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KIT Mutational Status Predicts Clinical Response to Glivec in Patients With Metastatic GIST

	What is the frequency of KIT mutations in GIST?
		Screening by denaturing HPLC
	Are GIST-associated mutations sensitive to imatinib in vitro?
	What is the relationship of KIT mutations to drug response?
	Conclusions

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Mutations Observed In The KIT Gene

Detection of KIT Gene
Mutations

	Extract DNA from paraffin-embedded tissue
	Amplify by PCR
	Look for presence of mutations by denaturing HPLC (Transgenomics WAVE system)
	Confirm mutations by direct sequencing

"147 patients enrolled"

	147 patients enrolled
	Tumor DNA successfully analyzed from 121 patients (82%)
	Exons 9, 11, 13 & 17 analyzed for all samples
	86% of tumors contained a mutation
	No tumor contained more than one mutation

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"All GIST-associated KIT mutations appear..."

	All GIST-associated KIT mutations appear sensitive to imatinib mesylate in vitro.
	Do KIT mutations impact drug response in patients?

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Conclusions

	KIT genotype in malignant GISTs predicts the likelihood of response and overall survival in patients treated with imatinib mesylate
		Exon 11 mutations are favourable
		No differences noted among subtypes of exon 11 mutations (e.g. deletion vs point mutation)
	KIT genotype correlates with PET response

Conclusions (cont.)

	KIT exon 9 mutant isoforms are drug sensitive in vitro, but tumors with this mutation appear less responsive in patients
		Exon 9 mutations are found only in small bowel and colonic GISTs
		Preliminary data suggest differences in downstream signaling intermediates    (J. Fletcher & M. Heinrich)

Conclusions (cont.)

	There is heterogeneity in the group of tumors lacking KIT gene mutations
		One patient in this group had a partial response to imatinib mesylate
	Analysis of patients in the Phase III trial (745 pts enrolled) will begin shortly
	Analyses of GISTs with primary and secondary resistance are underway

Clinical Application of
KIT Gene Mutation Screening

	Assays are becoming available in laboratories in Europe, Australia and the U.S.
	Caveats for cases reported as “wild-type”
		Sensitivity may depend on screening methodology (and experience)
		Some “wild-type” tumors may still respond
	OHSU Molecular Diagnostics Lab offers HPLC-based screening for mutations in exons 9 and 11
		We are happy to help other labs interested in adopting this technology for clinical testing

Acknowledgements

	Heinrich Laboratory
	Diana Griffith
	Cecily Wait
	Kevin Yee
	Ajia Town
	Kathleen Kemmer
	Laura McGreevey
	Corless Laboratory
	Andrea Haley
	Linda Jauron-Mills
	Carolyn Gendron
	Jonathan Fletcher
	George Demetri
	Charles Blanke
	Brian Druker
	Novartis Pharma AG
	GIST/STI Consortium (DFCI, OHSU, FCCC, Univ. of Helsinki, Novartis Pharma)