Multicenter Immunohistochemical ALK-Testing of Non–Small-Cell Lung Cancer Shows High Concordance after Harmonization of Techniques and Interpretation Criteria

Abstract

This so-called "ALK-Harmonization-Study" shows for the first time that predictive semiquantitative IHC reveals reliable and reproducible results across several labs when methodology and interpretation are strictly defined and the pathologists are uniquely trained. The application of validated ALK IHC assays and its comparison to ALK-FISH is highly needed in future clinical trials. This might answer the question if ALK-IHC cannot only serve as a prescreening tool, but as a stand-alone test at least in cases displaying an unequivocally staining pattern as well as an alternative predictive test in samples with reduced FISH interpretability.

Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…Rapid prescreening can be performed with immunohistochemistry (IHC) to assess for ALK rearrangements; if positive, FISH analysis can confirm ALK positivity. [65][66][67][68][69][70][71][72][73][74] NGS can also be used to assess whether ALK rearrangements are present, if the platform has been appropriately designed and validated to detect ALK rearrangements. [75][76][77] Crizotinib-an inhibitor of ALK, ROS1, and some MET tyrosine kinases (high-level MET amplification or MET exon 14 skipping mutation)-is FDA-approved for patients with locally advanced or metastatic NSCLC who have ALK gene rearrangements (ie, ALK-positive disease) or ROS1 rearrangements.…”

Assessment of ALK gene fusions in lung cancer using the differential expression and exon integrity methods

“…However, FISH methods are expensive, require a high degree of technological expertise and frequently produce non-interpretable results (7,8). By contrast, IHC is able to detect the levels of ALK protein, and several commercial systems with specific monoclonal antibodies against ALK protein are available (7,8). However, the protocol for IHC is complex and time-consuming, and final results of IHC are subject to antibody quality and pathologist experience (12).…”

“…FISH-based methods have an advantage in that the general morphology of tumor cells and the physical integrity of chromosome 2 may be observed simultaneously. However, FISH methods are expensive, require a high degree of technological expertise and frequently produce non-interpretable results (7,8). By contrast, IHC is able to detect the levels of ALK protein, and several commercial systems with specific monoclonal antibodies against ALK protein are available (7,8).…”

“…For ALK rearrangement detection, the U.S. Food and Drug Administration (FDA)-approved method for companion diagnostics is fluorescence in situ hybridization (FISH), which measures the physical integrity of the ALK gene in chromosome 2 (7). However, previous studies have identified that FISH is prone to technical difficulties, which may lead to non-interpretable results (8,9). In addition, FISH is unable to detect genomic gain or overexpression of the ALK gene (10).…”

“…Immunohistochemistry (IHC) is another method commonly used clinically for ALK detection in tumor tissues (8)(9)(10); it detects the levels of ALK protein, rather than gene rearrangement, in tumor cells. Studies have revealed that results obtained using IHC are highly concordant with those obtained using FISH (8,9), and IHC is able to capture ALK-positive tumors that are not detected using FISH (9,10). However, IHC is a time-consuming method, its success is subject to antibody quality and the experience of technologists, and the interpretation of IHC results is subjective (12).…”