in Lung Cancers: Analysis of Patient Cases Reveals Recurrent Mutations, Fusions, Kinase Duplications, and Concurrent Alterations.

PURPOSE

Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B alterations in lung cancer.

PATIENTS AND METHODS

A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic base substitutions, short insertions and deletions, copy number changes, and rearrangements.

RESULTS

Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were V600E, 38% were non-V600E activating mutations, and 18% were inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and fusions (2.8%). The fusions involved three recurrent fusion partners: , and . V600E was associated with co-occurrence of alterations, but other alterations were not and were instead associated with , , and alterations ( < .05). Potential mechanisms of acquired resistance to V600E inhibition are demonstrated.

CONCLUSION

This series characterized the frequent occurrence (4.4%) of alterations in lung cancers. Recurrent alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as , and exceed that of or . This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR alterations represent a subgroup of lung cancers in which targeted therapy should be considered.