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Gastrointestinal Stromal Tumor GIST New Therapeutic Approaches

Gastrointestinal Stromal Tumor GIST New Therapeutic Approaches. Prof. Mohamed Abdulla A. Professor of Clinical Oncology Kasr El-Aini School of Medicine Cairo University. IMC – Cairo – October 30 th , 2007. GIST: Definition. Mesenchymal (connective tissue) neoplasms

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Gastrointestinal Stromal Tumor GIST New Therapeutic Approaches

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  1. Gastrointestinal Stromal TumorGISTNew Therapeutic Approaches Prof. Mohamed Abdulla A. Professor of Clinical Oncology Kasr El-Aini School of Medicine Cairo University. IMC – Cairo – October 30th, 2007

  2. GIST: Definition • Mesenchymal (connective tissue) neoplasms • Located primarily in the GI tract, omentum, and mesentery • 0.2% of all GI tumors • 80% of GI sarcomas • Usually stain positive for KIT

  3. GIST: Epidemiology • An estimated 10-20 cases per million of GIST are diagnosed in the United States each year • 5000-6000 cases per year are diagnosed in the United States2 • Incidence in the Netherlands3 and Sweden: 12.7-14.5 cases per million • Highest incidence among group aged 50-65 years • Similar male/female incidence, although some reports suggest higher incidence in men

  4. GIST: Pathogenesis • Gene mutation key event in malignant transformation in most cases1,2 • KIT: 80%-85% • PDGFRA: 5%-7% • Wild Type: 12% • Mutation results in expression of abnormal, constitutively activated receptor tyrosine kinase activity

  5. Extracellular domain (exon 9) Transmembrane domain Juxtamembrane domain (exon 11) ATP Tyrosine kinase domain (exon 13/14) Kinase insert Tyrosine kinase domain II (exon 17) ProliferationSurvivalAdhesionInvasionMetastasisAngiogenesis = Mutation site = Imatinib contact point GIST: Pathogenesis (Continued) In GIST where mutant KIT is expressed, ATP-dependent signal transduction occurs in the absence of SCF1-3

  6. Histopathology Spindle cell Epithelioid cell Mixed morphology • At diagnosis, GIST generally is 2-30 cm1 • GIST can be classified into 3 broad categories2 • Spindle-cell type (70%) • Epithelioid-cell type (20%) • Mixed spindle-cell and epithelioid-cell type (nested morphology) (10%)

  7. Historical Classification of GISTs as Other Soft-Tissue Sarcomas A retrospective Swedish study determined that 60% of GI tumors now identified as GIST originally were classified as other tumors Other 7% GIST Leiomyoblastoma 13% 28% 18% 34% Leiomyosarcoma Leiomyoma N = 600 Nilsson B et al. Cancer. 2005;103:821-829.

  8. Spectrum of staining for KIT (CD117) in GIST Immunohistochemistry: CD117 Positivity Is a Reliable Marker of GIST • Approximately 95% of GISTs stain positive for CD117 (KIT)1 • Of those that do not, about 1/3 harbor a mutation in PDGFRA2

  9. Variable Pattern of KIT (CD117) Staining in GIST

  10. Differential Diagnosis of KIT-Undetectable Tumors Suspected to be GIST • KIT (CD117)is not detected in ~5% of GIST • Immunohistology for other protein markers or genetic analysis for KIT and PDGFRA may support a GIST diagnosis • Suspected GISTs without evidence of KIT (CD117) expression should be referred to an experienced GIST pathologist

  11. Emerging Marker: PKCθ • 85%-100% of GISTs stain positive for PKCθ • Other similar mesenchymal neoplasias do not stain positive for PKCθ3 KIT PKCθ GIST×10

  12. GIST: Risk Assessment • Accurate assessment of risk of aggressive malignant behavior in GIST poses a challenge • Morphologic features most predictive of outcome • Mitotic rate • Tumor size • Mutational status is useful in predicting treatment response and risk of progression

  13. Risk of Aggressive Tumor Behavior All GISTs should be considered to have potential for malignant behavior1,2

  14. Overall Survival by Risk Group GIST Risk Groups 1.0 0.9 0.8 0.7 Normal population 0.6 Very low Estimated Proportion Surviving 0.5 Intermediate Low 0.4 High 0.3 Overtly malignant 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years Since Diagnosis Nilsson B et al. Cancer. 2005;103:821-829.  2005 American Cancer Society.

  15. Autopsy 10% Incidental 21% 69% Symptomatic Circumstances of GIST Detection Approximately 1/3 of GISTs are asymptomatic

  16. Common Tumor Sites GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum Other (rectum, esophagus, mesentery, retroperitoneum) Colon 10% 15% Small intestine Stomach 25% 50%

  17. Clinical Presentation Symptoms of GIST at Diagnosis • Most patients present with nausea, vomiting, pain, weight loss, palpable tumor masses, and bleeding leading to anemia2 • Average duration of presenting symptoms is 4-6 months2

  18. Chemotherapy, Radiation, and Surgery in GIST Surgery • Principal treatment for resectable primary GIST Radiation • Results in injury to adjacent organs • Tumors exhibit radioresistance • Possible therapeutic role in rectal tumors Chemotherapy • Ineffective in sarcomas • Response limited: ~5% • Survival: no impact

  19. 1.0 0.8 0.6 Leiomyosarcoma Proportion Surviving 0.4 GIST 0.2 P < 0.05 0 0 12 24 36 48 60 Months After Diagnosis Poor Historical Survival Rates During thePre-Imatinib Era

  20. Surgery Treatment of choice for localized primary resectable GIST GIST: Current Treatment Options Imatinib • First-line treatment of malignant unresectable or metastatic GIST1,2

  21. Goal of Surgery Complete gross resection of tumor with pseudocapsule intact Risks Rupture of tumor increases risk of • Bleeding • Dissemination Warnings Segmental resection of stomach or intestine • Margins should be clear • No benefit in wide margins Inspect abdomen for metastases • Peritoneal surfaces • Liver Surgery for Primary Tumors GIST often canbe lifted from surrounding organs

  22. Survival Following Surgical Treatment of Primary GIST Adapted with permission from DeMatteo RP et al. Ann Surg. 2000;231:51-58.

  23. GIST Recurrence After Surgery • Recurrence of GIST following surgery is common • Majority of high-risk patients experience recurrence • Median time to recurrence is 2 years • Only 10% of patients remain disease-free after extended follow-up • 5-year survival rates are ~30%-60% • Investigational protocols are under way, with the goal of reducing the rate of recurrence after resection • Recurrent disease should be treated as metastatic disease

  24. 1.0 3 mitoses/30 HPF 1.0 <5 cm 0.75 >3 to 15 mitoses/30 HPF 0.75 5-10 cm 0.50 RFS 0.50 RFS >10 cm 0.25 0.25 >15 mitoses/30 HPF P = 0.0001 P = 0.03 0 0 0 20 40 60 80 0 20 40 60 80 Months Months Primary GIST:Risk Factors for Recurrence After Surgery Rates of RFS were predicted by mitotic index and tumor size

  25. Surgery for Recurrent or Metastatic GIST • Recurrent GIST should be treated as metastatic disease • Imatinib indicated as first-line treatment in both instances • Potential role for surgery after maximum response to imatinib mesylate • Resection of imatinib mesylate–resistant clones (under investigation) • Surgery for liver metastases • Often unsuitable for multifocal disease in liver • Consider RFA or hepatic artery embolization • Complementary use of surgery may benefit patients whose disease is stable on imatinib therapy

  26. First-Line Treatment of Unresectable or Metastatic GIST Imatinib Indicated for the treatment of adult patients with KIT- (CD117-) positive unresectable or metastatic malignant GIST

  27. Studies of Imatinib Therapy in GIST

  28. Phase 3 Trials: Overview

  29. Phase 3 EORTC 62005 Study: PFS (Primary End Point)

  30. Best Overall Response (ITT analysis) EORTC 62005 Study (N = 461) US Intergroup S0033 Study (N = 462) 48 45 45 45 32 32 Patients, % 27 26 26 25 13 9 6 5 3 3 Imatinib 400 mg/d Imatinib 800 mg/d Response Rates of Phase 3 Studies:EORTC 62005 and US Intergroup S0033 Study

  31. 400 mg Intergroup S0033 800 mg 400 mg EORTC 62005 800 mg US Intergroup S0033 and EORTC 62005 Studies: Similar PFS Regardless of Dose Administered 100 90 80 70 60 50 40 30 Overall Logrank test: Intergroup S0033 P = 0.026 EORTC 62005 P = 0.13 20 10 0 0 6 12 18 24 30 36 Months

  32. 62005 Trial1 S0033 Trial2 60 70 48 59.4 50 60 50 40 32 40 Patients, % 30 27.1 30 20 13 20 6 2.3 10 10 0 0 0 0 AI CR PR SD PD CR PR SD PD AI Phase 3 Studies: Response Rates After Crossover to Imatinib 800 mg/d One third of patients benefited from dose increase at progression Patients, %

  33. Phase 3 Studies: Conclusions • Two parallel phase 3 studies compared imatinib 400 mg/d and 800 mg/d in patients with metastatic unresectable GIST • US Intergroup S0033 study (N = 746) • EORTC 62005 study (N = 946) • EORTC 62005 study results1 • According to standard RECIST criteria, no significant difference in ORR between standard-dose and high-dose groups (50% vs 54%, respectively) • No significant advantage in PFS at 800 mg/d (P = 0.108)2 • US Intergroup S0033 study results3 • Doses similar in confirmed ORR (both 48%) • Similar 2-year PFS for standard dose vs high dose (47% vs 52%, respectively; P = 0.13)

  34. Discontinuation of Imatinib Increases Risk of GIST Progression Study BFR14 100 Continuous therapy (n = 23) 80 P = 0.0001 60 Patients, % 40 Stop therapy (n = 25) Median PFS: 6 months 20 0 0 2 4 6 8 10 12 14 16 Months After Randomization • Patients who achieved clinical benefit after 12 months were randomized to continue or stop imatinib therapy • Stop-therapy arm was discontinued because of high rates of disease progression • Reintroduction of imatinib enabled tumor control in all those patients

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