Lack of clinical efficacy of imatinib in metastatic melanoma

Ugurel, Selma; Hildenbrand, Ralf; Zimpfer, A; Rosée, Paul La; Paschka, Peter; Sucker, Antje; Keikavoussi, Petra; Becker, Juergen C.; Rittgen, Werner; Hochhaus, Andreas; Schadendorf, Dirk

doi:10.1038/sj.bjc.6602529

Cited by 225 publications

(121 citation statements)

References 35 publications

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“…15,19,20 As a result, it is not that surprising that multiple clinical trials have observed only minimal or no clinical efficacy of imatinib mesylate (Gleevec) in various types of tumors expressing KIT detected by immunohistochemical staining but lacking activating mutations, such as adenoid cystic carcinomas of the salivary gland, 22 pulmonary small cell carcinomas, 32,33 breast carcinomas, 34 ovarian carcinomas 35 and melanomas. 36 These studies 15,19,20,22,[32][33][34][35][36] support the concept that mutation-mediated activation of KIT or PDGFRA is a prerequisite for successful treatment with imatinib mesylate. 37 This conclusion is further supported by a recent study in which clinical response to imatinib mesylate was observed in a patient with metastatic thymic carcinoma harboring an activating KIT mutation.…”

Section: Discussionmentioning

confidence: 75%

Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations

et al. 2006

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Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in 450% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10-50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.

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Section: Discussionmentioning

confidence: 75%

Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations

et al. 2006

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“…This is an ineffective process, likely to miss groups of patients who would truly benefit from the drug. For example, in four phase II trials of imatinib for the treatment of advanced melanoma, there was insufficient evidence of activity to support continued development of the drug for this indication [22][23][24][25] However, KIT gene mutations have since been identified in the acral and mucosal subsets of melanoma, 26 -29 and a recent phase II trial that targeted these mutations yielded a 60% response rate. 6 Using genomic mutation signatures predictive of sensitivity to targeted therapies is the most effective way to identify patients most likely to benefit.…”

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confidence: 99%

Multiplex Mutation Screening by Mass Spectrometry

Beadling

Heinrich

Warrick

et al. 2011

The Journal of Molecular Diagnostics

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There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry-based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3CA, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3CA-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broadspectrum, prospective genotyping approach to personalized cancer medicine. The identification of somatic mutations that cause aberrant activation of intracellular signaling pathways has transformed the diagnosis and treatment of cancer. Mutations in specific genes define distinct subtypes of cancer, and provide invaluable markers for disease diagnosis and prognosis. Many of the mutated proteins also represent targets for novel therapeutic agents that are more specific, more efficacious, and less toxic than broad-based chemotherapeutic regimens.1-5 Indeed, matching the right drug to the right cancer genotype is a proven model for improving treatment and outcome in patients with chronic myelogenous leukemia (CML), nonsmall-cell lung carcinoma (NSCLC), gastrointestinal stromal tumor (GIST), colorectal carcinoma, and, most recently, malignant melanoma. 2,5-16The major successes from this therapeutic approach have been in diseases in which there is limited molecular heterogeneity, with all or most cases having a drug-sensitive mutation. Prime examples include BCR-ABL in CML 9 and KIT in GIST. 3,7 There is increasing evidence that many common cancers similarly harbor potentially druggable targets, albeit at relatively lower frequencies. For example, subsets of NSCLC have oncogenic mutations in EGFR, KRAS, BRAF, PIK3CA, or HER2 or a translocation involving the ALK gene. [17][18][19] In the more molecularly heterogeneous cancers, mutations in proteins other than the intended therapeutic target can profoundly affect response to therapy. Thus, in the case of EGFR inhibitor therapy in lung and colon cancer, KRAS and B...

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“…Initial phase II trials with this agent in melanoma were disappointing with no objective responses (Ugurel et al 2005;Wyman et al 2006). However, gain of function mutations, gene amplifications and over-expression of c-kit were subsequently reported in 30-40% of mucosal, acral and cutaneous melanomas with chronic sun damage (Curtin et al 2006).…”

Section: C-kitmentioning

confidence: 99%