NSCLC: Genetic Mutations May Determine Likelihood of Metastasis at Diagnosis

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Compared with ALK¬-positive patients, participants with ROS1 rearrangements were less likely to present with extrathoracic and brain metastases.
Compared with ALK¬-positive patients, participants with ROS1 rearrangements were less likely to present with extrathoracic and brain metastases.

Among patients with non–small cell lung cancer (NSCLC), ROS1 and ALK rearrangements may predict different metastasis distributions, according to an article published in JCO Precision Oncology.1

ROS1 mutations, which confer sensitivity to crizotinib, are detected in 1% to 2% of NSCLC cases. Previous study showed that, among patients with ROS1-positive disease, crizotinib delays disease progression for a median of about 19 months, after which treatment resistance evolves.

For this study, researchers attempted to distinguish metastasis distribution among ROS1-positive patients from that among ALK­­-positive patients, given that ALK mutations also confer sensitivity to crizotinib. The researchers also analyzed disease samples taken at different time points from ROS1-positive patients to determine possible mechanisms of crizotinib resistance.

Thirty-nine patients with ROS1 rearrangements and 196 patients with ALK rearrangements were identified; the median ages were 50 and 51, respectively, 72% and 69% were never-smokers, respectively, and 85% and 84% of patients were diagnosed with stage IV disease, respectively.

Compared with ALK­-positive patients, participants with ROS1 rearrangements were less likely to present with extrathoracic (59% vs 83.2%) and brain (19.4% vs 39.1%) metastases. At 5 years post-diagnosis this discrepancy continued, with 34% of ROS1-positive patients developing brain metastases vs 73% of ALK­-positive patients.

Despite these findings, patients with ALK-positive disease had a non-significantly longer median overall survival (3 vs 2.5 years; P = .786.)

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After disease progression during crizotinib therapy, biopsy analyses detected ROS1 resistance mutations in 53% of samples, the most common of which was G2032R (41%).

The authors concluded that “efforts to identify and validate mechanisms of resistance to crizotinib among larger cohorts of patients with ROS1-positive NSCLC are needed.”

Reference

  1. Gainor JF, Tseng D, Yoda S, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non–small-cell lung cancer. JCO Precis Oncol. 2017 Aug 16. doi: 10.1200/PO.17.00063 [Epub ahead of print]

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