Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

Kim, Min Hwan; Shim, Hyo Sup; Kang, Dae Ryong; Jung, Ji Ye; Lee, Chang Young; Kim, Dae Joon; Lee, Jin Gu; Bae, Min Sun; Kim, Hye Ryun; Lim, Sun Min; Kim, Eun Young; Park, Ji Soo; Chung, Kwansoo; Kim, Hyun Jung; Kim, Joo Hang; Cho, Byoung Chul

doi:10.1016/j.lungcan.2014.01.003

Cited by 54 publications

(52 citation statements)

References 32 publications

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“…Sensitivity and specificity of IHC (Novocastra, Clone 5A4, Newcastle, UK) screening was comparable to ours, 100% and 98.7%, respectively. Two of the latest Korean trials 8,9 also reported higher frequency of EML4-ALK mutation than Chinese, European or our trial. In comparable but pre-selected non-smoker population, 9% of patients were having EML4-ALK mutation confirmed by IHC and FISH tests 8,10.…”

Section: Discussionsupporting

confidence: 51%

Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

et al. 2016

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Introduction: The incidence of echinoderm microtubule-associated protein-like4-anaplastic lymphoma kinase (EML4-ALK) mutation among surgically treated patients with adenocarcinoma of the lung of the Eastern European ethnicity is underreported. The aim of this trial was the determination of EML4-ALK mutation frequency in investigated population, and the evaluation of correlations between lung adenocarcinoma subtype and clinical characteristics with mutation status.Patients and methods: This was a prospective trial which included 195 patients with adenocarcinoma of the lung who underwent surgical treatment. ALK mutation screening was performed by immunohistochemistry (IHC). IHC scores of 2+ and 3+ were regarded as positive. Confirmatory FISH was performed in all IHC positive and in 2:1 ratio in negative patients.Results: Overall ALK mutation rate established by IHC was 6.2%, while FISH confirmed rate of 5.1%. The FISH confirmed ALK positivity in 7.6% Hungarians, 5.5% Serbians, and 6.6% Slovakians. Acinar subtype of adenocarcinoma of the lung was significantly (p=0.02) related to EML4-ALK positive mutation status. Most of the patients were males (56.9%), smokers (50.8%), or former smokers (28.7%) with acinar (55.4%) or solid (35.9%) adenocarcinoma of the lung. Sensitivity and specificity of IHC were 100% and 98.9% respectively.Conclusions: ALK mutation rate in surgically treated patients with adenocarcinoma of the lung was found to be 6.2% by IHC and 5.1% by FISH. Acinar subtype of the adenocarcinoma of the lung was significantly related to ALK positive mutation.

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Section: Discussionsupporting

confidence: 51%

Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

et al. 2016

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“…After reading the title and abstract, 61 articles were selected to read the full articles by two investigators (ZX Zhang, XD Yin), 3 of them were excluded as the cohort was similar in other articles (studies excluded [9], [10], [11]; studies included [12], [13], [14]. Finally, 22 studies were found eligible for the systematic review which were published between 2007 and 2014 [15], [13], [16]–[24], [12], [25]–[32], [14], [33], in which 5 studies could not provide sufficient data for meta-analysis [16], [19], [20], [32], [14]. Figure 1 shows the flow chart of the search result.…”

Section: Resultsmentioning

confidence: 99%

Prognostic Value of Epidermal Growth Factor Receptor Mutations in Resected Non-Small Cell Lung Cancer: A Systematic Review with Meta-Analysis

et al. 2014

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BackgroundThe prognostic value of epidermal growth factor receptor (EGFR) mutations in resected non-small cell lung cancer (NSCLC) remains controversial. We performed a systematic review with meta-analysis to assess its role.MethodsStudies were identified via an electronic search on PubMed, Embase and Cochrane Library databases. Pooled hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis.ResultsThere were 16 evaluated studies (n = 3337) in the meta-analysis. The combined HR evaluating EGFR mutations on disease free survival was 0.96 (95% CI [0.79–1.16] P = 0.65). The combined HR evaluating EGFR mutations on overall survival was 0.86 (95% CI [0.72–1.04] P = 0.12). The subgroup analysis based on univariate and multivariate analyses in DFS and OS showed no statistically significant difference. There was also no statistically significant difference in DFS and OS of stage I NSCLC patients.ConclusionThe systematic review with meta-analysis showed that EGFR mutations were not a prognostic factor in patients with surgically resected non-small cell lung cancer. Well designed prospective study is needed to confirm the result.

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“…Despite this, no human ROS1 ligand has been found to date and the physiological function of this orphan receptor is still unclear. The C-terminal portion of ROS1 contains a kinase domain and a single transmembrane domain [9, 15–17]. …”

Section: Rationale For Targeting Ros1 Fusions In Nsclcmentioning

confidence: 99%

“…The screening strategy for ROS1 rearrangement was developed based on the experience of ALK testing in lung adenocarcinomas [17, 23, 32]. While ROS1 alterations may be detected with a variety of techniques, most laboratories rely on FISH assays using a dual-colour break-apart probe design.…”

Section: Detection Of Ros1 Gene Rearrangementsmentioning

confidence: 99%

Testing for ROS1 in non-small cell lung cancer: a review with recommendations

et al. 2016

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Rearrangements of the ROS1 gene occur in 1–2 % of non-small cell lung cancers (NSCLCs). Crizotinib, a highly effective inhibitor of ROS1 kinase activity, is now FDA-approved for the treatment of patients with advanced ROS1-positive NSCLC. Consequently, focus on ROS1 testing is growing. Most laboratories currently rely on fluorescence in situ hybridisation (FISH) assays using a dual-colour break-apart probe to detect ROS1 rearrangements. Given the rarity of these rearrangements in NSCLC, detection of elevated ROS1 protein levels by immunohistochemistry may provide cost-effective screening prior to confirmatory FISH testing. Non-in situ testing approaches also hold potential as stand-alone methods or complementary tests, including multiplex real-time PCR assays and next-generation sequencing (NGS) platforms which include commercial test kits covering a range of fusion genes. In order to ensure high-quality biomarker testing, appropriate tissue handling, adequate control materials and participation in external quality assessment programmes are essential, irrespective of the testing technique employed. ROS1 testing is often only considered after negative tests for EGFR mutation and ALK gene rearrangement, based on the assumption that these oncogenic driver events tend to be exclusive. However, as the use of ROS1 inhibitors becomes routine, accurate and timely detection of ROS1 gene rearrangements will be critical for the optimal treatment of patients with NSCLC. As NGS techniques are introduced into routine diagnostic practice, ROS1 fusion gene testing will be provided as part of the initial testing package.

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Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

Cited by 54 publications

References 32 publications

Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

Prognostic Value of Epidermal Growth Factor Receptor Mutations in Resected Non-Small Cell Lung Cancer: A Systematic Review with Meta-Analysis

Testing for ROS1 in non-small cell lung cancer: a review with recommendations

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