terapeutic consequences from molecolar biology for gist patients affected by neurofibromatosis type...
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TERAPEUTIC CONSEQUENCES TERAPEUTIC CONSEQUENCES FROM MOLECOLAR BIOLOGY FOR FROM MOLECOLAR BIOLOGY FOR
GIST PATIENTS AFFECTED BY GIST PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1NEUROFIBROMATOSIS TYPE 1
Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P
CTOS-Seattle, November 2007
supported by Conticanet
Mannheim University Hospital, Germany
Bonn University Hospital, Germany
Istituto Nazionale Tumori, Italy
BACKGROUNDBACKGROUND
• Patients affected by Neurofibromatosis type 1 have an
increased risk of GIST developing
• NF-1 associated GISTs seem to be wild type for
KIT/PDGFRA mutations
• This subset of GIST has likely a different oncogenic
molecular mechanism
• Lack of data on imatinib and other tyrosine kinases
inhibitors activity in this different setting
QUESTIONSQUESTIONS
• Should these patients enrolled in the ongoing
trials of imatinib?
• Should this decision taken on the basis of the
molecular analysis?
PATIENTSPATIENTS
28 PATIENTS OPERATED
• 13 MALES
• 15 FEMALES
• M:F=0,87:1
• Median age 57 (range 28-72)
DIAGNOSISDIAGNOSIS
NEUROFIBROMATOSIS TYPE 1
>2 following criteria:• > 6 cafe-au-lait macules (>5mm before puberty, >15 mm after)
• skin-fold freckles (groin, axilla, neck base)
• > neurofibromas (1 plexiform)
• skeletal dysplasia (orbital or tibial)
• Lisch nodules (>2 iris amartomas)
• optic glioma
• family history
DIAGNOSISDIAGNOSIS
GIST
• The diagnosis was confirmed histologically in terms
of morphology and immunophenotyping
• Seven tumors were reclassified as GIST after
pathologic review
• 2 MPNST
• 1 Schwannoma, 1 Neurofibroma
• 2 Leiomyosarcoma
• 1 Leiomyoma
All tumors were sympthomatic except one
PRESENTATIONPRESENTATIONPRESENT SERIES SPORADIC GIST
• Age 57 yrs (28-72)
• M:F=0,87:1
• LOCALIZED 82%
• METASTATIC 18%
• RISK STRATIFICATION
•High 30,5%
•Intermediate 39%
•Low/very low 30,5%
• Age 60 yrs (20-80)
• M:F=1,3:1
• LOCALIZED 50-85%
• METASTATIC 15-50%
• RISK STRATIFICATION
•High 23-35%
•Intermediate 20%
•Low/very low 45%
70%
SITESITEPRESENT SERIESPRESENT SERIES SPORADIC GISTSPORADIC GIST
25%14%
68%
Other: 11%
60%
30%
Other: 10%
7%
NUMBERS OF TUMORSNUMBERS OF TUMORS
PRESENT SERIES SPORADIC GIST
MULTIPLE TUMORSMULTIPLE TUMORS
43 % Occasional
IMMUNOCHEMISTRYIMMUNOCHEMISTRY
PRESENT SERIESPRESENT SERIES SPORADIC GISTSPORADIC GIST
• CD 117 pos 100%
• CD 34 pos 86%
• S-100 pos 19%
• Actine pos 24%
• PDGFRA pos 37,5%
• BCL-2 pos 43%
• CD 117 pos 95%
• CD 34 pos 70%
• S-100 pos 10%
• Actine pos 25%
• PDGFRA pos 70%
• BCL-2 pos 20-93%
PATHOLOGYPATHOLOGY
PRESENT SERIESPRESENT SERIES SPORADIC GISTSPORADIC GIST
• Spindle cell 75%
• Epithelioid 15%
• Mixed 10%
• Skenoid fiber 33%
• Associated Cajal
cell hyperplasia 21%
• Spindle cell 38-77%
• Epithelioid 8-38%
• Mixed 14-23%
• Skenoid fiber 34%
MOLECULAR ANALYSISMOLECULAR ANALYSIS
• c-KIT exons 9, 11,13,17
• PDGFRA exon 12, 14, 18
DNA extracted from paraffin embedded DNA extracted from paraffin embedded microdissected sections was sequenced for:microdissected sections was sequenced for:
25 PTS
MOLECULAR ANALYSISMOLECULAR ANALYSIS
• exon 11 (V560del)
• exon 9 (A504_Y505)
• Exon 18 (D842V)
PRIMARY MUTATIONSPRIMARY MUTATIONS
MOLECULAR ANALYSISMOLECULAR ANALYSIS
Exon 17 D820N mutation in metastatic
lesions after gleevec therapy
SECONDARY MUTATIONSECONDARY MUTATION
MOLECULAR ANALYSISMOLECULAR ANALYSIS Series N° of Pts KIT mut PDGFRA mut NF1 mut
Kinoshita, 2004 7 None None 2/3 pts Cheng, 2004 3 1 ex 11 None NS Anderson, 2005 12 None None NS Takazawa, 2005 9 2 ex 11, 1 ex 13 1 ex 12, 1 ex 18 NS Yantiss, 2005 3 1 ex 11 None NS Miettinen, 2006 15 None None NS Maertens, 2006 3 2 polimorphisms 5 silents 3/3 pts Nemoto, 2006 1 None None 1/1 pts Guillaud, 2006 1 None None NS Lee, 2006 1 None None NS Steward, 2007 2 None None 1/2 pts Kang, 2007 5 None None NS Present series 25 1 ex 11, 1 ex 9 1 ex 18 NS ________________________________________________________________
10 KIT-PDGFRA Mutations/ 90 patients analysed = 11, 1%
MOLECULAR ANALYSISMOLECULAR ANALYSISSPORADIC GISTNF-1 ASSOCIATED GIST
• KIT Mutations 7,8%
•Exon 11 5,6%
•Exon 9 1,1%
•Exon 13 1,1%
•Exon 17 0%
• PDGFRA Mutations 3,3%
•Exon 12 1,1%
•Exon 14 0%
•Exon 18 2,2%
• KIT Mutations 80%
•Exon 11 67,5%
•Exon 9 11%
•Exon 13 0,9%
•Exon 17 0,5%
• PDGFRA Mutations 7,5%
•Exon 12 0,9%
•Exon 14 0,3%
•Exon 18 6,3%
CLINICAL OUTCOMECLINICAL OUTCOME
• Prospective periodical assessment
• Five patients had other maligniancies
(2 gastrointestinal carcinoid; 1 cutaneous basalioma; 1 brain meningioma; 2 uterus carcinoma; 1 adrenal pheocromocytoma; 1 breast cancer)
• 8 patients develloped local recurrence or metastasis
• Six patients died of disease
SURVIVALSURVIVAL
• 5-year EFS 46,9% (median 48 months)
• 5-year DSS 54,3% (median NR)
Post-event median survival 34 months
Multiple tumors had a better outcome
IMATINIB THERAPY: resectable GISTIMATINIB THERAPY: resectable GISTPts Primary Setting Trial Imatinib EFS Status
----------------------------------------------------------------------------------1 Localized postop. EORTC 400mg/d 11 NED
62024
2 Localized postop. SSGVIII/ 400mg/d 8 NED
AIO
3 Syncronous postop. / 400mg/d 22 NED resectable metastasis
4 Multiple postop. / 400mg/d 45 NED recurrent tumors
5 Localized postop. EORTC Control 14 NED 62024 Arm
IMATINIB THERAPY: advanced GISTIMATINIB THERAPY: advanced GIST
Pts Site Risk Metastasis Molecular Resp. Post IM Status (prim.) analysis Surv
(EORTC 62005 trial)
-----------------------------------------------------------------------------------
1 ExGI H liver, WT PD 22 DOD peritoneal
2 Small H liver, WT PD 19 DOD Bowel peritoneal
3 Stomach I liver, EX 18 SD 22 DOD peritoneal
4 Small H peritoneal WT prim; PD 10 DOD Bowel Secondary
ex 17-----------------------------------------------------------------------------------Median survival after imatinib onset 21 months
IMATINIB THERAPY: IMATINIB THERAPY: ex vivoex vivo
• Kit phosporylation is stem cell factor dependent
• The MAPK pathway is more active then in sporadic GIST
• JAK-STAT 3 and P13K-AKT are less active then in sporadic GIST
• The MAPK phosporylation cannot be complete shut down by imatinb and the effect is not dose dependent
IMATINIB THERAPY: IMATINIB THERAPY: neurofibrin neurofibrin deficit is associated with high deficit is associated with high
levels of levels of Kit expressionKit expression
IMATINIB THERAPY: IMATINIB THERAPY: in vivoin vivo
IMATINIB THERAPY: IMATINIB THERAPY: in vivoin vivo
……IN BRIEFIN BRIEF
• The incidence of GIST in NF-1 is unknown, but
symptomatic tumors are often high or intermediate
risk (70%)
• Most tumors are wild type for KIT/PDGFRA
mutations (89%)
• The oncogenic mechanism causing the MAPK
pathway activation and KIT overexpression is related
to the neurofibrin deficit
CONCLUSIONSCONCLUSIONS
The molecular analysis is always raccomended
• to individuate sporadic mutation
• to clarify the prognostic meaning of mutations in
this subset of GIST
CONCLUSIONSCONCLUSIONS
Further studies are necessary to clarify the
effecacy of IM and other inhibitors of tyrosine
kinases in this setting
CONCLUSIONSCONCLUSIONS
• Localized wild type GIST should not be
elegible for adjuvant trials
• The molecular analysis should be done before
the enrollement
CONCLUSIONSCONCLUSIONS
• Local advanced GIST enrolled in trials of
preoperative imatinib should be carefully
surveilled
CONCLUSIONSCONCLUSIONS
• Metastatic GIST could benefit from
imatinib treatment
• Sunitinib could be the first alternative in
non responder tumors
CONCLUSIONSCONCLUSIONS
The future treatent of this subset of
GIST is likely dependent from further
investigations of the molecular pathways
activated by neurofibrin as new
molecular targets
THANKS!THANKS!