mutations have not been associated
  with this.

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Pathologic Features of GIST
Spindle cell 70
Epithelioid 20
8
GIST is related to the KIT by functional biology

• Where is KIT signaling important?
• pigmentation
• hematopoiesis
• mast cell development and function
• germ cell maintenance
• GI tract innervation

9
Hypopigmentation Features with LOSSOf KIT
Signaling (Piebaldism)
10

• Science 279577-580, 1998
• Positive c-kit staining in 46 of 49 GISTs
• Five of six GISTs had KIT juxtamembrane mutations
  
• Mutant forms of KIT were constitutively active
• Proposed that GIST may originate from ICCs

11
KIT and PDGFRA Mutations in 950 GISTs
12
GIST Clonal Evolution of Cytogenetic
Abnormalities
KIT ?Monosomy 14 gt Monosomy 22 gt deletion 1p
13
Impact of Genotype on Responsein KIT GIST
(S0033)
Heinrich et al. J Clin Oncol. 200523(Suppl
16)3s.
14
KIT Staining Tells PART of The Story
KIT positive (CD117) GIST
15
KIT Immunotesting alone may not be enough to make
the best decisions
KIT NEGATIVE GIST
16
Clinical ValidationImatinib Triples Overall
Survival in Patients with Advanced Metastatic
GIST
17
Overall Survival MetaGIST (meta-analysis)
18
Progression-Free Survival Entire MetaGIST
Population
19
Progression-Free Survival
20
Overall Survival
21
Randomized Study (BFR14) of Discontinuing
imatinib after 3 yrs PFS after Randomization
22
Genotype vs. Time to Treatment Failure on Imatinib
Heinrich et al. J Clin Oncol. 200523(Suppl
16)3s.
23
Initial Genotype vs. Timeto Treatment Failure on
Sunitinib
24
Secondary Imatinib-Resistance KITMutations in
GIST
25
Effect of Sunitinib and Imatinib on KITActivity
in Imatinib-Resistant GIST Lines
Heinrich et al, JCO, 2007
26
Evidence for Biological Heterogeneity for Among
GISTs

• KIT exon 9 mutations 98 arise in the small
  intestine
• PDGFRA mutations 98 arise in the stomach
• Secondary kinase mutations
• Common in imatinib-resistant GISTs with
  primary KIT exon 11 mutations
• Rare in imatinib-resistant GISTs with primary
  KIT exon 9 mutations
• KIT or PDGFRA mutations are found in 90 of adult
  GISTs but are rare in pediatric GISTs

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Prognostic Markers
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Phase II Trial (ACoSOG Z9000) Study Design

• Objectives Primary OS on imatinib mesylate in
• adjuvant
  setting
• Secondary 2- and
  5-year recurrence
• 
  Toxicity in adjuvant setting
• Treatment Imatinib mesylate 400 mg/d
• Inclusion High-risk GIST
• Imatinib mesylatenaïve, tumor
  c-KIT positive
• No prior adjuvant therapy
• No residual disease on post-op
  imaging

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Phase II Trial (ACoSOG Z9000) Study Design

• High-risk any of the following
• Tumor at least 10 cm in greatest dimension
• Presence of tumor rupture before or
  during surgery
• Intraperitoneal hemorrhage
• Multifocal intraperitoneal tumors

Complete resection of high-risk primary GIST
Follow for OS

?
?
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Z 9000 4 year ressults

• N 107
• Imatinib started at a median of 59 (range 25-84)
  days after operation
• Median age 58 years (range 19-79)
• Median tumor size 13 cm (range 3-42)
• 50 of tumors gastric, 42 small intestine
• Imatinib therapy well tolerated (ASCO 2005 Annual
  Meeting)
• Median follow-up of 4 years
• 1, 2, and 3 yr OS 99, 97, and 97,
  respectively.
• 1, 2, and 3 yr RFS 94, 73, and 61,
  respectively.
• Imatinib 400 mg for 1 year after resection of
  high-risk primary GIST prolongs RFS and OS
  compared with historical controls

DeMatteo RP, et al. ASCO 2008 GI Cancers
Symposium, Abstract A-8
31
Phase III Trial (ACOSOG Z9001) Study Design

• Objectives Primary OS with imatinib
  mesylate in
• 
  adjuvant setting relative to placebo
• Secondary
  Recurrence-free survival
• 
  Safety/efficacy in adjuvant setting
• Treatment Imatinib mesylate administered at 400
  mg/d
• Inclusion gt3 cm GIST
• Surgery within 70 days
  prior to registration
• KIT-positive GIST
• Imatinib mesylatenaive
• No prior adjuvant therapy

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Phase III Trial (ACOSOG Z9001) Study Design
Recurrence
Follow for OS
Resection of primary GIST
Recurrence
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ACOSOG Z 9001

• Prelim results
• N708 completely
  resected
• Median f/u 1.2
  yrs
• 1 yr RFS
• 
  Imatinib 97
• 
  Placebo 83
• 
  Significant for tumors gt6cm
• No effect OS 10 yr survival follow up is ongoing
• Imatinib approved for adjuvant for all GISTs
• Ongoing trials
• EORTC GISTgt3cm, 2
  yrs imatinib vs. placebo
• Scand sarcoma
  group 12 vs 36 mo Rx in high risk GIST

DeMatteo RP, et al. ASCO Proceedings 2007,
10079 Hueman MT, Schulick RD. Surg Clin NA
200888599
34
TX Strategies for Kinase Inhibitor Resistance
Heterogeneity in GIST

• Broader spectrum more potent KIT kinase
  inhibitors
• Crucial downstream targets as PI3-K
  
• KIT degradation
• HSP90 inhibitors, HDAC inhibitors
• KIT synthesis
• flavopiridol
• KIT dimerization
• Immunotherapy
• Alternate Alternate Pathways - ?IGF1R

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