ROS1 Gene Fusion in Advanced Lung Cancer in Women: A Systematic Analysis, Review of the Literature, and Diagnostic Algorithm

Abstract

Purpose Crizotinib, a mesenchymal-epithelial transition/anaplastic lymphoma kinase/c-ros oncogene 1 (ROS1) inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of patients with advanced ROS1-positive non–small-cell lung cancer (NSCLC). Therefore, interest in ROS1 testing is growing. ROS1 gene fusions affect approximately 0.5% to 2% of unselected NSCLCs. Limited data are available on the prevalence and distribution of ROS1 fusions in patients with advanced-stage NSCLC. Material and Methods A series of 727 lung adenocarcinomas from patients with stage IV disease, negative for epidermal growth factor receptor and anaplastic lymphoma kinase alterations, were tested for ROS1 fusions by fluorescent in situ hybridization analysis, with confirmation by immunohistochemistry. Results were correlated with clinicopathologic parameters and compared with data from the literature. Results ROS1 fusions were detected in 29 patients (4%), including 27 of 266 females (10.2%) and two of 461 males (0.4%; P = 1.2E-10). The mean age of patients with ROS1-positive disease was lower than that of patients with ROS1-negative disease (49.21 v 62.96 years, respectively; P = 1.1E-10). Eleven of 583 smokers (1.9%) and 18 of 144 nonsmokers (12.5%) showed ROS1 rearrangement ( P = 4.05E-7). By logistic regression analysis, ROS1 fusions were independently associated with female sex, younger age at diagnosis, and absence of smoking history, (odds ratios, 12.4, 7.9, and 3.6, respectively). These data, integrated with those reported in the literature, indicate that the prevalence of ROS1 fusions in females and in nonsmokers was higher in patients with advanced disease than in patients with operable disease (11.2% v 3.1%, P < .001; 11.6% v 2.8%, P < .001, respectively). The mean age at diagnosis was significantly lower in patients with advanced disease (49.8 years) than in patients with operable disease (55.6 years; P < .001). Conclusion Our data indicate that ROS1 fusions in patients with advanced-stage lung adenocarcinoma are more frequent in females, particularly if young and nonsmokers. A diagnostic algorithm for an accurate screening of ROS1 alterations was elaborated.

A Single-Institute Experience with C-ros Oncogene 1 Translocation in Non-Small Cell Lung Cancers in Taiwan

“…Interestingly, the prevalence of ROS1 translocation was significantly higher in the female group in our 479 EGFR wild-type cases in the prospective group. This sex-related trend was also found in other ROS1 epidemiological studies in Europe [ 29 ] and the United Nations [ 24 ].…”

Reflex ROS1 IHC Screening with FISH Confirmation for Advanced Non-Small Cell Lung Cancer—A Cost-Efficient Strategy in a Public Healthcare System

“…The proportion of EGFRand ALK-positive cases among never-smokers was estimated at 60% [34]. Lastly, the probability of ROS1 fusions among EGFR and ALK wild-type never-smokers was estimated at 12% [35]. We assumed that ROS1 fusions were exclusive of EGFRand ALK-detected aberrations, such that all ROS1-positive cases would be detected among EGFR and ALK wild-type cases.…”

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

“…In a recent study on 727 lung adenocarcinomas from patients with stage IV disease, ROS1 fusions were independently associated with female sex, younger age at diagnosis and absence of smoking history 59. Compared with ALK -positive adenocarcinoma, the ROS-1 positive counterpart is more significantly associated with a peripheral location 60–62…”