ROS1 expression and translocations in non‐small‐cell lung cancer: clinicopathological analysis of 1478 cases

Abstract

ROS1 translocations are rare events in resected NSCLCs from Caucasian patients. Immunohistochemical screening for ROS1 expression and clinicopathological parameters, including female sex, early tumour stages, adenocarcinomas with TTF1 and/or napsin expression, and a distinct histomorphological growth pattern, strongly facilitate case enrichment. Molecularly driven multistep concepts might not be optimal for case selection.

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

“…ROS1 immunohistochemistry using the commercially available D4D6 clone appears to have a sensitivity approaching 100% but variable specificity for detection of ROS1-rearranged lung ACAs, with some groups reporting 92% to 97% specificity 106,107 and others reporting an 8-fold relative frequency of immunohistochemical to FISH positivity. 110 The variability in the analytic features of this IHC marker are likely related in part to the scoring algorithm, and obviously the sensitivity and specificity can be optimized by redefining criteria for positivity. 103 Individual laboratories may choose alternative definitions for positivity depending on how they use ROS1 IHC; if a positive score is defined to optimize sensitivity in particular, IHC may be a cost-effective screening tool to integrate into an algorithmic biomarker testing strategy, limiting the volume of cases that require FISH screening.…”

“…104,106,107 ROS1 rearrangements have been described almost exclusively in tumors that lack other driving molecular alterations in genes such as EGFR, KRAS, and ALK; however, some groups have reported ROS1 translocations in conjunction with other driver alterations. 110 Additional data on the clinical significance of these combined alterations are needed; if these findings are validated and clinically relevant, more comprehensive testing (i.e., nonalgorithmic/sequential) strategies such as next-generation sequencing will be needed to provide optimal biomarker identification.…”

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

“…This recommendation is evidence based and supported by 9 studies, 30e38 6 of which informed on the association between ROS1 rearrangement and patient or tumor characteristics 30,31,34e37 and consisted of 1 prospective cohort study (PCS), 35 1 prospective-retrospective cohort study (PRCS), 31 and 4 retrospective cohort studies (RCSs). 30,34,36,37 The 3 remaining studies assessed clinical outcomes of patients treated with the ROS1-targeted therapy crizotinib 32,33,38 and included 1 nonrandomized clinical trial 33 and 3 RCSs. 32,38 All included studies were assessed for quality and none were found to have methodologic flaws that would raise concerns about the studies' findings (SDC Table 6).…”

ROS1 gene rearrangement and expression of splice isoforms in lung cancer, diagnosed by a novel quantitative RT-PCR assay

“…However, ROS1 is more often expressed in NSCLC without concomitant translocation (4-30% NSCLC) [9,10,13,15]. Accordingly, ROS1 protein expression was restricted to tumors that harbored ROS1 rearrangements or overexpressed non-rearranged ROS1 transcripts in our study.…”

“…The sensitivity of ROS1 immunostaining for rearrangements was reported to be 100% [9][10][11][12][13][14] and, as such, IHC was suggested as an effective screening tool in NSCLC. However, ROS1 is more often expressed in NSCLC without concomitant translocation (4-30% NSCLC) [9,10,13,15].…”