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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non-Small
A J van der Wekken1, R Pelgrim2, N 't Hart2
1Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. a.j.van.der.wekken@umcg.nl.
Abstract:
Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non-small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH.Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH-positive advanced NSCLC from four other hospitals were used for validation.Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC-positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH-positive but ALK-IHC-negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P = 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P = 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P = 0.01, respectively].Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy. Clin Cancer Res; 23(15); 4251-8. ©2017 AACR.
Insights
Immunohistochemistry (IHC) for ALK protein expression is superior to FISH testing for predicting treatment response in advanced non-small cell lung cancer (NSCLC) patients receiving crizotinib. This IHC method offers better prediction of tumor response and survival outcomes.
Area of Science:
- Oncology
- Molecular Diagnostics
- Thoracic Surgery
Background:
- ALK rearrangement detection via FISH is standard for identifying non-small cell lung cancer (NSCLC) patients eligible for ALK inhibitor therapy.
- Recent studies indicate ALK protein expression, assessed by immunohistochemistry (IHC), has predictive value in resectable NSCLC.
Purpose of the Study:
- To evaluate tumor response and survival rates in advanced NSCLC patients treated with crizotinib.
- To compare the efficacy of dichotomous IHC staining versus FISH for detecting ALK activation.
Main Methods:
- Patients with stage IV NSCLC treated with crizotinib were analyzed.
- ALK rearrangements were detected using both FISH and Ventana ALK (D5F3) CDx assay (IHC).
- Validation was performed using external cohorts of ALK-FISH-positive NSCLC patients.
Main Results:
- Dichotomous ALK-IHC outperformed ALK-FISH in predicting tumor response (AUC, 0.86 vs. 0.64) and survival (PFS AUC 0.86 vs. 0.36; OS AUC 0.78 vs. 0.41).
- ALK-IHC-positive patients showed response to crizotinib, except for three with primary resistance.
- No tumor response was observed in ALK-FISH-positive but ALK-IHC-negative patients, confirmed in validation cohorts.
Conclusions:
- Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA for predicting response and survival to crizotinib in advanced NSCLC.
- Clinical guidelines should be adapted to use dichotomous ALK-IHC as a standard companion diagnostic test for patient selection in ALK-targeting therapy.
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