GIST治疗最新进展：伊马替尼治疗失败后的治疗策略PPT.ppt

The Southwest Oncology Group’s previous experience with metastatic GIST patients treated with chemotherapy gives us a reference two- year survival estimate of just 26%. Speaker points: Almost all GISTs, have constitutively activated RTKs 80–85% of GISTs have activating mutations in KIT and 7% of GISTs have mutations in PDGFR-? Imatinib inhibits KIT, PDGFR-?, and other RTKs; it was evaluated in metastatic GIST However, resistant tumors develop secondary mutations in KIT or PDGFR Mechanisms of imatinib resistance in GIST were studied by Fletcher and colleagues (Fletcher et al, Proc Am Soc Clin Oncol, 2003) Mechanisms were heterogeneous While many patients initially benefit from imatinib therapy, the majority develop secondary resistance, typically after 1 year of therapy In a phase II study, 50% of patients benefited (Demetri et al, N Engl J Med, 2002) Also, up to 20% of GIST patients exhibit primary resistance to imatinib (Sawaki, Cancer Chemother Pharmacol, 2004); they fail to respond or are unable to tolerate imatinib Despite imatinib therapy, a large unmet need exists in GIST Over 80% of GIST have KIT gene mutations. Exon 11: Mutations in the intracellular juxtamembrane region occur in mast cell tumors and GIST. Comprise ~70% of all mutations in GIST Are generally point mutations (missense), in-frame deletions, or duplications Are associated with constitutive ligand-independent receptor dimerization and activation of the kinase domain (gain-of-function mutations) Occur more frequently in high-risk GIST than in intermediate-risk GIST (and are rarely or never found in leiomyomas or leiomyosarcomas) Predict a poor prognosis: 49% 5-year patient survival rate vs 86% 5-year survival rate of patients with non–exon 11 mutations Exon 9: Mutations in the extracellular juxtamembrane region involve a similar activation mechanism. Exon 13: Mutations in the split tyrosine kinase domain also occur in GIST. Other KIT mutations have been identified in other diseases. Exon 17: