Amplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

BACKGROUND/OBJECTIVES: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics.

METHODS

We conducted a single-center retrospective analysis of the presence of amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC).

RESULTS

amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. amplification was dominantly observed in female patients with EGFR exon 19 deletion. All -amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where amplification correlated with a histological transformation to SCLC.

CONCLUSIONS

amplification was identified in 5-8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.