Resistance Mutations Predict Metastatic Patterns in NSCLC

Submitted by admin5 on Thu, 08/17/2017 - 15:00

Specific gene rearrangements associated with increased resistance to standard therapy may predict different metastasis distributions in patients with non-small cell lung cancer (NSCLC), according to research published in JCO Precision Oncology (online August 16, 2017; doi:10.1200/PO.17.00063).

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ROS1 and ALK mutations in patients with NSCLC have been shown to confer sensitivity to crizotinib treatment. Previous research has shown that ROS1-positive disease is effectively treated by crizotinib for a median of 19 months, after which treatment resistance evolves. Currently, patterns of metastatic spread and reasons for crizotinib resistance in patients with ROS1-positive disease are in need of further study.

Alice T Shaw, MD, PhD, Massachusetts General Hospital (Boston, MA), and colleagues conducted a review aimed at distinguishing metastasis distribution and initial metastatic diagnosis among ROS1-positive patients from that of ALK-positive patients. Researchers identified 39 patients and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively.

In addition to analyzing metastatic distribution, researchers also collected disease samples from different times of patients with ROS1-positive disease to determine possible mechanisms of crizotinib resistance.

Results of the review showed that patients with ROS1 rearrangements were less likely than those with ALK rearrangements to present with extrathoracic (59.0% vs 83.2%, P = .002) and brain (19.4% vs 39.1%, P = .033) metastases. After a 5-year follow-up from diagnosis, 34% of patients with ROS1-positive disease developed brain metastases, compared with 73% of those with ALK-positive disease.

Researchers acknowledged that patients with ALK-positive disease demonstrated a slightly longer median overall survival (3.0 years vs 2.5 years, P = .786).

When analyzing for mechanisms of crizotinib resistance, researchers found that ROS1 resistance mutations were most common in G2032R (41%), D2033N (6%), and S1986F (6%).

Authors of the study concluded that ROS1 rearrangements are significantly associated with lower rates of extrathoracic metastases at initial diagnosis. Furthermore, identifying the prominent mechanisms of resistance to crizotinib “underscores the need to develop novel ROS1 inhibitors with activity against these resistant mutants,” they wrote.—Zachary Bessette