Impact of RAS-MAPK pathway genetic alterations on radiotherapy response in metastatic lung adenocarcinoma

A retrospective study at Memorial Sloan Kettering Cancer Center (New York, NY) investigated the impact of RAS-MAPK pathway genetic alterations on radiotherapy (RT) response in metastatic non-small cell lung carcinoma (NSCLC) spine metastases. The study included 181 patients, with a median follow-up of 15.2 months (IQR 8.0-31.9). The 3-year risk of local failure was 0.15 (95% CI 0.10-0.20). Higher 3-year local failure rates were observed for patients harboring NF1 driver alterations (0.33 versus 0.13; p=0.02) or BRAF driver alterations (0.31 versus 0.13; p=0.04). NF1 loss-of-function mutations conferred radioresistance in one of two NSCLC cell lines tested in vitro. KRAS mutations overall were not associated with local failure. However, comutation of KRAS/TP53 exhibited a trend toward higher 3-year local failure (0.31 versus 0.13; p=0.05). RAS-MAPK pathway driver alterations accounted for 53% of all local failures, and showed an elevated 3-year risk of local failure (0.36 versus 0.09; p<0.001), including when treated with stereotactic body RT (0.28 versus 0.05; p=0.001). The authors conclude that driver alterations in the RAS-MAPK signaling pathway confer radioresistance in metastatic NSCLC.