Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI. Issue 3 (September 2015)

• Record Type: Journal Article
• Authors: Klempner, Samuel J.; Bazhenova, Lyudmila A.; Braiteh, Fadi S.; Nikolinakos, Petros G.; Gowen, Kyle; Cervantes, Claudia M.; Chmielecki, Juliann; Greenbowe, Joel R; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.; Ali, Siraj M.; Ou, Sai-Hong Ignatius
• Is Part Of: Lung cancer. Volume 89:Issue 3(2015:Sep.)
• Page Start: 357
• Page End: 359
• Publication Date: 2015-09
• Subjects: Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2015.06.021
• Languages: English
• ISSNs: 0169-5002

Abstract

<abstract abstract-type="author" id="abs0005"> <title id="sect0005">Abstract</title> <sec> <title id="sect0010">Objectives</title> <p id="spar0010">The gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with <italic>EGFR</italic>-mutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include <italic>HER2</italic> amplification, <italic>MET</italic> amplification, <italic>PIK3CA</italic> mutation, epithelial–mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered.</p> </sec> <sec> <title id="sect0015">Materials and methods</title> <p id="spar0015">Hybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame <italic>CCDC6-RET</italic> rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional <italic>NCOA4-RET</italic> rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, <italic>EGFR</italic> amplification, <italic>HER2</italic> amplification, <italic>MET</italic> amplification, <italic>PIK3CA</italic> mutation, <italic>BRAF</italic> mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements.</p> </sec> <sec> <title id="sect0020">Results and conclusions</title> <p id="spar0020">This is the first report of <italic>RET</italic> rearrangement co-existing with activated <italic>EGFR</italic> mutations in <italic>EGFR</italic>-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, <italic>RET</italic> rearrangement may serve as a potential resistance mechanism to EGFR TKI in <italic>EGFR</italic>-mutated NSCLC.</p> </sec> </abstract>