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.
Petros ChristopoulosVolker EndrisFarastuk BozorgmehrMei ElsayedMartina KirchnerJonas RistauIvo BuchhalterRoland PenzelFelix J HerthClaus P HeusselMartin EichhornThomas MuleyMichael MeisterJürgen R FischerStefan RiekenArne WarthHelge BischoffPeter SchirmacherAlbrecht StenzingerMichael ThomasPublished in: International journal of cancer (2018)
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.
Keyphrases
- advanced non small cell lung cancer
- epidermal growth factor receptor
- free survival
- small cell lung cancer
- copy number
- squamous cell carcinoma
- tyrosine kinase
- early stage
- machine learning
- radiation therapy
- public health
- locally advanced
- ejection fraction
- radiation induced
- combination therapy
- multiple sclerosis
- genome wide
- brain metastases
- brain injury