EML4-ALK positive lung cancer
EML4-ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein the "echinoderm microtubule-associated protein-like 4" ("EML4") gene is fused to the "anaplastic lymphoma kinase" ("ALK") gene. This abnormal gene fusion leads to the production of a protein (EML4-ALK) that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells. The transforming "EML4-ALK" fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007. Signs and symptoms. The signs and symptoms of this  lung cancer variant seem to mimic those of the underlying major cell type. Diagnosis. Classification. Most lung carcinomas containing the "EML4-ALK" gene fusion are adenocarcinomas. Some studies suggest that the papillary adenocarcinoma and the signet ring cell adenocarcinoma variants are more likely to carry this fused gene than other histological variants. Screening. Screening for ALK positive lung cancer is now a standard of care in the United States and Canada. Screening can be done with immunostaining, FISH, or next-generation sequencing (NGS). Treatment. Crizotinib is a targeted therapy (FDA approved in 2011), manufactured by Pfizer and marketed under the  brand name Xalkori and Crizalk that targets the EML4/ALK fusion gene. Ceritinib is a second generation targeted therapy (FDA approved in 2014), manufactured by Novartis and sold under the brand name Zykadia that also targets the EML4 fusion gene, but as a second generation drug it has a smaller molecule that allows superior penetration of the Blood Brain Barrier (BBB) over Crizotinib and is more capable of protecting the Central Nervous System (CNS). Alectinib another second generation targeted therapy and was approved (for this) by Japan in 2014 and by US FDA in 2015., manufactured by Genentech and marketed  under the brand name Alecensa. Brigatinib a second generation targeted therapy (FDA approved in 2017), manufactured by Takeda and is marketed under the brand name Alunbrig. Ensartinib is a second generation targeted therapy (trial drug X-396), manufactured by XCovery. Lorlatinib is a third generation targeted therapy (awaiting FDA approval under trial drug PF-6463922), manufactured by Pfizer. TPX-0005 is a new third generation targeted therapy drug trial. Prognosis. Treatment with crizotinib achieves 60% response rate. However, crizotinib showed no improvement on overall survival compared to chemotherapy. This may be due to the fact that there was a 70% crossover rate to  crizotinib in patients treated initially with chemotherapy. Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35%. Epidemiology. "EML4-ALK" gene fusions occur almost exclusively in carcinomas arising in non-smokers. About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene. 4–6% of lung adenocarcinomas involve the fusion gene. "EML4-ALK" mutation rarely occurs in combination with "K-RAS" or "EGFR" mutations.