REVIEW
SUMMARY Molecular testing is essential in order to identify patients with ALK rearrangements or EGFR mutations who are candidates for ALKor EGFR-targeted tyrosine kinase inhibitor therapy, respectively. Whereas EGFR mutation analysis is largely established in the management of NSCLC, testing for translocations of the ALK gene has become a new requirement since the introduction of ALK inhibitors in the clinic. Representatives of three professional organizations involved in the diagnosis and management of lung cancer – the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) – systematically reviewed available data to develop evidence-based recommendations for molecular testing of lung cancers in clinical practice. The new guideline for molecular testing in lung cancer was published in April 2013. This overview focuses on the most important recommendations for ALK testing in the guideline, providing clear recommendations for the molecular analyses of lung cancer tissue including which patients and samples should be tested, and when and how ALK testing should be performed. Keywords: lung cancer, non-small cell lung cancer, anaplastic lymphoma kinase, ALK tyrosine kinase inhibitors, molecular testing, molecular testing guideline
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Molecular testing guidelines for selection of lung cancer patients for ALK tyrosine kinase inhibitors Christian Lenz1, Julius Alexander Steffen2, Arne Engelsberg3 1 Global Health Economics and Outcomes Research, Pfizer Oncology, Berlin 2 Imperial College London 3 European Medical Affairs, Pfizer Oncology, Berlin
L
ung cancer is the leading cause of cancer-related mortality in the world, with over one million deaths each year [1]. Recently major advances in our understanding of the pathogenesis of lung cancers, particularly non-small cell lung cancer (NSCLC), have led to the identification of many of the key molecular pathways that drive tumor growth. The prevalence of key oncogenic driver mutations in patients with NSCLC ranges from approximately 20 % harboring KRAS (V-Kiras2 Kirsten rat sarcoma viral oncogene homolog) mutations, and approximately 15 % harboring EGFR (epidermal growth factor receptor) mutations, to approximately 3 % to 5 % expressing an ALK (anaplastic lymphoma kinase) fusion gene, and approximately 2 % harboring HER2 (human epidermal growth factor receptor 2) mutations [2, 3, 4]. Anaplastic lymphoma kinase rearrangement in NSCLC
Anaplastic lymphoma kinase (ALK) is a 1,620 amino acid transmemJOURNAL PHARMAKOL. U. THER. 2/2013 · 22. JAHRGANG
brane protein and is a member of the insulin receptor superfamily of receptors. ALK was first described in 1994 in the context of a form of non-Hodgkin’s lymphoma where it was shown to acquire transforming capability when truncated and fused to another protein, nucleo phosmin (NPM), as a consequence of a chromosomal rearrangement [5]. In 2007, Soda and coworkers identified an EML4-ALK gene fusion in samples from five lung cancer patients and demonstrated the role of the resulting ALK fusion protein as important oncogenic driver in a subset of NSCLC [6]. The N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) gene product was demonstrated to be fused to the intracellular signaling portion of the ALK kinase domain. These fusions are the result of inversions within the short arm of chromosome 2 (involving 2p21 and 2p23, approximately 12 Mb apart) that juxtapose the 5′ end of the EML4 gene to the 3′ end of the ALK gene [6]. Those results suggested that targeting ALK fusions with specific inhibitors could be equally effective as targeting the © VERLAG PERFUSION GMBH