title: RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients.
abstract: RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated.
  
  
  
  We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy.
  
  
  
  A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months.
  
  
  
  RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sarfaty
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Moore
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Neiman
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dudnik
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Ilouze
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Oncology, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
authors.affiliation: Institute of Oncology, Kaplan Medical Center, Rehovot, Israel; Faculty of Medicine, Hebrew University, Jerusalem, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Katznelson
authors.affiliation: Faculty of Medicine, Hebrew University, Jerusalem, Israel; Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Hadas Gantz
authors.initials: HG
authors.lastname: Sorotsky
authors.affiliation: Champions Oncology, Baltimore, MD.
authors.forename: Keren
authors.initials: K
authors.lastname: Paz
authors.affiliation: Champions Oncology, Baltimore, MD.
authors.forename: Amanda
authors.initials: A
authors.lastname: Katz
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Cardiothoracic Surgery, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Milton
authors.initials: M
authors.lastname: Saute
authors.affiliation: Institute of Oncology, Rambam Health Care Campus, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: Mira
authors.initials: M
authors.lastname: Wolner
authors.affiliation: Institute of Oncology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Mor
authors.initials: M
authors.lastname: Moskovitz
authors.affiliation: Foundation Medicine, Cambridge, MA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, MA.
authors.forename: Julia
authors.initials: J
authors.lastname: Elvin
authors.affiliation: Foundation Medicine, Cambridge, MA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Cambridge, MA.
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petah Tikva, Israel.
authors.forename: Lior Soussan
authors.initials: LS
authors.lastname: Gutman
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petah Tikva, Israel.
authors.forename: Addie
authors.initials: A
authors.lastname: Dvir
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Gordon
authors.affiliation: Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: nirp@post.tau.ac.il.
authors.forename: Nir
authors.initials: N
authors.lastname: Peled
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000813:Anilides / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017671:Platinum Compounds / Q000627:therapeutic use*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use*; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D061067:Antibodies, Monoclonal, Humanized; C531357:CCDC62 protein, human; C573239:KIF5B-RET fusion protein, human; D015514:Oncogene Proteins, Fusion; D017671:Platinum Compounds; D011725:Pyridines; D014157:Transcription Factors; C558660:cabozantinib; C582435:pembrolizumab; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: Cabozantinib; Lung cance; PDL-1; Personalized medicine; RET