Abstract
PurposeFluorescence in situ hybridization (FISH) using tumor tissue is the gold standard for detection of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC). However, this method often is not repeatable due to difficulties in the acquisition of tumor tissues. Blood-based liquid biopsy using reverse transcription polymerase chain reaction (RT-PCR) is expected to be useful to overcome this limitation. Here, we investigated the feasibility of liquid biopsy using plasma and platelets for detection of ALK rearrangement and prediction of ALK inhibitor treatment outcomes.MethodsALK-FISH assays were performed in 1128 tumor specimens of NSCLC between January 2015 and June 2018. We retrospectively analyzed formalin-fixed paraffin-embedded (FFPE) tissues from previously confirmed FISH-positive (n = 199) and -negative (n = 920) cases. We recruited patients who had available tissue specimens and agreed to venous sampling. RNA was extracted from FFPE blocks, plasma, and platelets. Fusion RNA of echinoderm microtubule-associated protein-like 4 (EML4)-ALK was detected by quantitative PCR.ResultsThirty-three FISH-positive and 28 FISH-negative patients were enrolled. In validation, data compared with FISH, RT-PCR using FFPE tissues showed 54.5% sensitivity, 78.6% specificity, and 75.5% accuracy. Liquid biopsy had higher sensitivity (78.8%), specificity (89.3%) and accuracy (83.6%). Higher positivity for liquid biopsy was shown in subgroups with delayed (≥ 6 months from diagnosis) blood sampling (plasma, 85.7%; platelets, 87.0%). In 26 patients treated with crizotinib, the platelet-positive subgroup showed longer median duration of treatment (7.2 versus 1.5 months), longer median progression-free survival (5.7 months versus 1.7 months), a higher overall response rate (70.6% versus 11.1%), and a higher disease control rate (88.2% versus 44.4%) than the platelet-negative subgroup.ConclusionLiquid biopsy could have applications in the diagnosis of ALK-positive NSCLC, even when using RT-PCR, and platelets can be useful for predicting treatment outcomes of ALK inhibitors.
Highlights
Rearrangements in the anaplastic lymphoma kinase (ALK) gene occur in 3–7% of patients with non-small cell lung cancer (NSCLC) (Shaw et al 2009), and ALK-positive lung cancer has been defined as a distinct clinical and molecular subtype of NSCLC (Lin et al 2017; Shaw et al 2009; Soda et al 2007)
NSCLCs harboring ALK rearrangements are ALK-dependent for growth and survival, and show marked sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib (Shaw et al 2013; Solomon et al 2014), ceritinib (Shaw et al 2017; Soria et al 2017), and alectinib (Novello et al 2018; Peters et al 2017)
Journal of Cancer Research and Clinical Oncology (2019) 145:2071–2082 according to recent clinical trials, ALK-positive lung cancer could be considered as the best subgroup in advanced-stage NSCLCs, showing good long-term survival when ALK TKIs are given as first-line treatment and continue to subsequent treatment (Peters et al 2017; Solomon et al 2018)
Summary
Rearrangements in the anaplastic lymphoma kinase (ALK) gene occur in 3–7% of patients with non-small cell lung cancer (NSCLC) (Shaw et al 2009), and ALK-positive lung cancer has been defined as a distinct clinical and molecular subtype of NSCLC (Lin et al 2017; Shaw et al 2009; Soda et al 2007). Immunohistochemistry (IHC) is widely used and FDA-approved diagnostic test to identify ALK protein, and correlation between positive ALK IHC and a positive ALK-FISH is over 90% in general (Kerr and Lopez-Rios 2016; Lindeman et al 2018). This method often is not repeatable due to difficulties in the acquisition of tumor tissues (Kerr and Lopez-Rios 2016). Platelets can be immediately isolated and can undergo repetitive examinations for serial monitoring of biomarkers using RT-PCR (Best et al 2015; Nilsson et al 2011; Nilsson et al 2016)
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