Co-occurring Alterations Affect Outcomes in EGFR-Mutant Lung Cancer

Sequencing of cancer genomes has identified a number of oncogenic alterations, but these studies are often performed in patients with early-stage tumors, although it is the patients with advanced tumors who are generally treated with targeted therapies. Patients with advanced cancer may have multiple genetic alterations; however, the effects of co-occurring genetic alterations are not well understood. To determine if co-occurring alterations cooperated with the primary tumor driver to promote tumor progression and response to therapy, Blakely, Watkins, Wu, and colleagues sequenced cell-free DNA (cfDNA) from 1,122 patients with EGFR-mutant advanced non–small cell lung cancer (NSCLC) and 1,008 patients with EGFR mutation–negative advanced NSCLC. The EGFR-mutant patient cohort had widespread occurrence of additional genetic alterations including mutations in PIK3CA, BRAF, MET, MYC, CDK6, and CTNNB1. Further, the EGFR-mutant samples had an enrichment of certain genetic events, including co-alterations in CTNNB1, CDK6, or AR, compared with the EGFR mutant–negative samples. Patients with the EGFR p.Thr790Met mutation, which confers resistance to first-generation EGFR tyrosine kinase inhibitors (TKI), had enrichment of a number of co-occurring alterations including CDK6, CTNNB1, AR, MYC, KRAS, and PDGFRA. Longitudinal data were available for 97 patients with EGFR-mutant tumors, and analysis of these samples revealed acquisition of the EGFR p.Thr790Met mutation upon resistance to first-generation EGFR TKIs, and co-alterations in CCNE1, NF1, and PIK3CA after progression on second-line therapy. EGFR TKI responders had fewer cfDNA mutations than nonresponders. Co-occurring mutations associated with primary resistance to the third-generation EGFR TKI osimertinib were also observed. Collectively, these findings reveal that co-occurring genetic alterations are linked to therapeutic response and resistance in EGFR-mutant lung cancer and demonstrate that more detailed genomic information is required to understand tumorigenesis beyond a single driving oncogene.

Blakely CM, Watkins TB, Wu W, Gini B, Chabon JJ, McCoach CE, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 2017;49:1693–704.

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