Abstract
ALK FISH analyses of multiple specimens occasionally yield inconsistent intersample results in lung cancer patients, posing clinical challenges requiring intensive analysis of all potential causative pre- and post- analytic factors. In this study, 19 patients (8M/11F) with inconsistent intersample ALK FISH results were analyzed, representing 4.9% of patients assessed ≥ twice in our institution. Fifteen patients received ALK tyrosine kinase inhibitor(s) (TKIs). Nine patients died, and ten were alive for 8 to 74-month follow-ups (median, 40 months). Through strict and stringent laboratory and case-review policies, all postanalytic factors were excluded. Correlating clinical information, ALK results obtained by RNA sequencing (RNA-seq) and other concurrent tests, several pre-analytic factors were determined. A suboptimal specimen was likely the cause in three patients, supported by the failure of one or more concurrent tests or discrepant results between FISH and RNA-seq. ALK inhibition by TKIs might have been responsible for the change of ALK status from positive to negative in eight patients. Other potential explanations include the existence of multiple primary lung cancer lesions, tumor heterogeneity, and the clonal evolution of tumor cells, related or not to ALK TKI therapy. This study is helpful for both pathologists and clinicians encountering inconsistent and/or discrepant intersample results.
Highlights
Introduction3–7% of nonsmall cell lung cancer (NSCLC) patients have neoplasms with constitutive anaplastic large-cell lymphoma kinase (ALK) activity due to ALK abnormalities, most frequently in the form of intrachromosomal inversion and consequent ALK rearrangement with the partner echinoderm microtubule associated protein-like 4 (EML4) forming EML4-ALK fusion
3–7% of nonsmall cell lung cancer (NSCLC) patients have neoplasms with constitutive anaplastic large-cell lymphoma kinase (ALK) activity due to ALK abnormalities, most frequently in the form of intrachromosomal inversion and consequent ALK rearrangement with the partner echinoderm microtubule associated protein-like 4 (EML4) forming EML4-ALK fusion.Crizotinib, a first-in-class ALK tyrosine kinase inhibitor (TKI) [1], and all the other ALK tyrosine kinase inhibitor(s) (TKIs) such as certinib [2], alectinib [3], lorlatinib [4] and brigatinib [5] have shown significant effects in improving both progression-free survival and overall survival in patients with ALK positive lung cancer in the past decade
Status changed from positive in the first tested sample to negative in a subsequent sample. This change may indicate that ALK TKIs are effective in eliminating ALK rearranged tumor cells. These results suggest that therapeutic agents other than ALK TKIs may be needed at the time ALK fluorescence in situ hybridization (FISH) becomes negative
Summary
3–7% of nonsmall cell lung cancer (NSCLC) patients have neoplasms with constitutive anaplastic large-cell lymphoma kinase (ALK) activity due to ALK abnormalities, most frequently in the form of intrachromosomal inversion and consequent ALK rearrangement with the partner echinoderm microtubule associated protein-like 4 (EML4) forming EML4-ALK fusion. Crizotinib, a first-in-class ALK tyrosine kinase inhibitor (TKI) [1], and all the other ALK TKIs such as certinib [2], alectinib [3], lorlatinib [4] and brigatinib [5] have shown significant effects in improving both progression-free survival and overall survival in patients with ALK positive lung cancer in the past decade. Cancers 2020, 12, 1903 inhibitors, have shown great promise in clinical trials [6,7,8]. Unambiguous identification of ALK status in a lung cancer specimen plays a vital role in the clinical management of these patients. Multiple assays that have been developed and applied for the assessment of ALK status, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), polymerase chain reaction (PCR) and reverse-transcription PCR (RT-PCR) assays, and generation sequencing (NGS)-based
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