Drugs of interest to pathologists
Drugs related to surgical pathology
Author: Him G. Kwee, M.D. (see Reviewers/Authors page)
Revised: 23 December 2011, last major update October 2011
Copyright: (c) 2011, PathologyOutlines.com, Inc.
● Crizotinib is an anaplastic lymphoma kinase inhibitor
● Approved by US Food and Drug Administration in August 2011 for non-small cell lung carcinoma that is locally advanced or metastatic (Drug Des Devel Ther 2011;5:471)
● Approximate cost in 2011: $10,000 per month
Use for pathologists
● 4-5% of patients with non-small cell lung carcinoma (10,000 annually in US), have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), resulting in constitutive kinase activity that contributes to growth, invasion and migration of the carcinoma (Mol Cancer Ther 2007;6:3314)
● The kinase activity of the fusion protein is inhibited by crizotimib
● Patients with this fusion gene are predominantly younger males with adenocarcinoma, non-smokers or light smokers, with no mutations in Epidermal Growth Factor Receptor (EGFR) or KRAS
● Histologic features include acinar, papillary, cribriform, mucinous (intra- and extracytoplasmic) and signet-ring patterns of adenocarcinoma
● It is unclear if squamous cell carcinomas and mucoepidermoid carcinomas may contain EML4-ALK translocations
● The detection of the EML4-ALK translocations can be done by immunohistochemistry, FISH or reverse transcriptase PCR (J Thorac Oncol 2011;6:244)
● The FDA also approved the companion diagnostic test for the ALK fusion gene on the same day that crizotinib was approved, called Vysis ALK Break Apart FISH probe kit, marketed by Abbott Molecular, Inc.
● Most tumors with EML4-ALK translocations are positive for TTF1, may be p63 positive and have a lower frequency of p53 mutations (J Thorac Oncol 2011;6:244)
● Clinical trials are ongoing for crizotinib to treat advanced disseminated anaplastic large cell lymphoma, neuroblastoma and inflammatory myofibroblastic tumor (N Engl J Med 2011;364:776, N Engl J Med 2010;363:1727)
End of Drugs > Drugs related to surgical pathology > Crizotinib
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