ROS1 Rearrangements in Lung Cancer: A New Genomic Subset of Lung Adenocarcinoma

During the last decade, the treatment of advanced non–small-cell lung cancer (NSCLC) has rapidly evolved from a one-size-fits-all approach to one of personalized medicine. Lung adenocarcinoma, the most common form of NSCLC, is composed of several different genomic subsets defined by unique oncogenic alterations (Fig 1). In most cases, these oncogenic alterations are mutually exclusive with one another. A major therapeutic goal has been to develop specific therapies for each genomic subset of patients with lung cancer. To date, clinically effective targeted therapies exist for patients with NSCLC whose tumors harbor epidermal growth factor receptor (EGFR) mutations (eg, EGFR kinase inhibitors gefitinib and erlotinib) and for those with anaplastic lymphoma kinase (ALK) rearrangements (eg, ALK kinase inhibitor crizotinib). Randomized clinical trials have demonstrated improved response rate and progression-free survival with gefitinib and erlotinib when administered as first-line systemic therapy for advanced EGFR-mutant NSCLC compared with systemic chemotherapy. These agents have become the preferred initial therapy for advanced disease in patients with NSCLC whose tumors harbor EGFR mutations. Clinical trials comparing crizotinib with combination chemotherapy are currently under way for advanced ALK-rearranged NSCLC. Although many of the genomic subsets of lung adenocarcinoma comprise only a small percentage of all adenocarcinomas, each subset translates into a significant number of patients, because lung cancer is such a common disease. For example, in the United States, there will be approximately 6,000 new patients diagnosed annually with ALKrearranged NSCLC (incidence of approximately 3%), which is greater than the number of new patients diagnosed with chronic myeloid leukemia. Thus it will be critical to develop systematic screening strategies to identify genomic subsets of patients with NSCLC, because effective clinical therapies are available. In Journal of Clinical Oncology, Bergethon et al examine ROS1 translocations in patients with NSCLC. Genomic alterations in ROS1 have been described in a subset of gliomas and identified a few years ago to also occur in NSCLC. An original report identified a ROS1 translocation in an Asian patient with NSCLC, but additional studies on the prevalence of this genetic alteration in Asian and white patients have been lacking. In the current study, Bergethon et al identify ROS1 rearrangements in 1.7% (18 of 1,073) of patients with NSCLC using fluorescence in situ hybridization. Patients with lung cancer whose tumors harbored ROS1 rearrangements were more likely to have adenocarcinoma and to be Asian, younger (median age of approximately 50 years), and never smokers, clinical features that are also associated with both EGFR mutations and ALK rearrangements. Preclinical studies have also identified a kinase inhibitor, TAE684, that effectively inhibited the growth of the HCC78 lung cancer cell line harboring a ROS1 translocation. In the current study, the authors show that crizotinib inhibits growth of the HCC78 cell line. On the basis of this result, Bergethon et al used crizotinib to treat a patient with NSCLC whose tumor had a ROS1 rearrangement; the patient had a remarkable clinical response and near-complete radiographic response to crizotinib, clinically confirming the concept of oncogene addiction in ROS1-rearranged cancers. The findings from the current study suggest that patients with lung cancer with ROS1 rearrangements represent another unique population for whom there may be an effective targeted therapy. Given the prevalence of 1.7%, this will translate to 3,000 to 4,000 new patients diagnosed annually with ROS1-rearranged NSCLC in the United States alone. This is a significant number of new patients for whom crizotinib may be an effective systemic therapy. Adenocarcinoma Squamous cell carcinoma