Detection of ROS1 rearrangement in non-small cell lung cancer: current and future perspectives

Abstract

ROS1 rearrangement characterizes a small subset (1%–2%) of non-small cell lung cancer and is associated with slight/never smoking patients and adenocarcinoma histology. Identification of ROS1 rearrangement is mandatory to permit targeted therapy with specific inhibitors, demonstrating a significantly better survival when compared with conventional chemotherapy. Detection of ROS1 rearrangement is based on in situ (immunohistochemistry, fluorescence in situ hybridization) and extractive non-in situ assays. While fluorescence in situ hybridization still represents the gold standard in clinical trials, this technique may fail to recognize rearrangements of ROS1 with some gene fusion partner. On the other hand, immunohistochemistry is the most cost-effective screening technique, but it seems to be characterized by low specificity. Extractive molecular assays are expensive and laborious methods, but they specifically recognize almost all ROS1 fusions using a limited amount of mRNA even from formalin-fixed, paraffin-embedded tumor tissues. This review is a discussion on the present and futuristic diagnostic scenario of ROS1 identification in lung cancer.

Lung cancer family history and exposure to occupational/domestic coal combustion contribute to variations in clinicopathologic features and gene fusion patterns in non‐small cell lung cancer

“…62 Our results regarding ALK and ROS1 fusion were similar to previous reports with the exception of elevated ROS1 fusion frequency (3.9%). 29,30,49,62 A meta-analysis including 1178 ALK rearranged cases from 20 541 NSCLC patients indicated that age, gender, smoking status, histology, tumor stage, and ethnicity may be a source of between-study heterogeneity. 19 According to the reference studies from three nations, there is obvious across population/subpopulation similarity and heterogeneity.…”

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

“…Although the recently updated CAP/IASLC/AMP molecular testing guidelines allow the use of ROS1 IHC for screening purposes, there has been only one antibody available to date (D4D6). [9][10][11] The sensitivity for this clone was controversial, probably reflecting the different interpretation criteria and the small numbers that were tested in most studies (reviewed in 9,10,[25][26][27][28] ). The recent release of a new clone (SP384), with only one published report available to date, provides an in vitro diagnostic alternative.…”

Correlation of ROS1 Immunohistochemistry With ROS1 Fusion Status Determined by Fluorescence In Situ Hybridization

“…Currently, one of the more commonly used IHC assays in the clinic is the ROS1 D4D6 rabbit monoclonal antibody (Cell Signaling Technologies, Danvers, Massachusetts), which is a research-use-only (RUO) assay. 6 With an RUO product, a variety of protocols, detection kits, and staining platforms are used. [9][10][11] This leads to variation in staining and interpretation of ROS1 IHC.…”

“…clinical practice, owing to its usefulness in clinical trials for determining ROS1 positivity. 6 An RT-PCR assay, on the other hand, is highly sensitive for detecting specific fusions, which the assay was designed to detect. However, owing to the more than 25 known different fusions and additional unknown fusions, it is difficult to design a multiplex PCR that is able to detect all possible rearrangements.…”

“…[3][4][5] In ROS1 rearrangements, the kinase domain of ROS1 (3 0 region) is conserved and fuses with one of the multiple known fusion partners (eg, CD74, EZR, FIG1, CCD6, KDELR2, LRI3, SDC4, SLC34A2, TPM3, and TPD52L1). 6 Testing for ROS1 status is important to be able to identify patients who may have a good response to crizotinib and possibly to other ROS1 therapies. 7,8 Multiple technologies can be used to test for ROS1 positivity; however, the gold standard for testing ROS1 positivity is fluorescence in situ hybridization (FISH).…”