Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Desai
Jayesh
J
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Shankar
Sridhar
S
Heinrich
Michael C
MC
Fletcher
Jonathan A
JA
Fletcher
Christopher D
CD
Manola
Judi
J
Morgan
Jeffrey A
JA
Corless
Christopher L
CL
George
Suzanne
S
Tuncali
Kemal
K
Silverman
Stuart G
SG
Van den Abbeele
Annick D
AD
van Sonnenberg
Eric
E
Demetri
George D
GD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002999:Clone Cells / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D011859:Radiography; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D017384:Sequence Deletion; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha