Lung Cancer 2020 Aug 01;146:209-216. doi: 10.1016/j.lungcan.2020.05.026.

Investigation on the prognostic impact of concurrent genomic alterations in crizotinib-treated EML4-ALK-rearranged advanced non-small cell lung cancer patients.

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BACKGROUND: Despite the efficacy of crizotinib in non-small cell lung cancer (NSCLC) with genomic rearrangement between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), clinical outcomes are heterogeneous among these patients. In our study, we investigated concurrent molecular factors that could contribute to the heterogeneity of their clinical outcomes to crizotinib therapy. METHODS: We retrospectively analyzed the clinical and targeted sequencing data from 32 crizotinib-treated patients with EML4-ALK-rearranged advanced NSCLC. RESULTS: Analysis of the mutation profile revealed the detection of concurrent deleterious mutations in 17 patients (53 %, 17/32). Of which, 5 patients had deleterious copy number variations and 12 patients had deleterious single nucleotide variations. Seven patients did not harbor any concurrent mutations from the genes included in the panel. The remaining 8 patients harbored concurrent mutations which were either non-deleterious or variants of uncertain significance. TP53, detected from 34 % (11/32) of the patients and the most commonly co-occurring mutation in our cohort, was not significantly associated with survival outcomes. Interestingly, significantly shorter progression-free survival (P = 0.032) was observed in patients harboring concurrent deleterious mutations, particularly copy number amplifications (PFS, P = 0.0021; OS, P = 0.034), than those without concurrent deleterious mutations. Harboring more copy number variations, reflected by chromosomal fluctuation coefficient varscore, was associated with shorter progression-free survival (P = 0.02). CONCLUSION: Our study revealed that concurrent deleterious mutations, particularly copy number amplifications in oncogenic genes have prognostic implications in patients with EML4-ALK-rearranged NSCLC receiving crizotinib therapy. These observations advance the understanding of the heterogeneity of treatment responses among patients with EML4-ALK-rearranged tumors.

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