• Lénaïg Mescam-Mancini, Sylvie Lantuéjoul, Denis Moro-Sibilot, Isabelle Rouquette, Souquet Pierre-Jean PJ Servie de Pneumologie, CH Lyon Sud, France., Clarisse Audigier-Valette, Jean-Christophe Sabourin, Chantal Decroisette, Linda Sakhri, Elisabeth Brambilla, and Anne McLeer-Florin.
• Département d'Anatomie et Cytologie Pathologiques, Pôle de Biologie et Pathologie, CHU Grenoble, France; Plateforme de Génétique Moléculaire des Tumeurs, Pôle de Biologie et Pathologie, CHU Grenoble, France.
• Lung Cancer. 2014 Feb 1; 83 (2): 168-73.

ObjectivesROS1 proto-oncogene translocations define a new molecular subgroup in non-small cell lung cancers (NSCLC) and are associated with a response to the MET/ALK inhibitor, crizotinib. These rearrangements are described in 0.9-1.7% NSCLC, in wild-type EGFR, KRAS and ALK ("triple negative") lung adenocarcinomas. Rapid and efficient identification of these alterations is thus becoming increasingly important.Materials And MethodsIn this study, 121 triple negative lung adenocarcinomas were screened by both IHC with the ROS1 D4D6 antibody, and FISH using two commercially available ROS1 break-apart probes. To address a possible cross-reactivity of the ROS1 antibody with other protein kinase receptors, we screened 80 additional cases with known EGFR, KRAS, PI3KCA, BRAF, HER2 mutations or ALK-rearrangement.ResultsWe diagnosed 9 ROS1-rearranged adenocarcinomas, with both a positive FISH result (51-87% rearranged nuclei) and a positive IHC staining (2+/3+ cytoplasmic staining). Only one of the ROS1-positive FISH cases was characterized by a classical split pattern, the others showed a variant pattern, most commonly involving a loss of the 5' telomeric probe. Considering a positivity threshold of 2+ stained cells, the sensitivity of the ROS1 D4D6 antibody compared to FISH was 100% and the specificity 96.9%, as two HER2-mutated tumors were positive with D4D6 antibody, without any translocation in FISH. All the ROS1-positive cases were at an advanced stage, arising in never or light smokers. They were mainly solid cribriform and acinar adenocarcinomas, with signet ring cells noted in 5 cases, and calcifications in 3 cases. One positive case was an invasive mucinous carcinoma.ConclusionOur results show that a screening algorithm based on an IHC detection of ROS1 fusion proteins, confirmed if positive or doubtful by a ROS1 break-apart FISH assay, is pertinent in advanced "triple negative" lung adenocarcinomas, since the prevalence of ROS1-positive cases in this selected population reaches 7.4% in our series.Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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