ROS1 gene rearrangement ‘specific for lung cancer in never-smokers’
medwireNews: Lung adenocarcinomas harboring genetic rearrangements of the receptor tyrosine kinase proto-oncogene ROS1 are more frequent in people who have never smoked than in smokers, a study by South Korean researchers shows.
The recently identified “ROS1-rearranged” molecular subtype accounted for 3.4% of lung tumors in an East Asian never-smoking population, and was associated with chemotherapy treatment outcomes.
Given the availability of specific ROS1 inhibitors, “the identification of ROS1 rearrangement before the initiation of treatment should be a routine practice in personalized therapy,” recommend Byoung Chul Cho (Yonsei University College of Medicine, Seoul) and co-authors writing in the Annals of Oncology.
ROS1 rearrangements result in the formation of fusion proteins that have constitutive tyrosine kinase activity; to date, eight ROS1 fusion genes have been identified. The frequency of ROS1 rearrangement in an unselected non-small-cell lung carcinoma population ranges from 0.9% to 1.7%, but the frequency in specific populations and its clinical relevance is unknown.
To investigate, Cho et al evaluated tumor samples from 208 Korean adults with histologically confirmed lung adenocarcinoma who reported smoking fewer than 100 cigarettes in their lifetime.
Tumors were screened for ROS1 rearrangement using fluorescent in situ hybridization and confirmed by immunohistochemistry; tumors were also screened for ALK rearrangement and EGFR and KRAS mutations.
ROS1 rearrangement was detected in seven of 208 samples, giving a frequency of 3.4%. Patient characteristics did not differ between those with and without ROS1 rearrangement, note the authors.
No tumor with ROS1 rearrangement had either ALK rearrangement or KRAS mutation; however, one ROS1-rearranged tumor had a concurrent EGFR mutation. CD74-ROS1 fusions were found in two ROS1-positive patients, while no fusion partner was found in the other five.
The median duration of follow up was 29.6 months. With regard to treatment outcomes, the overall response rate following pemetrexed therapy was 60.0% in ROS1-positive patients versus just 8.5% in wild-type patients. This translated into a significantly longer median progression-free survival (PFS; not reached vs 3.3 months).
No patient with either ROS1 or ALK rearrangement had a clinical response to EGFR-tyrosine kinase therapy; accordingly, PFS was significantly shorter in ROS1-positive patients than in wild-type patients (2.5 vs 7.8 months).
In regression analysis, the adjusted hazard ratio for disease progression on pemetrexed was 0.09 for patients with ROS1-rearranged tumors. “This suggests that ROS1 rearrangement is a strong predictive factor for a longer median PFS to pemetrexed,” write the authors.
They conclude that ROS1 rearrangement, together with EGFR mutations and ALK rearrangements, “are the genetic alterations that are specific for lung cancer in never-smokers” and “compromise a unique and nonoverlapping molecular subset.”
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By Joanna Lyford