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The Clinical and Molecular Profile of ALK in NSCLC

Shaw, AT et al. NEJM 2011;365:158–167. Reproduced with permission of Massachusetts Medical Society ©2011

The gene fusion of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) is one of several molecular alterations that have been identified in non-small cell lung cancer (NSCLC).1

Clinical characteristics associated with ALK-positive NSCLC

A number of studies have examined clinical or demographic factors associated with EML4-ALK gene rearrangements. Compared with patients who have ALK-negative disease, the factors that are associated with ALK-positive NSCLC are:

  • Younger median age (<60 years)2-6
  • Non-smoking or light smoking history2-6,8

Most NSCLCs with EML4-ALK gene rearrangements are adenocarcinomas or have a mixed histology.2,4-8

Initial data suggested that tumours with EML4-ALK gene rearrangements did not have mutations in the genes for epidermal growth factor receptor (EGFR) 2-5,7,8 or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS).4-8 However, recently, cases of EGFR mutations or KRAS mutations in association with EML4-ALK rearrangements have been reported.6,9,10

Despite the correlations between these clinical or histological features and ALK status, it is possible for any patient with NSCLC to have ALK-positive disease. The EML4-ALK fusion gene has been found in older patients with a smoking history.3 This suggests that clinical characteristics alone may not detect all patients and that molecular testing is necessary to determine ALK status.

Adapted with permission. Rodig SJ, et al. Clin Cancer Res 2009;15:5216–5223

Currently, the exact prevalence of EML4-ALK in NSCLC is unknown (see table below), but it has been estimated that between 3% and 5% of North American patients with NSCLC have this genetic inversion.11 Data vary between studies because of differences in patient selection criteria and EML4-ALK detection methods. 12

Prevalence of EML4-ALK gene rearrangements in various studies
StudyNationality of patients with NSCLCNo. with
EML4-ALK
Percent with 
EML4-ALK
Analytic method
Soda et al. 200713Japanese5/756.7%RT-PCR
Inamura et al. 200814Japanese5/2212.2%RT-PCR
Takeuchi et al. 200815Japanese11/3643.0%RT-PCR
Perner et al. 200816Swiss and US16/6032.7%FISH, RT-PCR
Koivunen et al. 200817Korean and US8/3052.6%RT-PCR
Korean6/1673.6%
US2/1381.4%
Shinmura et al. 200818Japanese2/772.6%RT-PCR
Rodig et al. 20093US20/3585.6%FISH
Martelli et al. 20099Italian and Spanish9/1207.5%RT-PCR
Wong et al. 20095Chinese13/2664.9%RT-PCR
Shaw et al. 20094US*19/14113.5%FISH
Boland et al. 20097US6/3351.8%FISH, RT-PCR
Sakairi et al. 20102Japanese7/1096.4%FISH, RT-PCR
Takahashi et al. 20108Japanese5/3131.6%RT-PCR
Zhang et al. 20106Chinese12/10311.6%RACE-coupled PCR sequencing
Salido et al. 201119Spanish2/1071.9%FISH

*These patients were selected for genetic screening because of their higher risk of EML4-ALK based on clinical/demographic characteristics.

FISH: Fluorescence in situ hybridisation
RACE: rapid amplification of cDNA ends
RT-PCR: reverse transcriptase-polymerase chain reaction

Find out more about Current Understanding and Natural History of ALK-positive NSCLC

References: 
  1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol 2011;12:175–180
  2. Sakairi Y, Nakajima T, Yasufuku K, et al. EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Clin Cancer Res 2010;16:4938–4945
  3. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the Western population. Clin Cancer Res 2009;15:5216–5223
  4. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbour EML4-ALK. J Clin Oncol 2009;27:4247–4253
  5. Wong DW-S, Leung EL-H, So KK-T, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from non-smokers with wild-type EGFR and KRAS. Cancer 2009;115:1723–1733
  6. Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRASmutations and is correlated with ALK expression. Mol Cancer 2010;9:188
  7. Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol 2009;40:1152–1158
  8. Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol2010;17:889–897
  9. Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol2009;174:661–670
  10. Yang J, Zhang X, Su J, et al. Concomitant EGFR mutation and EML4-ALK gene fusion in non-small cell lung cancer. Poster presented at the American Society of Clinical Oncology conference, June 3-7 2011, Chicago, IL [Abstract number 10517]
  11. Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst 2010;102:672–675
  12. Horn L, Pao W. EML4-ALK: Honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009;27:4232–4235
  13. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–567
  14. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol2008;3:13–17
  15. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 2008;14:6618–6624
  16. Perner S, Wagner PL, Demichelis F, et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia 2008;10:298–302
  17. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res2008;14:4275–4283
  18. Shinmura K, Kageyama S, Tao H, et al. EML4-ALK fusion transcripts, but no NPM-, TPM3-, CTCL-, ATIC-, or TGF-ALK fusion transcripts, in non-small cell lung cancer. Lung Cancer 2008;61:163–169
  19. Salido M, Pijuan L, Martínez-Avilés L, et al. Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer. J Thorac Oncol 2011;6:21–27