Oncology oncology diagnosis and management

Oncology

1. TERAPEUTIC CONSEQUENCES
FROM MOLECOLAR BIOLOGY FOR
GIST PATIENTS AFFECTED BY
NEUROFIBROMATOSIS 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

2. BACKGROUND
•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

3. QUESTIONS
•Should these patients enrolled in the ongoing
trials of imatinib?
•Should this decision taken on the basis of the
molecular analysis?

4. PATIENTS
28 PATIENTS OPERATED
•13 MALES
•15 FEMALES
•M:F=0,87:1
•Median age 57 (range 28-72)

5. DIAGNOSIS
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

6. DIAGNOSIS
GIST
•The diagnosis was confirmed histologically in terms
of morphology and immunophenotyping
•Seven tumors were reclassified as GIST after
pathologic review
•2MPNST
•1 Schwannoma, 1 Neurofibroma
•2 Leiomyosarcoma
•1 Leiomyoma
All tumors were sympthomatic except one

7. PRESENTATION
PRESENT 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%

8. SITE
PRESENT SERIES SPORADIC GIST
25%
14%
68%
Other: 11%
60%
30%
Other: 10%
7%

9. NUMBERS OF TUMORS
PRESENT SERIES SPORADIC GIST
MULTIPLE TUMORS
43 % Occasional

10. IMMUNOCHEMISTRY
PRESENT SERIES SPORADIC 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%

11. PATHOLOGY
PRESENT SERIES SPORADIC GIST
•Spindle cell 75%
•Epithelioid 15%
•Mixed 10%
•Skenoid fiber33%
•Associated Cajal
cell hyperplasia 21%
•Spindle cell 38-77%
•Epithelioid 8-38%
•Mixed 14-23%
•Skenoid fiber34%

12. MOLECULAR ANALYSIS
•c-KIT exons 9, 11,13,17
•PDGFRA exon 12, 14, 18
DNA extracted from paraffin embedded
microdissected sections was sequenced for:
25 PTS

13. MOLECULAR ANALYSIS
•exon 11(V560del)
•exon 9(A504_Y505)
•Exon 18(D842V)
PRIMARY MUTATIONS

14. MOLECULAR ANALYSIS
Exon 17 D820Nmutation in metastatic
lesions after gleevec therapy
SECONDARY MUTATION

15. MOLECULAR ANALYSIS
Series N°of Pts KIT mut PDGFRA mut NF1 mut
Kinoshita, 20047 None None 2/3 pts
Cheng, 2004 3 1 ex 11 None NS
Anderson, 200512 None None NS
Takazawa, 2005 9 2 ex 11, 1 ex 131 ex 12, 1 ex 18 NS
Yantiss, 20053 1 ex 11 None NS
Miettinen, 200615 None None NS
Maertens, 20063 2 polimorphisms5 silents 3/3 pts
Nemoto, 2006 1None None 1/1 pts
Guillaud, 20061 None None NS
Lee, 2006 1 None None NS
Steward, 2007 2None None 1/2 pts
Kang, 2007 5 None None NS
Present series 251 ex 11, 1 ex 91 ex 18 NS
________________________________________________________________
10KIT-PDGFRA Mutations/ 90patientsanalysed = 11, 1%

16. MOLECULAR ANALYSIS
SPORADIC GISTNF-1 ASSOCIATED GIST
•KIT Mutations7,8%
•Exon 115,6%
•Exon 91,1%
•Exon 131,1%
•Exon 17 0%
•PDGFRA Mutations 3,3%
•Exon 12 1,1%
•Exon 14 0%
•Exon 18 2,2%
•KIT Mutations 80%
•Exon 1167,5%
•Exon 9 11%
•Exon 130,9%
•Exon 170,5%
•PDGFRA Mutations 7,5%
•Exon 12 0,9%
•Exon 14 0,3%
•Exon 18 6,3%

17. CLINICAL 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

18. SURVIVAL
•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

19. IMATINIB THERAPY: resectable GIST
Pts Primary SettingTrialImatinib EFS Status
----------------------------------------------------------------------------------
1Localized postop.EORTC 400mg/d 11NED
62024
2Localized postop.SSGVIII/ 400mg/d 8 NED
AIO
3Syncronous postop. / 400mg/d 22NED
resectable
metastasis
4 Multiple postop. / 400mg/d 45NED
recurrent
tumors
5 Localized postop. EORTC Control 14 NED
62024 Arm

20. IMATINIB THERAPY: advanced GIST
Pts Site Risk Metastasis MolecularResp. 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 22DOD
peritoneal
4 Small H peritonealWT prim; PD 10 DOD
Bowel Secondary
ex 17
-----------------------------------------------------------------------------------
Median survival after imatinib onset 21 months

21. IMATINIB THERAPY: ex 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

22. IMATINIB THERAPY: neurofibrin
deficit is associated with high
levels of Kit expression

23. IMATINIB THERAPY: in vivo

24. IMATINIB THERAPY: in vivo

25. …IN 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

26. CONCLUSIONS
The molecular analysis is always raccomended
•to individuate sporadic mutation
•to clarify the prognostic meaning of mutations in
this subset of GIST

27. CONCLUSIONS
Further studies are necessary to clarify the
effecacy of IM and other inhibitors of tyrosine
kinases in this setting

28. CONCLUSIONS
•Localized wild type GIST should not be
elegible for adjuvant trials
•The molecular analysis should be done before
the enrollement

29. CONCLUSIONS
•Local advanced GIST enrolled in trials of
preoperative imatinib should be carefully
surveilled

30. CONCLUSIONS
•Metastatic GIST could benefit from
imatinib treatment
•Sunitinib could be the first alternative in
non responder tumors

31. CONCLUSIONS
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

32. THANKS!
…[email protected]