title: 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.
abstract: OBJECTIVE
  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 EGFR-mutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial-mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered.
  
  
  METHODS
  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 CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET 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, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements.
  
  
  CONCLUSIONS
  This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: Divsion of Hematology-Oncology, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92307, USA.
authors.forename: Lyudmila A
authors.initials: LA
authors.lastname: Bazhenova
authors.affiliation: Comprehensive Cancer Centers of Nevada, Las Vegas, NV 89169, USA.
authors.forename: Fadi S
authors.initials: FS
authors.lastname: Braiteh
authors.affiliation: University Cancer and Blood Center, Athens, GA 30607, USA.
authors.forename: Petros G
authors.initials: PG
authors.lastname: Nikolinakos
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gowen
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Cervantes
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Greenbowe
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA; Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA. Electronic address: Ignatius.ou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D023281:Genomics / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret
keywords: Acquired resistance; EGFR mutations; Non-small cell lung cancer; Post-progression; RET rearrangement