Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non-Small Cell Lung Cancer.
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.
Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. a.j.van.der.wekken@umcg.nl.
A J
AJ
van der Wekken
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
R
R
Pelgrim
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
N
N
't Hart
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
N
N
Werner
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
M F
MF
Mastik
Department of Pulmonary Diseases, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
L
L
Hendriks
Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
E H F M
EHFM
van der Heijden
Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
M
M
Looijen-Salamon
Department of Pulmonary Diseases, Free University Medical Centre, Amsterdam, the Netherlands.
A J
AJ
de Langen
Department of Pulmonary Diseases, ZGT Almelo/Hengelo, Hengelo, the Netherlands.
J
J
Staal-van den Brekel
Department of Pathology/LabPON, ZGT Almelo/Hengelo, Hengelo, the Netherlands.
S
S
Riemersma
Department of Pulmonary Diseases, Catharina Cancer Institute, Catharina Hospital Eindhoven, the Netherlands.
B E
BE
van den Borne
Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
E J M
EJM
Speel
Department of Pulmonary Diseases, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
A-M C
AC
Dingemans
Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
T J N
TJN
Hiltermann
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
A
A
van den Berg
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
W
W
Timens
Department of Pathology and Medical Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
E
E
Schuuring
Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
H J M
HJM
Groen
D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000302:isolation & purification; D044963:Biopsy, Fine-Needle; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000302:isolation & purification
D014408:Biomarkers, Tumor; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases