Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors
Purpose: Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was to correlate molecular and radiologic patterns...
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| Published in: | Clinical cancer research Vol. 13; no. 18; pp. 5398 - 5405 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Philadelphia, PA
American Association for Cancer Research
15-09-2007
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Purpose: Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal
tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was
to correlate molecular and radiologic patterns of imitinib-refractory disease with existing conventional criteria for disease
progression.
Experimental Design: Patients with metastatic GIST treated with imatinib were followed with serial computed tomography/magnetic resonance imaging
and [ 18 F]fluoro-2-deoxy- d -glucose positron emission tomography. Where feasible, biopsies were done to document disease progression.
Results: A total of 89 patients were followed for a median of 43 months. Forty-eight patients developed progressive disease. A unique
“resistant clonal nodule” pattern (defined as a new enhancing nodular focus enclosed within a preexisting tumor mass) was
seen in 23 of 48 patients and was thought to represent emergence of clones resistant to imatinib. Nodules were demonstrable
a median of 5 months (range, 0-13 months) before objective progression defined by tumor size criteria and were the first sign
of progression in 18 of 23 patients. Median survival among patients whose first progression was nodular was 35.1 months, compared
with 44.6 months for patients whose first progression met Southwest Oncology Group criteria ( P = 0.31). Comparative tumor biopsies were done in 10 patients at baseline and from progressing nodules. Genotypic analyses
of KIT and PDGFRA kinases were done, revealing new activating kinase mutations in 80% (8 of 10) of these patients.
Conclusion: The resistant clonal nodule is a unique pattern of disease progression seen in patients with GISTs after an initial response
to imatinib and reflects the emergence of imatinib-resistant clones. Conventional tumor measurements (Southwest Oncology Group/Response
Evaluation Criteria in Solid Tumors) do not detect this subtle finding. A new enhancing nodule growing within a preexisting
tumor mass should be classified as a new lesion and be regarded, at least, as partial progression of GIST. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1078-0432 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-06-0858 |