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Dal GIST al K-RAS OVVERO Dall’ E.E. al D.N.A. Come è cambiata e sta cambiando l’Anatomia Patologica Gallarate Aprile 20

Dal GIST al K-RAS OVVERO Dall’ E.E. al D.N.A. Come è cambiata e sta cambiando l’Anatomia Patologica Gallarate Aprile 2009. Imatinib mesylate (also called Gleevec® or STI571) is approved by the U.S. Food and Drug Administration (FDA) for the treatment

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Dal GIST al K-RAS OVVERO Dall’ E.E. al D.N.A. Come è cambiata e sta cambiando l’Anatomia Patologica Gallarate Aprile 20

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  1. Dal GIST al K-RAS OVVERO Dall’ E.E. al D.N.A. Come è cambiata e sta cambiando l’Anatomia Patologica Gallarate Aprile 2009

  2. Imatinib mesylate (also called Gleevec® or STI571) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of some forms of adult and pediatric chronic myelogenous leukemia (CML), and for the treatment of a rare form of cancer called gastrointestinal stromal tumor (GIST).

  3. STI571 Foto cd117

  4. GLEEVEC foto

  5. Foto cml

  6. Foto gist

  7. MIB1

  8. Alfa-actina

  9. Alfa-actina

  10. CD117

  11. 5% GastroIntestinal Stromal Tumors Acivating mutations in c-KIT and PDGFRA About 80-90% of patients show mutations * Antonescu RC, Clin Cancer Res 2005; 11: 4182-90

  12. GastroIntestinal Stromal Tumors Acivating mutations in c-KIT and PDGFRA About 75% of GISTs shows mutations on exon 11 and are related to Imatinib sensitivity (>80% clinical response) About 10%- 15% of GISTs shows mutations on exon 9 and have an aggressive clinical behaviour Fletcher JA and Rubin BP ; Current Opinion in Genetics & Development, 2007; 17: 3-7

  13. GastroIntestinal Stromal Tumors Imatinib or Sunitinib Resistance Mutations in exon 9 are generally associated to primary resistance Mutations in exon 13, 14 and 17 of c-KIT gene are subsequent to exon 11 mutations and are generally associated to acquired resistance Antonescu RC, Clin Cancer Res 2005; 11: 4182-90 Heinrich MC, J.Clin. Oncol. 2006; 24: 4764-74

  14. Mutazioni iniziali e secondarie Mutazioni iniziali Mutazioni secondarie Exon 11 Exon 13 Exon 17 Exon 9 GLEEVEC Resistenza primaria Resistenza secondaria Membrana cellulare CD117

  15. Dr. Lei Chen and others at M.D. Anderson Cancer Center in Houston have identified a secondary mutation that occurs in KIT kinase domain 1 (exon 13). This secondary mutation correlates with resistance to Gleevec. Among the 130 patients in the M.D. Anderson study, 12 who had an excellent initial response were chosen for further study. Seven of these patients originally had exon 11 mutations and five had exon 9 mutations. Five of these patients developed resistance in a total of six tumors. In each case, in addition to the original exon 11 or exon 9 mutation, a new secondary exon 13 mutation, Val654Ala, was identified. In each of these cases, the secondary mutation was identical and the resistant tumors now contained both the primary mutation (exon 11 or exon 9) and the new exon 13 mutation. In the seven patients who did not develop resistance no secondary mutations were found.

  16. Dalla diagnosi di LEIOMIOBLASTOMA a quella di GIST CD117 + Valutazione mutazioni esoni 9 1113 17 Parametri prognostici

  17. GIST is a rare form of cancer BUT LUNG ? COLON ?

  18. TAILOR AIFA TArceva Italian Lung Optimization tRial

  19. Lo studio deve valutare se i casi di K polmonare non mutati per EGFR siano responsivi al Tarceva dando per acquisito che i mutati lo siano • Siamo sicuri che tutti casi ( o almeno gli adenoK giovanili ) siano studiati per stato mutazionale di EGFR ? • Quanti fanno sistematicamente una valutazione dello stato mutazionale di EGFR nel K polmonare ed in quali casi ?

  20. La famiglia HER (erbB) ed i suoi ligandi EGF TGFa Amphiregulin b-cellulin HB-EGF Epiregulin NRG2 NRG3 Heregulins b-cellulin Heregulins Cysteine-rich domains 100 100 100 44 82 33 36 59 24 48 79 28 Tyrosine kinase domain C-terminus ErbB-1Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4

  21. Location of mutations in TK domain of EGFR gene del ELREA (E746-A750)

  22. Exon 19 del E745-A750 Exon 20 T790M Mechanisms of resistance to TK inhibitors

  23. PARLIAMO DI K COLON E DI K-RAS CANCRO COLON-RETTO 90 CASI x 105 ANNUI IN LOMBARDIA 8000 CASI ANNUI RICADUTA CIRCA 4000 Pz

  24. La famiglia HER (erbB) ed i suoi ligandi HERCEPTIN EGF TGFa Amphiregulin b-cellulin HB-EGF Epiregulin NRG2 NRG3 Heregulins b-cellulin CETUXIMAB Heregulins Cysteine-rich domains 100 100 100 44 82 33 36 59 24 48 79 28 Tyrosine kinase domain C-terminus ErbB-1Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4

  25. NESSUN RISULTATO ATTENDIBILE • DIFFICOLTA’ TECNICHE DI RECUPERO ANTIGENICO • NON RESPONSIVITA’ CASI POSITIVI ALLA IIC • RESPONSIVITA’ CASI NEGATIVI ALLA IIC

  26. Centr EGFR

  27. COLON NORMALE CARCINOMA -- POLISOMIA

  28. 2 green2 red 4 green4 red Perdita materiale nucleare 2 green2 red CELLULA NORMALE CELLULA TUMORALE

  29. CARCINOMA – AMPLIFICAZIONE

  30. CARCINOMA – AMPLIFICAZIONE

  31. APPROCCIO AUTOMATICO DI LETTURA

  32. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study M.Moroni, S.Veronese,S.Benvenuti, G.Marrapese,A. Sartore-Bianchi, F.Dinicolantonia,M.Gambacorta,S.Siena, A.Bardelli. Lancet Oncology 2005

  33. EGFR gene copy number analysis Disomy Polysomy Focal amplification > 40% polysomic cells with > 3 EGFR copies EGFR/CEP 7> 2,50 copies per cell

  34. PFS and OS according to the proposed cut off values Sartore-Bianchi A et al. J Clin Oncol 2007

  35. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with Cetuximab : A FISH study Personeni N. et Al Clin Cancer Res 2008 E’ in corso uno studio pluricentrico per standardizzazione tecnica e interpretazione risultati F.I.S.H. Her1 su sezioni

  36. SEQUENZA E G F R : ASSENZA DI MUTAZIONI ESONI 18 , 19 , 20 , 21

  37. TK signaling cascade

  38. Mutated KRAS is prevalent in many different tumor types Adapted from: Friday BB and Adjei AA. Biochim. Biophys. Acta. 2005; 1756:127-144

  39. G12S G12D WT ……GGA GCT GGT GGCGTA GGC …… Wild-type K-RAS Mutations G12D Gly12Asp GGT>GAT G12A Gly12Ala GGT>GCT G12V Gly12Val GGT>GTT G12S Gly12Ser GGT>AGT G12R Gly12Arg GGT>CGT G12C Gly12Cys GGT>TGT G13D Gly13Asp GGC>GAC

  40. 2008 ASCO Annual Meeting Gastrointestinal (Colorectal) Cancer KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFIRI with or without Cetuximab : the CRYSTAL experience Van Cutsem E et al; JCO 26; 2008 (May 20 Suppl; abstr 2) 540 archived tumor material WT Patients (64.4%) Progression Free survival (PFS) p=0.0167 Overall response (OS)p=0.0025 KRAS mutated Patients (35.6%) Progression Free survival (PFS) p=0.75 Overall response in (OS) p=0.46 Conclusion : KRAS mutation status has a predictive value for treatment with FOLFIRI + Cetuximab in the first-line treatment of mCRC

  41. 2008 ASCO Annual Meeting Gastrointestinal (Colorectal) Cancer KRAS status and efficacy of first-line treatment of patients with mCRC with FOLFOX with or without Cetuximab : the OPUS experience Bokemeyer C et al; JCO 26; 2008 (May 20 Suppl; abstr 4000) 233 tumor samples 99/233 (42.5%) KRAS mutated 134/233 (57.5%) KRAS WT PFS and overall Response Rate (RR) by KRAS mutation status Conclusions: The benefit from addiction of Cetuximab to standard treatment is higher for KRAS WT population.

  42. p =0.005 (Fisher's exact test) Time To Progression according KRas and BRaf mutational status Logistic regression Odds Ratio = 0.071 (CI95%=(0.008, 0.619); p=0.017)

  43. RAF RAF Constitutive activation of EGFR effectors MoAb RAS Protein kinase BRaf mutations

  44. MoAb pAkt PTEN inactivation or loss of expression (Phosphatase and Tensin homolog deleted on chromosome 10)

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