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Imatinib in Melanoma: A Selective Treatment Option Based on KIT Mutation Status?

Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany

Dirk Schadendorf, Selma Ugurel

Skin Cancer Unit, German Cancer Research Center Heidelberg and Department of Dermatology, Mannheim University Medical Center, Mannheim, Germany

To the Editor:

We read with great interest the article by Curtin et al¹ on activating KIT mutations in melanoma. The authors differentiate four subtypes of primary melanoma depending on sun exposure and localization: acral melanoma, mucosal melanoma, melanoma on chronically sun-damaged skin, and melanoma arising from skin without signs of chronic sun damage. The latter subgroup has recently been shown to be characterized by frequent activating mutations in B-RAF and N-RAS, members of the MAP kinase pathway, whereas these mutations are rare in the other three subtypes.² In the current Curtin et al article,¹ these very same three subtypes were demonstrated to hold high frequencies (28% to 39%) of genetic aberrations in KIT, a receptor tyrosine kinase, whereas in contrast these aberrations were absent (0%) in melanomas arising from skin without chronic sun damage.¹ The detected KIT aberrations included different mutations as well as copy number increases and were associated with an enhanced KIT protein expression. Eleven (69%) of 16 KIT mutations were predicted to affect the juxta-membrane domain, presumably resulting in a constitutive activation of KIT. These mutations are frequently found in gastrointestinal stromal tumors (GIST) and have been shown to be highly sensitive to imatinib, a tyrosine kinase inhibitor targeting ABL, PDGF-R, and KIT, thus accounting for the high response rates to imatinib in this tumor entity.³ These findings indicate, as also noted by Curtin et al, that imatinib might be a promising treatment option for melanoma. However, two clinical phase II trials testing this drug in metastatic melanoma revealed no objective responses and poor survival rates in 16⁴ and 25⁵ assessable patients, respectively. Based on these disappointing clinical results, we and others came to the conclusion that imatinib has no therapeutic effect in metastatic melanoma and should no longer be tested in this tumor entity. Prompted by the findings of Curtin et al, however, we re-evaluated the patient population participating in our two-center study,⁴ which revealed that only two patients (12%) displayed the characteristics of high-KIT–aberration/high-imatinib–sensitivity tumors (one acral melanoma, one mucosal melanoma), whereas 13 patients (81%) belonged to the group of low-KIT–aberration/low-imatinib–sensitivity tumors (ie, 11 melanomas of the trunk or extremities without chronic sun damage, four melanomas of unknown primary); one patient with a primary melanoma of the eye could not be assigned to either group. Considering the data of Curtin et al, only two patients of our study population were likely to carry KIT aberrations with a probability of approximately 40%, rendering this study too underpowered to demonstrate any efficacy of imatinib in melanoma. To test the hypothesis that melanomas harboring genetic aberrations in KIT are likely to benefit from imatinib treatment, we propose a clinical trial investigating imatinib in metastatic melanoma originating from primary tumors of acral skin, mucosa, or chronically sun-damaged skin, correlating the treatment outcome with the mutational status of KIT. If this hypothesis turns out to be true, imatinib could be established as the first individualized mutation-driven targeted therapy in melanoma.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Curtin JA, Busam K, Pinkel D, et al: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340-4346, 2006[Abstract/Free Full Text]

2. Curtin JA, Fridlyand J, Kageshita T, et al: Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135-2147, 2005[Abstract/Free Full Text]

3. Frost MJ, Ferrao PT, Hughes TP, et al: Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther 1:1115-1124, 2002[Abstract/Free Full Text]

4. Ugurel S, Hildenbrand R, Zimpfer A, et al: Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92:1398-1405, 2005[CrossRef][Medline]

5. Wyman K, Atkins MB, Prieto V, et al: Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: Significant toxicity with no clinical efficacy. Cancer 106:2005-2011, 2006[CrossRef][Medline]

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• Somatic Activation of KIT in Distinct Subtypes of Melanoma
  John A. Curtin, Klaus Busam, Daniel Pinkel, and Boris C. Bastian
  JCO 2006 24: 4340-4346 [Abstract] [Full Text]

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