Getting the GIST of it: Why
Molecules Matter to Surgeons
Surgery Grand Rounds
November 21, 2011
Martin McCarter, M.D.
Associate Professor of Surgery
GI Tumor & Endocrine Surgery
University of Colorado Denver
Conflict of Interest
Employee of University of Colorado
School of Medicine
Getting the GIST of it: Why
Molecules Matter to Surgeons
Outline: GIST as a paradigm
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What is GastroIntestinal Stromal Tumor
Natural history of GIST
Molecular classification
Signaling kinases
The imatinib story
Metastatic and adjuvant treatment
GIST post imatinib
What’s next for GIST
GIST – Formerly Known As:
Leiomyoma
Leiomyosarcoma
Leiomyoblastoma
GIST: Identification of KIT
Gain-of-Function Mutations
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•
•
•
KIT staining was positive in 46 of 49 GIST (94%)
5 of 6 GIST had mutations in KIT gene
Mutant forms of KIT are constitutively active
Proposed that GIST may originate from Interstitial
cells of Cajal
• KIT is receptor for Stem Cell Factor
Hirota et al. Science. 1998;279:577.
GIST: Interstitial Cells of Cajal
• Originally described by Ramon Cajal
• KIT-positive fibroblast-like cells
• Pacemaker cells of the gut
– Intercalated between intramural neurons
and smooth muscle cells
– Generate electrical slow waves
• Loss of ICC function has been
implicated in diabetic
gastroenteropathy and gastroenteric
arrhythmia
Takayama et al. Arch Histol Cytol. 2002;65:1.
Scope of the Problem
• ~ 10,000 new soft tissue sarcomas per year
• ~ 3000 GIST per year in the United States
• Estimated annual incidence ~ 10 cases
per million
Staging of GIST
T1 = <2 cm
T2 = 2-5 cm
T3 = 5-10 cm
T4 = >10 cm
Mitotic Rate
Low <5/50HPF
High >5/50HPF
AJCC Staging Manual 7th ed.
Pathologic Features of GIST
• Median age at presentation is 63
• Size about 5-7 cm
• Location
• Stomach 55%
• Small Intestine 35%
• Rectum 5%
• Other 5%
Joensuu H and DeMatteo RP. Annu Rev Med. 2011 Jan 26. [Epub ahead of print]
Natural History of GIST
DeMatteo RP et al. Ann Surg 2000 Jan;231(1):51-8.
1.0
<5 cm
0.75
<5-10 cm
0.50
>10 cm
0.25
P=0.03
0
0
20
40
60
Length of study (mo)
Singer et al. J Clin Oncol. 2002;20:3898.
80
Proportion surviving
free of recurrence
Proportion surviving
free of recurrence
GIST: Recurrence-Free Survival
Following Surgical Treatment of
Primary GIST
1.0
≤3 mitoses/30 hpf
0.75
>3 to ≤15 mitoses/30 hpf
0.50
0.25
P=0.0001
>15 mitoses/30 hpf
0
0
20
40
60
Length of study (mo)
80
KIT and PDGFRα Mutations in GIST
Joensuu H , DeMatteo RP. Annu Rev Med. 2011 Jan 26. [Epub ahead of print]
Signaling Protein Kinases
• Transient signal from surface
membrane receptor through to
intracellular and nuclear machinery
• Regulate cell functions
• Dependant on a phosphorylation step
• Potential target IF cancer cell is largely
dependant on it for growth
Development of Imatinib
• CML was the target
• Known (Philadelphia 9/22) chromosomal translocation
• Resulted in BCR-ABL fusion protein
• Screened designer drugs to fit BCR-ABL phosphate
pocket and inhibit tyrosine kinase
Imatinib and GIST
An International Story
1
1 BCR-ABL protein described 1973
Imatinib and GIST
An International Story
2
1
1 BCR-ABL protein described 1973
2 Imatinib developed for BCR-ABL 1990’s
Imatinib and GIST
An International Story
2
1
1 BCR-ABL protein described 1973
2 Imatinib developed for BCR-ABL 1990’s
3 KIT mutation described 1998
3
Imatinib and GIST
An International Story
4
2
1
1 BCR-ABL protein described 1973
2 Imatinib developed for BCR-ABL 1990’s
3 KIT mutation described 1998
4 First GIST patient treated with Imatinib 2000
3
Imatinib Mesylate (Gleevec):
Proposed Mechanism of Action
• Inhibits KIT, Bcr-Abl,
PDGFR
• Occupies the ATP
binding pocket of the
KIT kinase domain
• This prevents substrate
phosphorylation and
signaling
• A lack of signaling
inhibits proliferation and
survival
Kinase
domains
P
ATP
PPP
Imatinib
mesylate
Adapted from Savage and Antman. N Engl J Med. 2002;346:683.
Scheijen and Griffin. Oncogene. 2002;21:3314.
SIGNALING
First Patient With GIST to Receive
Imatinib Mesylate: Proof-of-Concept
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•
Exploratory study with oral imatinib mesylate at 400 mg/d
Dramatic clinical response
– Disappearance of excess metabolic activity at
4 weeks by 18FDG-PET
– 75% reduction in tumor size at 8-month follow-up
– Tumor biopsies showed histologic evidence of myxoid
degeneration and lack of mitotic activity
– Symptomatic relief
Joensuu et al. N Engl J Med. 2001;344:1052.
Imatinib Induced Pathologic
Changes
CD 117
H&E
Demetri GD, et al. N Engl J Med. 2002;347:472-80
Key Studies in GIST
Metastatic Disease – B2222 Trial
Demetri GD, et al. N Engl J Med. 2002;347:472-80
Key Studies in GIST
Long Term F/U of B2222 Trial
Significant correlation
between tumor bulk and
OS (P=0.0043)
• Nine-year OS rate all patients was 35% (38% for patients with CR/PR;
49% for patients with SD)
• Nine-year OS by tumor bulk at baseline was: 58% in group 1, 40% in
group 2, 20% in group 3, and 23% in group 4
von Mehren et al. ASCO June 2011
Key Studies in GIST
Adjuvant Treatment Following Resection
ACOSOG Z-9001
• Completely resected GIST >3 cm
• Randomized to placebo vs. imatinib for 12 months
• Primary endpoint is recurrence free survival
Recurrence Free Survival
Overall Survival
DeMatteo RP et al. Lancet. 2009 Mar 28;373(9669):1097-104. Epub 2009 Mar 18.
Key Studies in GIST
Adjuvant Treatment Following Resection
DeMatteo RP et al. Lancet. 2009 Mar 28;373(9669):1097-104. Epub 2009 Mar 18.
Key Studies in GIST
Adjuvant Treatment Following Resection
SSGXVIII/AIO
• Completely resected High Risk GIST (>5 mitosis/50HPF)
• Randomized to 12 vs. 36 months of imatinib
• Primary endpoint is recurrence free survival
Recurrence Free Survival
Joensuu et al. Presented at ASCO June 2011
Overall Survival
Results of SSGXVIII/AIO: Subgroup Analysis
Subgroup
No. of patients
Age
≤65
>65
Sex
Male
Female
Tumor site
Stomach
Other
Tumor size
≤10 cm
>10 cm
Mitoses/50 HPF (local)
≤10 mitoses
>10 mitoses
Mitoses/50 HPF (central)
≤10 mitoses
>10 mitoses
Tumor rupture
No
Yes
Tumor mutation site
KIT exon 9
KIT exon 11
Wild type
Other
Hazard ratio (95% CI), RFS
36 mo better
P-value
12 mo better
256
141
0.47 (0.30–0.74)
0.49 (0.28–0.85)
0.001
0.01
201
196
0.46 (0.28–0.76)
0.46 (0.28–0.76)
0.002
0.002
202
195
0.42 (0.23–0.78)
0.47 (0.31–0.73)
0.005
<0.001
219
176
0.40 (0.23–0.69)
0.47 (0.29–0.76)
<0.001
0.002
209
154
0.76 (0.43–1.32)
0.29 (0.17–0.49)
0.33
<0.001
238
133
0.58 (0.34–0.99)
0.37 (0.23–0.61)
0.04
<0.001
318
79
0.43 (0.28–0.66)
0.47 (0.25–0.89)
<0.001
0.02
26
256
33
51
0.61 (0.22–1.68)
0.35 (0.22–0.56)
0.41 (0.11–1.51)
0.78 (0.22–2.78)
0.34
<0.001
0.16
0.70
0.1
Joensuu et al. Presented at ASCO June 2011
1.0
10
Lessons Post Imatinib Approval
Mutation Analysis
Event-free survival (%)
GIST: KIT and PDGFRA Mutations Predict Event-Free Survival
KIT exon 11 vs exon 9 (P<0.0001)
KIT exon 11 vs no mutation (P<0.0001)
KIT exon 9 vs no mutation (P=0.1428)
100
90
80
70
60
50
40
30
20
10
0
KIT exon 11 (n=85)
KIT exon 9 (n=23)
No kinase mutation
(n=9)
0
100
200
300
400
Days
Heinrich et al. J Clin Oncol. 2003;21:4342.
500
600
700
800
Lessons Post Imatinib Approval
Risk Stratification
Miettinen M, Lasota J Semin Diag Pathol 2006;23(2):70-83, NCCN Guidelines 2010 J Natl Compr Canc
Netw. 2010 Apr;8 Suppl 2:S1-41
Prediction Tools
http://www.mskcc.org/mskcc/html/98103.cfm
Gold et al. Lancet Oncol. 2009 Nov;10(11):1045-52.
The More We Learn About GIST The
More Questions We Generate
Questions
• What are the surgical goals for GIST?
• Can we stop or interrupt treatment?
• How long to treat – metastatic, adjuvant?
• What about imatinib resistance?
• What to do with incidental or micro GIST’s?
• Should we use imatinib in the neoadjuvant setting?
• If so, how long?
• Is surgery ever needed?
• Is there a role for debulking GIST?
• What to do with a margin positive (R1) resection?
• Is pediatric or familial GIST any different?
Surgical Goals for GIST
• Negative margins
• Avoid rupture
• Preserve function
• Nodes generally not necessary
(except in young patients)
How Long to Treat? Can Treatment be
Stopped or Interrupted?
• 56/147 patients initially enrolled in the B2222 study continued
imatinib treatment beyond 3 years, with some patients
remaining on treatment for 10yrs
• 26 patients (17.7%) have remained on continuous imatinib
• Risk of progression drastically decreased after 6 years of
imatinib therapy
Years after start of imatinib therapy
0–2
>2–4
>4–6
>6–8
>8–9
>9–10
No. of patients at riska
147
66
29
19
17
14
Progression/Censoredb
71/11
22/3
19/1
1/1
1/2
NA
Rate of progression
(Probability of event [%])
48.3
35.4
48.7
5.3
5.9
NA
Probability of progression according to duration of imatinib therapy (life-table method)
von Mehren et al. ASCO June 2011
Molecular Basis for Primary and Secondary
Tyrosine Kinase Inhibitor Resistance in GIST
• Secondary mutation induce conformational change altering the ATP binding site
• Type of secondary mutation may be important in overall survival
• May manifest as isolated clonal or polyclonal disease
Gounder MM , Maki RG. Cancer Chemother Pharmacol. 2011 Jan;67 Suppl 1:S25-43. Epub 2010 Nov 30.
Micro GIST’s
• The prevalence is much higher than the
clinical incidence
• Micro GIST’s smaller than 1 cm
• Found in up to 50% of autopsy series
• Many already have KIT mutation
• EUS surveillance 13% (3/23) progressed
• Potential for malignancy unknown
• Resect any >2cm (consensus)
Joensuu H , DeMatteo RP. Annu Rev Med. 2011 Jan 26. [Epub ahead of print], NCCN Guidelines 2010 J
Natl Compr Canc Netw. 2010 Apr;8 Suppl 2:S1-41
Neoadjuvant Therapy for GIST
Before
After
• Two phase II trials (19 and 30 patients)
• Suggest similar response rates
• Safe to give pre-op (no need to stop)
• Overall recurrence dictated by size
Is there a Role for GIST Tumor Debulking?
69 Patients underwent debulking
- pre-operatively determined to have:
• Stable disease (n=23) – bulky (>1cm) disease left in 4%
• Limited disease progression (n=32) – bulky disease in 16%
• Generalized disease progression (n=14) 50% emergent
indication – bulky disease left in 43%
Raut C, et al. J Clin Oncol 2006 May 20;24(15):2325-31.
Considerations for Debulking GIST
• Average duration of response ~ 2 years
• Surgical timing around 6 - 24 months
• Stable disease – all resectable?
• Limited disease progression – selected
resection
• Impending obstruction
• GI bleeding
• Paraneoplastic syndrome
Microscopic (R1) Positive Margin
Sites of First Recorded Recurrence by Margin Status
ACOSOG Z-9000 & Z-9001
• 72/819 Pts (8.8%) had R1 resection
• Median f/u 49 months
Recurrence
Local
Resection Margin
R0
R1
8 (4.4%)
4 (16.0%)
Regional
86 (47.5%)
13 (52.0%)
Distant
87 (48.1%)
8 (32.0%)
Chi Square 6.4, p=0.04
61% (placebo) to 65% (imatinib) of R1 resections did not experience a recurrence
85-95% of recurrences are regional or distant
McCarter et al, Western Surgical Association, Nov 2011
Microscopic (R1) Positive Margin
Recurrence free survival at 3 years
is 60% vs. 76% in the R1 vs. R0
group respectively. HR=1.51 (95%
CI: 0.76, 2.99) p=0.24
Recurrence free survival at 3 years
is 82% vs. 79% in the R1 vs. R0
group respectively. HR=1.095 (95%
CI: 0.66, 1.83) p=0.73
McCarter et al, Western Surgical Association, Nov 2011
Familial GIST
Joensuu H , DeMatteo RP. Annu Rev Med. 2011 Jan 26. [Epub ahead of print]
Familial GIST
Germline Mutation in KIT
• Mastocytosis
• Achalasia
• GIST
• 90% have GIST by age 70
• Hundreds of GIST in small intestine
• Low mitotic rate
• Indolent except for blockage and bleeding
Pediatric GIST
• Age <21
• Strong CD 117 staining
• Wild type – no identifiable mutation
• Can involve lymph nodes
• Higher recurrence rate
• Longer survival (more indolent course)
Cost of Imatinib
• Standard dose is 400mg QD
• 100mg tablet costs $20-30
• One year of imatinib ~ $64,000
What’s Next for GIST
• Serum imatinib concentration and response
• Improving prediction of micro GIST
• Targeting secondary mutations
• Patient initiated tumor banking
Gounder MM , Maki RG. Cancer Chemother Pharmacol. 2011 Jan;67 Suppl 1:S25-43. Epub 2010 Nov 30.