CHICAGO KIT gene mutations that are susceptible to imatinib occur in some acral and mucosal melanomas, opening up new therapeutic options for patients with melanoma, according to a study presented as a poster at the annual meeting of the American Society of Clinical Oncology.
KIT mutations were found in 23% of acral melanomas and 16% of mucosal melanomas, reported Dr. Michael C. Heinrich, professor of medicine at the Oregon Health and Science University, Portland, and his colleagues. The mutation frequency was greater among tumors of the anorectum, vulva, and vagina (44%) than among the head and neck (8%).
In contrast, KIT mutations accounted for only 2% of cutaneous melanomas and for 8% of conjunctival melanomas. No mutations were found in an additional 60 choroidal melanomas.
"Based on our study, approximately 40%-50% of all types of melanoma have an oncogenic mutation that could be treated with drugs that are or will be in clinical studies within the next 18 months," Dr. Heinrich said in an interview.
For the study, DNA from archival melanomas was amplified by polymerase-chain reaction (PCR) and the products were screened for mutations in KIT exons 11, 13, 17 (n = 189), BRAF exon 15 (n = 116), and NRAS exons 1 and 2 (n = 117). Mutations were confirmed by direct sequencing.
In addition, immunohistochemistry for CD117 (KIT) was performed on a subset of cases. Lastly, the researchers assessed increases in KIT copy number in specific melanoma subtypes using quantitative real-time PCR.
Six of seven KIT mutations identified were of the type predicted to be sensitive to imatinib (Gleevec). KIT mutations did not overlap with NRAS mutationswhich were also common in acral and mucosal tumorsor with BRAF mutations, which were absent in mucosal tumors.
"In the not too distant future, we envision that advanced melanoma tumors would be routinely tested for these types of mutations and the results used to make clinical decisions about the best medical treatment. This would be similar to the existing breast cancer model where ER [estrogen receptor] and HER2 [human epidermal growth factor receptor 2] testing are routine pathology tests that are used to individualize treatment programs," said Dr. Heinrich.
Imatinib is indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, myelodysplastic/myeloproliferative diseases, hypereosinophilic syndrome and/or chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, and KIT-positive gastrointestinal stromal tumors.
Using a PCR-based assay, the researchers found that KIT was increased in acral and mucosal melanoma cases, though most of the tumors with increased KIT did not have a mutation. Extra KIT copies were not as common in cutaneous and conjunctival tumors. KIT (CD-117) expression was detected in 39% of 105 tumors; however, there was no correlation between CD-117 staining and tumor genotype. KIT mutations of the type known to be sensitive to imatinib do not necessarily correlate with either KIT copy number or CD-117 expression, the researchers noted.
The study was prompted by a recent rectal melanoma case in which a patient with a KIT mutation had a dramatic response to imatinib.
Dr. Heinrich reported that he has received research funding from Novartis and Pfizer Inc., is a consultant for Novartis, and has equity interest in MolecularMD. One of his coauthors has received research funding from Novartis and Pfizer and is a consultant for Novartis.