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Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

ABSTRACT: Capture-based next-generation sequencing (NGS) is a potentially useful diagnostic method to measure tumor tissue DNA in blood as it can identify concordant mutations between cell-free DNA (cfDNA) and primary tumor DNA in lung cancer patients. In this study, the sensitivity, specificity and accuracy of capture-based NGS for detecting ALK fusion in plasma cfDNA was assessed. 24 patients with tissue ALK-positivity and 15 who did not harbor ALK fusion were enrolled. 13 ALK-positive samples were identified by capture-based NGS among the 24 samples with tissue ALK-positivity. In addition to EML4-ALK, 2 rare fusion types (FAM179A-ALK and COL25A1-ALK) were also identified. The overall sensitivity, specificity and accuracy for all cases were 54.2%, 100% and 71.8%, respectively. For patients without distant metastasis (M0-M1a) and patients with distant metastasis (M1b), the sensitivities were 28.6% and 64.7%, respectively. In the 15 patients who received crizotinib, the estimated median PFS was 9.93 months. Thus, captured-based NGS has acceptable sensitivity and excellent specificity for the detection of ALK fusion in plasma cfDNA, especially for patients with distant metastasis. This non-invasive method is clinically feasible for detecting ALK fusion in patients with advanced-stage NSCLC who cannot undergo traumatic examinations or have insufficient tissue samples for molecular tests.

SUBMITTER: Cui S

PROVIDER: S-EPMC5356840 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

Cui Shaohua S Zhang Wei W Xiong Liwen L Pan Feng F Niu Yanjie Y Chu Tianqing T Wang Huimin H Zhao Yizhuo Y Jiang Liyan L

Oncotarget 20170101 2

Capture-based next-generation sequencing (NGS) is a potentially useful diagnostic method to measure tumor tissue DNA in blood as it can identify concordant mutations between cell-free DNA (cfDNA) and primary tumor DNA in lung cancer patients. In this study, the sensitivity, specificity and accuracy of capture-based NGS for detecting ALK fusion in plasma cfDNA was assessed. 24 patients with tissue ALK-positivity and 15 who did not harbor ALK fusion were enrolled. 13 ALK-positive samples were iden ...[more]

PMID: 27926526

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Project description:BackgroundNext-generation sequencing has mostly been used for genotyping cell-free DNA (cfDNA) in plasma. However, this assay has several clinical limitations. We evaluated the clinical utility of a novel polymerase chain reaction-free nanowire (NW)-based plasma cfDNA assay for detecting ALK fusion and mutations.Patients, materials, and methodsWe consecutively enrolled 99 patients with advanced non-small cell lung cancer undergoing a fluorescence in situ hybridization (FISH) test for ALK fusion; ALK-positive (n = 36). The NW-based assay was performed using 50-100 μL of plasma collected at pretreatment and every 8 weeks during ALK inhibitor treatment.ResultsThere was high concordance between the NW-based assay and the FISH test for identification of ALK fusion (94.9% with a kappa coefficient value of 0.892, 95% confidence interval [CI], 0.799-0.984). There was no difference in the response rate to the first anaplastic lymphoma kinase inhibitor between the ALK-positive patients identified by the NW-based assay and by the FISH test (73.5% vs. 72.2%, p = .931). In the ALK variant analysis, variants 1 and 3 subgroups were detected in 27 (75.0%) and 8 (22.2%) patients, respectively. Among 24 patients treated with crizotinib, variant 3 subgroup was associated with worse median overall survival than variant 1 subgroup (36.5 months; 95% CI, 0.09-87.6 vs. 19.8 months; 95% CI, 9.9-not reached, p = .004]. A serial assessment identified that ALK L1196M resistance mutation emerged before radiologic progression during crizotinib treatment.ConclusionThe newly developed simple NW-based cfDNA assay may be clinically applicable for rapid diagnosis of ALK fusion with its variant forms and early detection of resistance.Implications for practiceThe authors developed a novel one-step polymerase chain reaction-free nanowire (NW)-based plasma cell-free DNA (cfDNA) assay. This study evaluated the clinical utility of this novel method for the diagnosis of EML4-ALK fusion in advanced non-small cell lung cancer (NSCLC). The NW-based assay and FISH test showed high concordance rate in 99 patients with advanced NSCLC. Serial cfDNA assessment demonstrated this method provided early detection of resistance before radiologic progression during crizotinib treatment. Taken together, plasma cfDNA genotyping by the NW-based cfDNA assay may be useful for the rapid diagnosis of ALK fusion, classifying variants, and early detection of resistance.

Dataset Information

Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

Publications

Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

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