ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers

Abstract

A B S T R A C T PurposeChromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. Patients and MethodsUsing a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. ResultsOf 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P Ͻ .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. ConclusionROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.

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“…30,37 However, this association has not been consistently observed across studies. 34 Other clinical characteristics, such as younger age, female sex, and non-Asian ethnicity, have been associated with ROS1 rearrangement in isolated studies only.…”

“…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).…”

“…Although relatively rare, accounting for <2% of nonesmall cell lung carcinomas 30,31,34 and 2% to 3% of lung adenocarcinomas, 30,34,35 structural rearrangements involving the ROS1 gene generate an oncogenic fusion that can be treated successfully with targeted inhibitors. A single phase I clinical trial of 50 NSCLC patients demonstrated that the presence of a ROS1 rearrangement by FISH or RT-PCR predicts response to targeted inhibition using crizotinib, with a response rate of 72% and median progression-free survival of 19.2 months.…”

“…34 Other clinical characteristics, such as younger age, female sex, and non-Asian ethnicity, have been associated with ROS1 rearrangement in isolated studies only. 30,31,35 Therefore, clinical characteristics should not be used to either select or exclude patients from testing for ROS1 rearrangements. ROS1 rearrangements occur in a mutually exclusive fashion with other oncogenic driver alterations (such as EGFR and KRAS mutation and ALK rearrangement).…”

“…30,35,181,215,216 Although other studies have indicated that these findings may reflect testing bias, 217 the documentation of an association between younger patient age and an actionable biomarker is another consideration in selecting patients for testing. The boundary between young and not young is not well defined, however, and a clear evidence-based cutoff for this guideline cannot be established.…”