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ALK-rearrangements and testing methods in non-small cell lung cancer: a review.

ABSTRACT: The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a necessary step in identifying optimal treatment modalities. Here we review ALKmediated signal transduction pathways and compare the molecular protocols used to identify dysregulated ALK expression in NSCLC. We also discuss the use of crizotinib and second generation ALK tyrosine kinase inhibitors in the treatment of ALK positive NSCLC, and the known mechanisms of crizotinib resistance in NSCLC.

SUBMITTER: Shackelford RE

PROVIDER: S-EPMC4063252 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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ALK-rearrangements and testing methods in non-small cell lung cancer: a review.

Shackelford Rodney E RE Vora Moiz M Mayhall Kim K Cotelingam James J

Genes & cancer 20140401 1-2

The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a nece ...[more]

PMID: 24955213

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Project description:Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Project description:Lung cancer is one of the most common malignancies and the leading cause of cancer‑associated mortality in Korea. A significant amount of effort has been put into the development of new and more effective treatments and biological markers for the prediction of therapeutic responses, which has led to the identification of various genetic changes in cancer, that are the so‑called 'growth drivers' of carcinogenesis. Certain genetic alterations have become new treatment targets, and it has been suggested that different mutations are associated with different clinicopathological characteristics and prognosis. The present study aimed to evaluate the status of the key 'driver' mutation anaplastic lymphoma kinase (ALK) fusion in Korean patients with non‑small cell lung cancer (NSCLC) and its association with clinicopathological characteristics, including the presence of other genetic mutations. The present study also compared different methods for ALK fusion detection, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and next‑generation sequencing (NGS) to evaluate which method is the most effective. A total of 482 patients with NSCLC who underwent ALK FISH analysis were evaluated for clinicopathological features, such as age, sex, smoking history, tumor stage, histological subtype, immunohistochemical profile, including ALK and EGFR mutation statuses, and survival. Some ALK FISH‑positive and ‑negative cancers were newly submitted to NGS analysis for DNA and RNA alterations. The ALK fusion‑positive tumors were associated with a younger age, female patients, frequent nodal metastases, advanced stage and shorter survival. Comparing the results of ALK FISH, IHC and NGS analyses, it was concluded that in practice, ALK testing should better be diversified concerning FISH and IHC, and NGS analysis would be a good alternative to FISH, with an additional advantage of being able to concurrently detect different mutations.

Dataset Information

ALK-rearrangements and testing methods in non-small cell lung cancer: a review.

Publications

ALK-rearrangements and testing methods in non-small cell lung cancer: a review.

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