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Study defined role of ROS1 gene mutation in subset of NSCLC

Bergethon K. J Clin Oncol. 2012;doi:10.1200/JCO.2011.35.6345.

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An abnormality in the ROS1 gene due to chromosomal rearrangement drove the growth of non–small cell lung cancer tumors, according to study results published in the Journal of Clinical Oncology.

Based on earlier studies indicating that ROS1-positive tumors could possess sensitivity to crizotinib (Xalkori, Pfizer), an anaplastic lymphoma kinase (ALK) inhibitor, researchers used a ROS1 fluorescent in situ hybridization assay to screen patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, OS and ALKrearrangement status.

The researchers screened tumor samples from a series of 1,073 patients with NSCLC treated at Massachusetts General Hospital Cancer Center (n=574), Vanderbilt University Medical Center (n=443), University of California Irvine Medical Center (n=52) and Fudan University Shanghai Cancer Center (n=4). Medical records for study participants were reviewed for relevant data on clinicopathologic characteristics such as age, gender, stage, histology, smoking history and OS, which was measured from the date of diagnosis until the date of death.

According to study analysis, 1.7% (18/1,073) of the screened tumors were identified as ROS1 rearranged, whereas 2.9% (31/1,073) were identified as ALK rearranged. None of the samples exhibited alterations in both genes. While ROS1-positive and ROS1-negative groups showed no difference in OS, patients with ROS1 rearrangements were observed to be significantly younger and more likely to be never-smokers (each P<.001).

“ROS1 encodes a protein that is important for cell growth and survival, and deregulation of ROS1 through chromosomal rearrangement drives the growth of tumors,” researcher Alice Shaw, MD, PhD, of the MGH Cancer Center, said in a press release. “This finding is important because we have drugs that inhibit ROS1 and could lead to the sort of dramatic clinical response we describe in this paper.”

In vitro studies were used to confirm the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib — in particular, the HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 exhibited evidence of sensitivity. As part of an expansion cohort of an early phase study of crizotinib responsiveness, researchers enrolled a ROS1-positive patient with advanced NSCLC whose tumor demonstrated neither EGFR mutation nor ALK rearrangement.

The patient, administered crizotinib at the standard dose of 250 mg twice daily, was observed to experience a significant improvement in symptoms in less than 1 week and had resolved hypoxia by 2 weeks. Follow-up scans at 8 weeks demonstrated near complete resolution of the patient’s multifocal lung tumor, which was subsequently confirmed at 12 weeks. 

Disclosure: The researchers report receiving funding from AstraZeneca, Pfizer, Novartis, Abbott Molecular and ARIAD.

The article published by Dr. Kristin Bergethon and colleagues characterized and established ROS1 chromosomal rearrangement as yet another unique molecular class of lung cancer, that is actionable. Most important, this patient class shares remarkably similar clinical profile with mutant EGFR and ALK rearranged lung cancer, namely young age of onset and non-smoking history. As an insulin receptor family kinase, ROS1 oncogenic fusion was originally reported in glioblastoma as FIG-ROS1, and then identified also in lung cancer (SLC34a2-ROS1, CD74-ROS1) more recently. Using a ROS1 FISH assay, Bergethon et al. screened 1,073 NSCLC patients and established that ROS1 fusion occurred at 2.9% prevalence, but with 6% among never-smokers, with no overall survival prognostic impact.

The authors should be congratulated in demonstrating the clinical translational impact of ROS1-rearranged NSCLC as an actionable target, exhibiting sensitivity to the ALK-MET inhibitor crizotinib both in cell line preclinical studies and in an advanced ROS1-positive (but EGFR mutation-negative and ALK fusion-negative) NSCLC patient with dramatic near complete response to crizotinib. Beyond ROS1 fusion, more novel genomic alterations in lung cancer, such as novel non-EML4 ALK fusion (C2orf44-ALK), and RET fusions (KIF5B-RET, CCDC6-RET) (Takeuchi K et al.; Kohno T et al.; Lipson D et al., Nat Med 12 February 2012 Epub ahead of print) will expectedly continue to be uncovered from high throughput genomic sequencing studies in a fast pace. We are now beginning to see emerging evidence of the sequencing effort impacting clinical therapeutics use, lending further supportive argument towards lung cancer genetic/genomic classification and clinical cancer sequencing.

Patrick C. Ma, MD, MS
Director of Aerodigestive Oncology Translational Research
Taussig Cancer Institute
The Cleveland Clinic

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