Transcript Hematology/Oncology Grand Rounds

Gastrointestinal Stromal
Tumors
Sheng-wei Ye , M.D.
Department of abdominal surgery, Yunnan
tumor hospital
June 13, 2006
Case Report
74 yo woman presented with lower
abdominal pain for 6 months
 She developed a fever and leukocytosis,
but no wt. loss, night sweats
 Colonoscopy 6 wks prior to admission
showed diverticular disease, no other
abnormality.
 CT ABD / PEL: 9x8 cm solid mass in
pelvis

Case Report

Exploratory laparotomy revealed a 8x7x6
cm solid mass arising from the wall of the
small bowel, plus an intra-abdominal
abcess. The mass was completely
resected.
Case Report…

Path: spindle cell morphology,
IHC: CD34+ actin+ c-kit+
 “increased mitotic figures” – high grade
 gastrointestinal stromal tumor (GIST)

Her post-operative course was
complicated with DVT and PE
 CT at 3 months post-op showed no
evidence of tumor, and she was doing well

GastroIntestinal Stromal Tumors
(GIST)

Definition
Rare soft tissue tumor of the GI tract,
mesentery, and omentum
 Histologic subtypes include spindle, epitheliod,
mixed
 Express CD34, Actin, and recently recognized
as almost uniformly c-KIT+


Normal Counterpart

Interstitial cells of Cajal (ICC), a cell bridging
smooth muscle and neuronal tissues of the
autonomic system (similar
phenotype)
Rossi et al. Int. J. Cancer 107:171, 2003
Joensuu et al Lancet Oncol 3:655, 2002
Epidemiology





0.1-3% of all GI cancers
Incidence 1-2/100,000 based on historical data
(difficult to interpret due to changing diagnostic
criteria in the past)
Estimates now of 5000-6000/new cases per year
in US with updated diagnostic criteria
Tends to occur in middle aged persons with a
slight male predilection
Occur throughout the GI tract
Site of primary tumor
Stomach (50-70%),
 small intestine (20-30%)
 colorectal (10-20%)
 Esophagus 5%
 Other – e.g. mesentery, omentum (rare)

Clinical Presentation
Symptoms depend on the site and size of
the tumor
 Include:

Abdominal pain
 Dysphagia
 Gastrointestinal bleeding
 Symptoms of bowel obstruction
 Small tumors may be asymptomatic


Primary tumor only (46%), Metastatic
disease (47%)
Rossi et al. Int. J. Cancer 107:171, 2003
Joensuu et al Lancet Oncol 3:655, 2002
Diagnosis
Clinical Presentation
 Light microscopy in conjunction with
Immuno-histochemistry

Immunohistochemistry
Positive staining for CD117, a cell surface
antigen on the extracellular domain of the KIT
receptor
 Positivity alone without a typical morphological
appearance may be a false positive
 < 2% of tumors are negative for CD 117
 Such tumors are labeled “Stromal cell neoplasm
most consistent with GIST”
 60-70% of tumors are also positive for
CD 34

Before Treatment
Imatinib x 4 weeks
KIT IHC
H&E
Demetri et al NEJM 347:472, 2002
Benign Vs Malignant

Features favoring benign lesions in general like:








Size less than 5 cm
Low number of mitosis per HPF
No mucosal invasion
Low cellularity
Low markers of cell proliferation
The above have shown to be associated with malignant
behavior in some but not in other studies.
With prolonged follow up any GIST has the potential to
behave in a malignant fashion.
50% of primary localized tumors that are resected
relapse after 5 years of follow up.
Malignant Versus Benign
Size
Mitotic count
Very Low risk
<2 cm
<5/50 HPF
Low risk
2-5 cm
<5/50 HPF
Intermediate
risk
<5 cm
5-10 cm
 >5 cm
>10 cm
Any size
6-10/50 HPF
<5/50 HPF
>5/50 HPF
 Any count
>10/50 HPF
High risk
Human pathology, Vol 33, May 2002
Prognostic Factors

No uniform prognostic guidelines, poor Px
associated with
increasing tumor size
 metastatic disease at presentation
 high grade (high mitotic index)

Primary Treatment = Surgery
~67% primary tumors resectable,
 However, 40-90% recur (most often: intraabdominal, liver)

GIST: Pre-Imatinib Outcomes

All GIST



Single primary tumor completely resected



5 year survival 50-65%
Medial survival 66 months
Metastatic disease or recurrent disease


5 year survival 28-43%
Median survival 19 months
Median survival 9-12 months
Chemotherapy? – not effective



Phase III trial of doxorubicin + dacarbazine (n=118)
RR 17% with CR (5%) and PR/SD (12%)
Duration of response with PR/SD 6mo, CR 19mo

Zalupski et al. JNCI 83:926, 1991
Rossi et al. Int. J. Cancer 107:171, 2003
DeMatteo et al. Ann. Surg. 231:51, 2000
Disease specific survival and tumor
size
Ann Surg 231:51-57, 2000
History of GIST?



Until the late1960’s stromal tumors arising in the GI tract
were referred to as smooth muscle neoplasms of the
gastrointestinal tract.
Immuno-histochemistry in the 1980’s demonstrated that
some of these tumors lacked features of smooth muscle
differentiation, some had markers of neuronal
differentiation and some had neither of the above
markers.
This led to Mazur and clark to coin the general term
“Gastrointestinal stromal tumors” to collectively refer a
group of mesenchymal tumors of neurogenic or
myogenic differentiation.
History of GIST
In the 1990’s it was shown that a
significant proportion (60-70%)of tumors
showed CD 34 immunopositivity
 But schwann cell and true smooth muscle
cell neoplasms were also positive
 Lots of confusion prevailed until late
1990,s…

Discovery of Kit




In 1986 a new acute transforming feline
retrovirus, the Hardy-Zuckerman 4 feline
sarcoma virus (HZ4-FeSV) was isolated from a
feline fibrosarcoma.
The viral genome of HZ4-FeSV contained a new
oncogene that was designated v-kit
C-kit is the cellular homologue of the oncogene
v-kit
It encodes a transmembrane tyrosine kinase
receptor called kit.
Nature 1988 Sep 1;335(6185):88-9
What is Kit?





Kit is a 145-KD glycoprotein
The kit receptor can be detected by immunohistochemical staining for CD117
CD117 is an epitope on the extra-cellular domain of the
Kit receptor
Steel factor (SLF), also known as stem-cell factor, is the
ligand for Kit
Binding of SLF to Kit results in receptor homodimerization, activation of KIT tyrosine kinase activity,
and resultant phosphorylation of a variety of substrates
that serve as effectors of intracellular signal transduction.
Kit
Human pathology, Vol 33, May 2002
Kit and relationship to GIST




SCF-KIT interaction has been shown to be
essential for development of melanocytes,
erythrocytes, germ cells, mast cells and ICCs
Mice with mutations involving kit have cellular
defects in hematopoiesis, melanogenesis and
gametogenesis and also lack the network of
interstitial cells of Cajal.
In 1995 it was shown that the interstitial cells of
Cajal express the Kit receptor
Nature 1995 Jan 26;373(6512):347-9
Kit and relationship to GIST







Hirota et al investigated the mutational status of c-kit in
mesenchymal tumors of the GI tract.
They examined 49 mesenchymal tumors that were
diagnosed as gastrointestinal stromal tumors
94% (46/49) of these expressed KIT.
82% (40/49) were CD34-positive
78% (38/49) were positive for both KIT and CD34
Also demonstrated that ICC were positive for kit and CD
34.
They also demonstrated that mutations of c-kit resulted
in gain of function of the enzymatic activity of the KIT
tyrosine kinase
Kit and GIST


Mutations of several different exons of the c-kit
gene (exon 11 and rarely, exons 9 and 13 )can
cause constitutive activation of the tyrosine
kinase function of c-kit.
These mutations result in:




Auto-phosphorylation of c-kit
Ligand-independent tyrosine kinase activity
Uncontrolled cell proliferation
Stimulation of downstream signaling pathways
KIT Tyrosine Kinase is
Constitutively Phosphorylated and
Mutated in GIST

KIT over-expressed in GIST (>90%) by
IHC


Sarloma-Rikala et al. Mod Pathol 11:728,
1998
Gain-of-function mutations in c-kit are
present in GIST
Hirota et al. Science 279:577,1998
 Rubin Cancer Res 61:8118, 2001

Hirota et al. Science 279:577,1998
KIT mutations in GIST
JM region in e11
Hirota et al. Science 279:577,1998
KIT or KITD
+
mIL3R
KIT-plasmid
BAF/3
GIST mutations
mIL3R
BAF/3 +
KIT or KITD
GIST mutations
WT KIT
BAF/3
WT KIT
BAF/3
Hirota et al. Science 279:577,1998
BAF/3 Expressing KIT with GIST
Mutations Grow Autonomously in Mice
GIST mutations
WT KIT
BAF/3
Hirota et al. Science 279:577,1998
48 GIST evaluated
 ALL had constitutively phosphorylated KIT
 92% (44) had KIT mutations
 Insertions, deletions, in frame mutations of
exons 9, 11, 13, 17
 No correlation with traditional markers of
malignancy or prognosis

Rubin Cancer Res 61:8118, 2001
Mutated Tyrosine Kinases in GIST:
PDGFRa




Subset of GIST
tumors without KIT
mutations (KIT-WT)
PDGFRa was
constitutively P-lated
in KIT-WT GIST
~30% of KIT-WT
GIST had PDGFRa
mutations
No GIST had both
KIT and PDGFRa
mutations
Heinrich et al Science 299:708, 2003
Mutations in KIT and PDGFR in GIST
KIT
PDGFRa
(~92% of GIST)
(~30% of KIT-WT)
Ligand
Binding
Ligand
Binding
Dimerization
e9
Dimerization
13%
e11 71%
Juxtamembrane
e13
TK1, ATP Binding
TK1, ATP Binding
Kinase Insert
Kinase Insert
TK2, P-transferase
e17
4%
4%
TK2, P-transferase
e12 28%
e18 71%
Juxtamembrane
Mutations: constitutive activation
Rubin Cancer Res 61:8118, 2001
Hirota et al. Science 279:577,1998
MAPK, PI3K, STAT5,
Jak2, Ras
Heinrich et al Science 299:708, 2003
Imatinib Mesylate is a small
molecular inhibitor designed
against BCR-ABL, but also
cross-reacts to inhibit KIT and
PDGFRa
Imatinib Mechanism
BCR-ABL or KIT or PDGFRa
BCR-ABL or KIT or PDGFRa
Signals for growth, survival
Adapted from Imatinib / CML Prescribing Guidelines, Novartis
Preclinical experiments



A C-kit expressing human myeloid leukemia cell
line, M-07e,was treated with STI 571 before
stimulation with Steel factor (SLF) and STI 571
inhibited c-kit autophosphorylation.
The activity of STI 571 in a human mast cell
leukemia cell line (HMC-1), which had an
activated mutant form of C-kit was tested. STI
571 had a more potent inhibitory effect on the
kinase activity of this mutant receptor than it did
on ligand-dependent activation of the wild-type
receptor.
Heinrich Blood, Vol. 96 No. 3 (August 1), 2000: pp. 925-932
Preclinical experiments




A human GIST cell line, (GIST882) which
expressed an activating KIT mutation (K642E)
leading to constitutive tyrosine phosphorylation
was tested
Tyrosine phosphorylation was rapidly and
completely abolished after incubating the cells
with Imatinib.
GIST882 cells evidenced decreased proliferation
and the onset of apoptotic cell death after
prolonged incubation with Imatinib
Oncogene 2001;20:5054-5058
First patient to be treated with
Imatinib







54 year old female with metastatic GIST diagnosed in 1996
Liver metastases and multiple small intra-abdominal metastases
were excised in February 1998 and in September 1998
Seven cycles of chemotherapy with doxorubicin, ifosfamide, and
dacarbazine with no response
In March 1999 had bowel obstruction and on laparotomy had diffuse
intraabdominal mets.
Received thalidomide and interferon with no response
Treatment with 400 mg Imatinib once daily was started in March
2000.
N. Engl. J. Med., 344: 1052-1056, 2001
Imatinib in GIST
Demetri et al NEJM 347:472, 2002
Imatinib Mesylate in GIST


Open-label, randomized, Phase II (scaled up Ph I), multicenter trial
147 patients with advanced GIST (unresectable or metastatic)



Prior therapy included surgery (98%), chemotherapy (51%), XRT (15%)
CD117 (KIT) positive tumors (did not look at mutation status)
Randomized to 400 mg or 600 mg qD of Imatinib
Randomize
400 mg Daily
CR, PR, SD
PD
Continue 400 mg
600 mg Daily
CR, PR, SD
PD
600 mg Daily
Stop
Therapy
Demetri et al NEJM 347:472, 2002
Imatinib Mesylate in GIST
Demetri et al NEJM 347:472, 2002
Imatinib Mesylate in GIST
(Progression free survival)
Historical Comparison:
Median survival 9-12 months!
Demetri et al NEJM 347:472, 2002
Presentation
4 weeks
16 weeks
Demetri et al NEJM 347:472, 2002
Before Treatment
Imatinib x 4 weeks
KIT IHC
H&E
Demetri et al NEJM 347:472, 2002
…Case Report

She did well for 9 months, but then
developed recurrent abdominal pain…
Case Report



CT-biopsy of mass showed recurrent GIST
Pt. treated with neo-adjuvant Imatinib 600 mg qD
Stable disease, with mass decreasing from 10x10
cm to 8x7cm
Case Report
Stable disease with PET signal ablation
after 3 months of neo-adjuvant Imatinib
 Underwent her 2nd resection
 Continued on adjuvant Imatinib
 After 2-3 months, developed progressive
edema and anasarca (grade 3) due to
Imatinib
 Drug held, then later restarted at a lower
dose, pt. continues to do well on 200mg
qD

Is an Identified KIT or PDGFRa
Mutation Requisite to treat GIST
with Imatinib?

Imatinib is now a labeled treatment for GIST

Studies have correlated response to Imatinib to the
presence of KIT mutations, however, not absolute

What about the minority of GIST tumors that do not have
KIT or PDGFRa mutations? Should they be offered
Imatinib?
Journal of Clinical Investigation 114:379, 2004
New Trick for Imatinib? : GISTs Lacking
KIT/PDGFR mutations respond to Imatinib (!?!)
Pt
Age
Site (# tumors)
Response
Duration
(months)
1
50
Liver, Stomach
CR
26
2
60
Liver
PR
24
3
48
Lungs
CR
26
4
25
Liver (3)
SD
17
5
67
Liver (4)
SD (3) PR (1)
7
6
18
Stomach
SD
15

Tested and Negative for all known mutations of
KIT (e9, 11, 13, 17) and PDGFRa (e12, 14, 18)
J Clin Invest 114:379, 2004: Extracted from Supplemental Table 1
If Imatinib is not acting to inhibit
a specific KIT or PDGFRa gainof-function mutation, how is it
working?
Direct or Indirect Mechanism ?
Indirect Innate Immune Mechanism
of Action of Imatinib
Imatinib
?
X
KIT
NK
DC
KILL
GIST
IFNg
Imatinib boosts NK Cell Activation
In Patients with GIST
Co-culture of pt.
BM-derived DC
and NK
 IFNg Measured
in Supernatant
 Lines show
data from serial
pt. samples

J Clin Invest 114:379, 2004
NK Cell Activation is Associated with
Prolonged Progression Free Survival in
GIST Patients Receiving Imatinib
N=22
(After 2 months of
Imatinib Therapy)
N=21
J Clin Invest 114:379, 2004
Lichenoid Dermatitis in Pt. on
Imatinib: DC / NK Mediated?
mDC
NK
J Clin Invest 114:379, 2004
What Other Scenarios Could this
Innate Immune Effect be Utilized?

Any pt treated with Imatinib (e.g. CML, GIST,
etc…)



Are other malignancies that may be NK cell
sensitive candidates for Imatinib trial?


Treatment failure – an association with lack of innate
immune effect?
Does long term response correlate with innate
immune activation?
Malignant melanoma, renal cell carcinoma
Myeloid leukemia after mismatched allogeneic
SCT?

Therapy during allogeneic SCT to boost innate
immune recognition of leukemia?
An Open Mind About Targeted
Therapies
Targeted therapies are by definition
engineered to mediate a desired effect
 As always, it is impossible to predict and
control all of the biologic effects of a
molecule in living organisms
 We must be open minded about
unexpected biological effects of future
targeted therapy
