|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1147-1148 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9408
In ReplyPortland VA Medical Center and Oregon Health & Science University, Portland, OR We appreciate Dr De Giorgi's comments regarding the issue of apparent imatinib resistance in gastrointestinal stromal tumors (GISTs) harboring KIT exon 9 mutations. The study recently published by Debiec-Rychter and colleagues1 showing that patients with exon 9–mutant tumors had improved progression-free survival (PFS) while receiving 800 mg/d imatinib has raised a number of important questions in this regard. As Dr De Giorgi suggests, the apparent difference in dose responsiveness of exon 9–mutant GISTs as compared with exon 11–mutant GISTs might be explained by an inherent difference in the drug sensitivities of the two mutant kinases. However, in vitro studies do not support a significant difference in their sensitivities to imatinib inhibition.2 Moreover, in the Debiec-Rychter study,1 the improved PFS of exon 9–mutant GISTs treated with 800 mg/d imatinib did not quite match that of exon 11–mutant GISTs treated with either 400 or 800 mg/d imatinib, suggesting that tumors with exon 9 mutations are less responsive to this therapy overall. The explanation for this difference remains unknown, but it is interesting to note that exon 9–mutant tumors are anatomically restricted to the small intestine and colon, whereas exon 11–mutant tumors occur throughout the gastrointestinal tract. It is possible that the two tumor types arise from different stem-cell populations and that these stem cells differ in their relative dependence on KIT signaling and/or their ability to efflux imatinib from the cell cytoplasm. Regardless of the reason for the relative insensitivity of exon 9–mutant GISTs to imatinib, we agree with Dr De Giorgi that the definition of primary resistance in these tumors may need to be revised in future studies. Thus, tumors that progress within 6 months of treatment on 800 mg/d imatinib might be considered fully resistant, whereas those that show disease stabilization or measurable response for longer than 6 months before progression might be classified as having secondary resistance. It is clear from our work and from the work of other laboratories that new mutations interfering with drug sensitivity can accumulate in the setting of late resistance, and that these mutations overlap with those acquired in tumors with primary exon 11 mutations.3-5 What remains unclear is whether this pattern of resistance will become dominant when exon 9–mutant tumors are routinely treated with 800 mg/d imatinib, as is true for imatinib-treated exon 11–mutant tumors, or whether other mechanisms of resistance will be defined in this population. With the increasing availability of other kinase inhibitors for the treatment of GIST, it is important that the mechanisms of imatinib resistance be more fully delineated, so that choices for second- and third-line treatments are rationally defined. We would also note that this discussion highlights our contention that GISTs do not constitute a single uniform entity, but rather represent a group of closely related neoplasms. As such, we believe that molecular classification of these tumors is increasingly important for optimal diagnosis, clinical management, and interpretation of clinical studies.6 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Michael C. Heinrich, Novartis, Pfizer, MolecularMD; Christopher L. Corless, Novartis Stock: Michael C. Heinrich, MolecularMD Honoraria: Michael C. Heinrich, Novartis, Pfizer; Christopher L. Corless, Novartis Research Funds: Michael C. Heinrich, Novartis, Pfizer; Christopher L. Corless, Novartis, Pfizer Testimony: N/A Other: N/A REFERENCES 1. Debiec-Rychter M, Sciot R, Le CA, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006[CrossRef][Medline] 2. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003 3. Antonescu CR, Besmer P, Guo T, et al: Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11:4182-4190, 2005 4. Debiec-Rychter M, van OA, Marynen P: Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 128:270-279, 2005[CrossRef][Medline] 5. Heinrich MC, Corless CL, Blanke CD, et al: Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764-4774, 2006 6. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 22:3813-3825, 2004
Related Correspondence
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
