J Clin Oncol. 2012 Jan 3. [Epub ahead of print]
ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers.
Bergethon K, Shaw AT, Ignatius Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ.
Kristin Bergethon, Alice T. Shaw, Ryohei Katayama, Eugene J. Mark, Julie M. Batten, Eunice L. Kwak, Jeffrey W. Clark, Jeffrey A. Engelman, Mari Mino Kenudson, and A. John Iafrate, Massachusetts General Hospital, Boston, MA; Sai-Hong Ignatius Ou and Christina Siwak-Tapp, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange; Keith D. Wilner, Pfizer, La Jolla, CA: Christine M. Lovly, Nerina T. McDonald, Pierre P. Massion, Adriana Gonzalez, David P. Carbone, and William Pao, Vanderbilt University Medical Center; Pierre P. Massion, Nashville Veterans Affairs Medical Center, Nashville, TN; Rong Fang and Hongbin Ji, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Haiquan Chen, Fudan University Shanghai Cancer Center; and Haiquan Chen, Shanghai Medical College, Fudan University, Shanghai, China.
Chromosomal 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 METHODS
Using 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.
Of 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 < .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.
ROS1 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.