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Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P

CTOS-Seattle, November 2007. TERAPEUTIC CONSEQUENCES FROM MOLECOLAR BIOLOGY FOR GIST PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1. Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P. Mannheim University Hospital, Germany Bonn University Hospital, Germany

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Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P

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  1. CTOS-Seattle, November 2007 TERAPEUTIC CONSEQUENCES FROM MOLECOLAR BIOLOGY FOR GIST PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1 Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P Mannheim University Hospital, Germany Bonn University Hospital, Germany Istituto Nazionale Tumori, Italy supported by Conticanet

  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 All tumors were sympthomatic except one • 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

  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 60% 14% 25% 7% 68% 30% Other: 11% Other: 10%

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

  10. IMMUNOCHEMISTRY PRESENT SERIES SPORADIC GIST • CD 117 pos 95% • CD 34 pos 70% • S-100 pos 10% • Actine pos 25% • PDGFRA pos 70% • BCL-2 pos 20-93% • CD 117 pos 100% • CD 34 pos 86% • S-100 pos 19% • Actine pos 24% • PDGFRA pos 37,5% • BCL-2 pos 43%

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

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

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

  15. MOLECULAR 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/ 90patients analysed = 11, 1%

  16. MOLECULAR ANALYSIS NF-1 ASSOCIATED GIST SPORADIC 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%

  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 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

  20. IMATINIB 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

  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! ….chiara.mussi@chir.ma.uni-heidelberg.de

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