EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations

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Abstract

In non-small cell lung cancer, epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have a major impact upon the level of response to treatment with specific tyrosine kinase inhibitors. This review describes the molecular basis of ALK inhibition, summarizes current data on the effectiveness and safety of ALK inhibition therapy, describes the different testing methodologies with their advantages and disadvantages, provides a suggested testing algorithm and puts forward a proposal for an external quality assessment program in ALK testing.

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Most cited references 49

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Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

Alice Shaw, Beow Yeap, Mari Mino-Kenudson … (2009)

The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.

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The path to personalized medicine.

Margaret A Hamburg, Francis Collins (2010)

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RET, ROS1 and ALK fusions in lung cancer.

Kengo Takeuchi, Manabu Soda, Yuki Togashi … (2012)

Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion-positive and 13 ROS1-fusion-positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion-positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥ 50 years, male sex, high pathological stage and negative kinase-fusion status.

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Author and article information

Contributors

: +31-20-4444048 , e.thunnissen@vumc.nl

Journal

Journal ID (nlm-ta): Virchows Arch

Journal ID (iso-abbrev): Virchows Arch

Title: Virchows Archiv

Publisher: Springer-Verlag (Berlin/Heidelberg )

ISSN (Print): 0945-6317

ISSN (Electronic): 1432-2307

Publication date (Electronic): 24 July 2012

Publication date PMC-release: 24 July 2012

Publication date (Print): September 2012

Volume: 461

Issue: 3

Pages: 245-257

Affiliations

[1 ]Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands

[2 ]Institute for Pathology, University Hospital Basel, Basel, Switzerland

[3 ]Institute for Pathology, Charité, Charité Campus Mitte, Berlin, Germany

[4 ]Department of Pathology, Solna, Karolinska University Hospital, Stockholm, Sweden

[5 ]Department of Pathology, Aberdeen University Medical School, Aberdeen, Scotland UK

[6 ]Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico Clara Campal, Hospital Universitario Sanchinarro, Madrid, Spain

[7 ]Institute for Surgical Pathology, Universitätsspital Zurich, Zurich, Switzerland

[8 ]Department of Pathology, Maria Sklodowska-Curie Institute of Oncology, Warszawa, Poland

[9 ]Department of Pathology, Antwerp University Hospital, Edegem, Belgium

[10 ]Department of Pathology, Centre Jean Perrin, Clermont-Ferrand, France

[11 ]Sezione di Anatomia Patologica, Azienda Policlinico di Modena, Modena, Italy

Article

Publisher ID: 1281

DOI: 10.1007/s00428-012-1281-4

PMC ID: 3432214

PubMed ID: 22825000

SO-VID: bd0d1a44-8e4a-4874-be0a-abb89b0cf7aa

History

Date received : 13 April 2012

Date revision received : 21 June 2012

Date accepted : 2 July 2012

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ScienceOpen disciplines: Pathology

Keywords: algorithm,anaplastic lymphoma kinase,guidelines,rearrangement,non-small cell lung cancer,crizotinib

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ScienceOpen disciplines: Pathology

Keywords: algorithm, anaplastic lymphoma kinase, guidelines, rearrangement, non-small cell lung cancer, crizotinib

EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations

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Abstract

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Most cited references 49

Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

The path to personalized medicine.

RET, ROS1 and ALK fusions in lung cancer.

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