V559A and N822I double KIT mutant melanoma with predictable response to imatinib

Dear Editor, Since the initial report of KIT mutations in subtypes of melanoma, several reports of KIT-targeted therapies have been published (Carvajal et al., 2009; Hodi et al., 2008; Lutzky et al., 2008). Activating KIT mutations have been documented in a variety of neoplastic diseases including, in addition to melanoma, mastocystosis, acute myeloid leukemia, seminoma and gastrointestinal stromal tumors (Went et al., 2004). Herein, we report a case of a KIT double mutation in anorectal melanoma not previously described in melanoma, but with a response to imatinib mesylate that might have been expected given the knowledge from other cancers. The patient is an 87-year-old woman who developed constipation and a palpable rectal mass in the summer of 2009. Biopsy of the mass demonstrated an ulcerated melanoma invading the submucosa and muscle to a depth of approximately 11 mm with angiolymphatic invasion. Computerized tomography (CT) scans of the chest, abdomen and pelvis revealed metastatic disease in the pelvis, inguinal region and lungs. Substantial growth of the disease was documented on serial CT scans 3 months apart with the largest lung nodule increasing 44% (14 to 25 mm). The patient declined treatment with systemic chemotherapy and was not a candidate for the available clinical trials but she did express an interest in some form of therapy. Her melanoma was assessed for KIT mutational status. A double mutation was identified, comprising the exon 11 mutation V559A and the exon 17 mutation N822I. The patient subsequently initiated treatment with imatinib 400 mg daily in November 2009. Surveillance CT scans in February 2010 revealed that most metastatic lesions were stable to minimally decreased, including a right inguinal lymph node (16 to 14 mm), a right upper lobe lung nodule (20 to 18 mm), a right lower lobe lung nodule (25 to 23 mm) and a right ischioanal lesion (19 to 15 mm). There was complete disappearance of multiple subcentimetre lung nodules; however, there was also some growth of other lung nodules, the largest of which increased from 25 to 28 mm. The findings were consistent with a mixed response, although in accordance with RECIST criteria, the patient’s response would best be classified as stable disease ( 7% decrease in sum of diameters of target lesions). No repeat biopsy was attempted. The dose of imatinib was titrated from 400 to 800 mg with the aim of overcoming any possible resistance to therapy and improving the patient’s response. Unfortunately, the patient developed significant fatigue, dyspnea on exertion and lower extremity edema. Treatment was held, and after recovery from these acute symptoms, attempts were made to reinitiate imatinib at the lower dose of 400 mg. The patient was not able to tolerate resumption of therapy, and she experienced further clinical decline and progression of disease; ultimately, she succumbed to her metastatic melanoma in August, 2010. Efforts to define the genetic landscape of melanomas have led to the recognition that alterations in the KIT gene constitute the predominant mutation in melanomas arising from chronic sun-damaged skin and acral and mucosal anatomical locations (Curtin et al., 2005, 2006). KIT mutations in melanoma are now only beginning to be catalogued. The experience with KIT mutations in GISTs, however, is much more extensive, and this experience provides a conceptual framework for understanding the pathobiology of and therapeutic approaches to treating neoplastic diseases driven by KIT mutations (Corless and Heinrich, 2008). KIT mutations underlie approximately 85% of GISTs; and the vast majority ( 70%) occurs within exon 11 corresponding to the autoinhibitory juxtamembrane domain. KIT exon 9 lies within the extracellular ligand-binding region, and mutations within this exon account for 10 to 15% of KIT mutations in GIST. KIT mutations within the kinase domain (either exon 13 or exon 17) occur with much less frequency (<5%). To date, molecular analyses have identified approximately two dozen unique KIT mutations in melanoma (Woodman and Davies, 2010). Similar to GIST, the majority of KIT mutations in melanoma occur within the juxtamembrane autoinhibitory region encoded by exon 11. Unique to melanoma, though, the