EML4-ALK positive lung cancer

EML4-ALK positive lung cancer
Micrograph showing ALK positive lung adenocarcinoma. H&E stain.
Specialty	Oncology

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 () that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells.^[1]

The transforming EML4-ALK fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007.^[2]

Signs and symptoms[]

The signs and symptoms of this lung cancer variant seem to mimic those of the underlying major cell type.^{[citation needed]}

Diagnosis[]

Classification[]

Most lung carcinomas containing the EML4-ALK gene fusion are adenocarcinomas.

Some studies suggest that the papillary adenocarcinoma and the ^[3] variants are more likely to carry this fused gene than other histological variants.

Screening[]

Micrograph showing an ALK positive adenocarcinoma of the lung. ALK immunostain.

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).^{[citation needed]}

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.^{[citation needed]}

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).^{[citation needed]}

Alectinib another second generation targeted therapy and was approved (for this) by Japan in 2014^[4] and by US FDA in 2015.,^[5] 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.^{[citation needed]}

Lorlatinib is a third generation targeted therapy (awaiting FDA approval under trial drug PF-6463922), manufactured by Pfizer.^{[citation needed]}

TPX-0005 is a new third generation targeted therapy drug trial.^{[citation needed]}

Prognosis[]

Treatment with crizotinib achieves 60% response rate.^[6] However, crizotinib showed no improvement on overall survival compared to chemotherapy.^[7] This may be due to the fact that there was a 70% crossover rate to crizotinib in patients treated initially with chemotherapy.^[8] Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35%.^[9]

Epidemiology[]

EML4-ALK gene fusions occur almost exclusively in carcinomas arising in non-smokers.^[10][11] About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene.^[12] 4–6% of lung adenocarcinomas involve the fusion gene.^[6]

EML4-ALK mutation rarely occurs in combination with K-RAS or EGFR mutations.

References[]

External links[]

• Entrez Gene EML4 echinoderm microtubule associated protein like 4 Homo sapiens