ALK positive lung cancer

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

ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein, most frequently, the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. Less frequently, there will be novel translocation partners for the ALK gene, in place of EML4.^[1] 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.^[2]

The transforming EML4-ALK fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007.^[3]

Signs and symptoms[edit]

The signs and symptoms of this cancer include

• A cough that doesn't go away
• Chest pain that gets worse with deep breathing, coughing, or laughing
• Hoarseness
• Weight loss without trying or loss of appetite
• Coughing up blood
• Shortness of breath
• A weak or tired feeling
• Wheezing^[4]

Diagnosis[edit]

Classification[edit]

Most lung carcinomas containing the ALK gene fusion are adenocarcinomas.

Some studies suggest that the papillary adenocarcinoma and the signet ring cell adenocarcinoma^[5] variants are more likely to carry this fused gene than other histological variants.

The median age at diagnosis is around 50 years and the majority are female. ^[4][6]

Screening[edit]

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[edit]

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^[7] and by US FDA in 2015.,^[8] 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.^[9]

Lorlatinib is a third generation targeted therapy (FDA approved in 2018), manufactured by Pfizer.^[10]

NVL-655 is a fourth generation targeted therapy (currently in clinical trials), developed by Nuvalent.^[10][11]

Although treatment with immune checkpoint inhibitors has proved effective with some types of non-small cell lung cancer, it seems to be generally ineffective with ALK positive non-small cell lung cancer.^[12]

Prognosis[edit]

Treatment with crizotinib achieves 60% response rate.^[13] However, crizotinib showed no improvement on overall survival compared to chemotherapy.^[14] This may be due to the fact that there was a 70% crossover rate to crizotinib in patients treated initially with chemotherapy.^[15] Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35%.^[16]

According to patient advocacy group ALK Positive, a study in December 2018 found that the median survival for people with stage 4 (IV) ALK-positive lung cancer was 6.8 years with the right care.^[4]

Epidemiology[edit]

EML4-ALK gene fusions occur almost exclusively in carcinomas arising in non-smokers.^[17][18] About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene.^[19] 4–6% of lung adenocarcinomas involve the fusion gene.^[13]

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

References[edit]

External links[edit]

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