Major sites of GIST metastases: GIST: Clinical Presentation GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum Esophagus (2%) Colon/Rectum (5%) Other (mesentery, retroperitoneum) 8% Major sites of GIST metastases: liver peritoneum bone lung 25% Small intestine 60% Stomach Adapted from: Corless et al. J Clin Oncol 2004;22:3813-25.

GIST Evaluation Factors for Consideration GIST histologic type (spindle/epithelioid/mixed) KIT-positive/-negative Biologic risk potential (low/intermediate/high) Tumour size and location (1 section/1 cm tumour) Cellularity (low/moderate/high), cellular atypia (mild/moderate/marked) Mitotic count/50 HPF Tumour necrosis Mucosal ulceration Lympho-vascular invasion Margin status Adapted from Marginean C. GIST Consensus Meeting 2007, Ottawa.

RTK Mutation Frequencies KIT (80%) PDGFRA (5-8%) Exon 8 (<1%) Exon 9 (10%) Exon 11 (67%) Exon 12 (1%) Exon 13 (1%) Exon 14 (<1%) Exon 17 (1%) Exon 18 (5%) Adapted from Hurlbut D. GIST Consensus Meeting 2007, Ottawa.

GIST Imaging CT Delineates the large exophytic masses and local and distant metastases Guides tissue biopsy PET Differentiates tissues and assesses tumor metabolic activity For early treatment-response evaluation Large heterogeneous duodenal GIST (D) with multifocal hepatic metastases (M). The biliary tree and pancreatic duct are not dilated. Image reprinted with permission from Lau et al. Clin Radiol 2004;59:487-98.

Primary GIST: Risk Factors for Recurrence After Surgery Rates of RFS were predicted by mitotic index and tumour size 0.25 0.50 0.75 1.0 20 40 60 80 Months 3 mitoses/30 HPF >3 to 15 mitoses/30 HPF >15 mitoses/30 HPF P=0.0001 Recurrence-free survival Mitotic index 0.25 0.50 0.75 1.0 20 40 60 80 <5 cm 5-10 cm >10 cm P=0.03 Months Recurrence-free survival Tumour size Singer et al. J Clin Oncol 2002;20:3898-905. Adapted with permission from ASCO.

ACOSOG Z9001 Study: Relapse Events at One Year The ACOSOG Z9001 Study, which randomized 644 patients to a TK inhibitor or placebo after GIST surgical resection, was halted early when the relapse rate was 67.5% lower at one year in the arm receiving the TK inhibitor (hazard ratio=0.325;P=0.0000014 for active treatment vs. placebo). Adapted from: DeMatteo et al. ASCO 2007, Abs 10079.

Treatment Algorithm for Patients with Primary Metastatic or Recurrent GIST Primary disease Recurrent disease No metastasis Metastasis or unresectable Imatinib Surgery Response or stable disease Progression Post-operative imatinib (adjuvant) Under clinical investigation: - Nilotinib - RAD001 - PKC412 Sunitinib or surgery? Surgery? Adapted from van der Zwan SM, DeMatteo RP. Cancer 2005;104:1781-8.