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ROS1 rearrangements can be detected in circulating tumor cells of NSCLC
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The evaluation of circulating tumor cells in patients with non–small cell lung cancer revealed ROS1 rearrangements, information which can be used to aid in disease diagnosis and monitoring, according to study results.
The study showed that circulating tumor cells (CTCs) from these patients showed meaningful heterogeneity of ROS1 gene abnormalities compared with tumor biopsies and elevated chromosomal instability. These mechanisms could potentially lead to an evasion of ROS1 inhibitor therapy, researchers wrote.
Using an approach previously tested to detect ALK rearrangements, Francoise Farace, PhD, a researcher at the Institut Gustave-Roussy at the University of Paris-Sud in Villejuif, France, and colleagues sought to identify ROS1 rearrangements in the CTCs of patients with ROS1-rearranged NSCLC.
“A new paradigm for NSCLC treatment has recently emerged with the discovery of molecularly defined subsets of patients who can be treated effectively by therapies targeted to a specific driver gene,” Farace told HemOnc Today. “ROS1 fusion genes have recently been identified in approximately 1% of NSCLC. It has been reported that patients with ROS1-rearranged NSCLC can benefit from the ALK/MET tyrosine kinase inhibitor crizotinib and clinical trials are ongoing in this population to evaluate this further.”
ROS1 gene fusion occurs with several genetic partners, often leading to cellular transformation and constitutive ROS1 kinase activity. ROS1-rearranged NSCLC has been associated with younger age at the time of diagnosis, an adenocarcinoma histology and patients considered never-smokers, features which also are associated with ALK and EGFR genetic modifications.
The researchers used filter-adapted fluorescent in situ hybridization for CTC analyses. Researchers also aimed to characterize the heterogeneity of the CTCs by assessment of their chromosomal instability.
The analysis included four patients with ROS1-rearranged NSCLC who were treated with crizotinib (Xalkori, Pfizer), a ROS1 inhibitor. Two of these patients achieved a partial response with crizotinib (6.8 months and 7.1 months), one patient had stable disease for 3 months and one patient experienced disease progression.
Researchers detected ROS1 rearrangement in the CTCs of every patient. The median number of ROS1-rearranged CTCs at baseline was 34.5 per 3 mL blood (range, 24-55).
The analysis also included four ROS1-negative patients. The median background hybridization of ROS1-rearranged CTCs in these patients was 7.5 per 3 mL blood (range, 7-11).
Tumor heterogeneity was significantly higher in CTCs at baseline compared with biopsies of paired tumors in the three patients who experienced a partial response or stable disease (P < .0001). Two patients who progressed during treatment with crizotinib demonstrated significantly increased ROS1 copy numbers (P ˂ .02).
The researchers also observed high DNA content and chromosomal gain in the CTCs of ROS1-rearranged patients, which indicated high levels of numerical chromosomal instability and aneuploidy.
“We showed that ROS1 rearrangement was detected in the CTCs of all four patients with ROS1-rearrangement previously confirmed by tumor biopsy,” Farace said. “CTCs from ROS1-rearranged patients show considerable heterogeneity of ROS1-gene abnormalities, a high DNA content, gain of chromosomes, indicating high levels of aneuploidy and numerical chromosomal instability. These data may suggest that elevated numerical [chromosomal instability] may be a potential mechanism of resistance to ROS1-inhibitor therapy in ROS1-rearranged NSCLC tumors.” – by Anthony SanFilippo
For more information:
Francoise Farace, PhD, can be reached at Gustave Roussy Cancer Campus, 114, Rue Édouard-Vaillant, 94805 Villejuif Cedex, France; email: Francoise.Farace@gustaveroussy.fr.
Disclosure: The researchers report no relevant financial disclosures.
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