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Int J Cancer. 2018 Jun 15;142(12):2589-2598. doi: 10.1002/ijc.31275. Epub 2018 Jan 24.

EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer.

Author information

1
Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
2
Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany, member of the German Center for Lung Research (DZL).
3
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
4
Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
5
Department of Pneumology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
6
Department of diagnostic and interventional Radiology with Nuclear Medicine, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
7
Department of Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
8
Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
9
Department of Thoracic Oncology, Lungenklinik Löwenstein, Löwenstein, Germany.

Abstract

In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2 and V3 as detected by next-generation sequencing or reverse transcription-polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4-ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3-driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3-positive status was associated with earlier failure after treatment with first and second-generation ALK TKI (median progression-free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum-based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first-line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4-ALK fusion variant V3 is a high-risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.

KEYWORDS:

ALK+ NSCLC; EML4-ALK fusion variant; metastasis; survival; treatment failure

PMID:
29363116
DOI:
10.1002/ijc.31275
[Indexed for MEDLINE]

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