• Florian Cabillic, Audrey Gros, Frédéric Dugay, Hugues Begueret, Laura Mesturoux, Dan Cristian Chiforeanu, Leila Dufrenot, Vincent Jauffret, Dominique Dachary, Romain Corre, Alexandra Lespagnol, Gwendoline Soler, Julien Dagher, Véronique Catros, Michèle Le Calve, Jean-Philippe Merlio, and Marc-Antoine Belaud-Rotureau.
• *Université de Rennes 1, Faculté de Médecine, Rennes, France; †Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France; ‡Service de Cytogénétique et Biologie Cellulaire, CHU de Rennes, Rennes, France; §Service de Biologie des Tumeurs, CHU de Bordeaux, Bordeaux, France; ‖UMR CNRS 6290, IFR 140, Rennes, France; ¶Service de Pathologie, CHU de Bordeaux, Pessac, France; #Service d'Anatomie et Cytologie Pathologiques, CHU de Rennes, Rennes, France; **Service de Pneumologie, CHU de Rennes, Rennes, France; and ††Service de Génétique Moléculaire et de Génomique Médicale, CHU de Rennes, Rennes, France.
• J Thorac Oncol. 2014 Mar 1; 9 (3): 295-306.

IntroductionAnaplastic lymphoma kinase (ALK) rearrangements occur in 1% to 7% of non-small-cell lung cancers (NSCLCs). Crizotinib, an ALK inhibitor, has been demonstrated to provide dramatic clinical benefits in ALK-positive advanced-stage NSCLC. Fluorescent in situ hybridization (FISH) has been established in clinical trials as the standard procedure method for detecting ALK rearrangements. Although the detection of ALK by immunohistochemistry (IHC) has been proposed for the screening of patients, large-scale studies are warranted to validate such a hierarchical approach.MethodsIn this article, we report the largest series thus far of parallel FISH and IHC ALK testing in 3244 consecutive NSCLC cases analyzed at two independent French centers.ResultsFISH-positive and/or IHC-positive results were demonstrated in 150 of 3244 cases (4.6%). An imbalanced sex ratio was detected, with women exhibiting a 2.2-fold relative risk for an alteration. Strikingly, only 80 of 150 specimens were classified as ALK positive by both techniques. The specimens with discordant FISH/IHC analyses were FISH-positive/IHC-negative (36), FISH-negative/IHC-positive (19), or FISH-noncontributive/IHC-positive (15). Thus, a single FISH or IHC analysis performed alone would have failed to detect approximately one-fourth of the ALK-positive cases with similar findings in our two centers.ConclusionsThis study highlights the feasibility of systematic NSCLC testing by both FISH and IHC in routine practice. Many preanalytical factors may account for the apparent discrepancies between both methods, suggesting that hierarchical screening may underscore ALK-positive cases. This significant level of discrepancy supports the need of combined testing to optimize the detection of ALK-inhibitor-eligible patients given that some patients with discordant testing were found to respond to crizotinib.

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