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Ann Oncol. 2015 Jan;26(1):238-44. doi: 10.1093/annonc/mdu484. Epub 2014 Oct 24.

Discrepancies between FISH and immunohistochemistry for assessment of the ALK status are associated with ALK 'borderline'-positive rearrangements or a high copy number: a potential major issue for anti-ALK therapeutic strategies.

Author information

1
Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice IRCAN Team 3, INSERM U1081/UMR CNRS 7284, Faculty of Medicine of Nice, University of Nice Sophia Antipolis, Nice.
2
Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice.
3
Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice IRCAN Team 3, INSERM U1081/UMR CNRS 7284, Faculty of Medicine of Nice, University of Nice Sophia Antipolis, Nice Hospital Integrated Biobank.
4
Department of Pneumology.
5
IRCAN Team 3, INSERM U1081/UMR CNRS 7284, Faculty of Medicine of Nice, University of Nice Sophia Antipolis, Nice Department of Thoracic Surgery, Pasteur Hospital, Nice.
6
Department of Pneumology, Centre Antoine Lacassagne, Nice, France.
7
IRCAN Team 3, INSERM U1081/UMR CNRS 7284, Faculty of Medicine of Nice, University of Nice Sophia Antipolis, Nice Department of Pneumology.
8
Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice IRCAN Team 3, INSERM U1081/UMR CNRS 7284, Faculty of Medicine of Nice, University of Nice Sophia Antipolis, Nice Hospital Integrated Biobank hofman.p@chu-nice.fr.

Abstract

BACKGROUND:

Patients with advanced lung adenocarcinomas expressing ALK rearrangements are highly responsive to crizotinib, a dual ALK/c-MET inhibitor. Immunohistochemistry (IHC) is an easy clinically and routinely applicable cost-effective assay for ALK, c-MET and ROS1 protein expression for potential treatment with crizotinib. The purpose of this study was to evaluate the percentage and the pattern of ALK-rearranged cells, the variation in the native ALK copy number, as well as ALK, c-MET and ROS1 protein expression, and their significance on outcome of crizotinib-treated lung adenocarcinoma patients.

PATIENTS AND METHODS:

Consecutive lung adenocarcinoma specimens (n = 176) 'double-negative' (wild-type EGFR and KRAS) were tested for ALK rearrangements/copy number alterations and for ALK, c-MET and ROS1 protein expression using automated standardized protocols. Preliminary data on the outcome of crizotinib-treated patients were recorded.

RESULTS:

FISH analysis identified 26/176 (15%) cases with ALK rearrangements. Seven cases had discordant results between the ALK FISH and IHC. Five cases with discordant FISH-positive/IHC-negative revealed FISH 'borderline' positivity (15%-20%). Three cases overexpressed c-MET and responded to crizotinib, and two cases with ALK-'borderline' rearranged cells only, not associated with c-MET expression, progressed under crizotinib. Two cases with discordant FISH-negative/IHC-positive revealed ALK gene amplification without associated c-MET or ROS1 protein expression.

CONCLUSIONS:

The discrepancies observed between the IHC and FISH data revealed unexpected biological events, rather than technical issues, which potentially can have a strong impact on the therapeutic strategy with crizotinib.

KEYWORDS:

ALK; crizotinib; discrepancy; fluorescence in situ hybridization; immunohistochemistry; lung adenocarcinoma

PMID:
25344360
DOI:
10.1093/annonc/mdu484
[Indexed for MEDLINE]

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