PMID- 35529790 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220510 IS - 2218-6751 (Print) IS - 2226-4477 (Electronic) IS - 2218-6751 (Linking) VI - 11 IP - 4 DP - 2022 Apr TI - Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients. PG - 617-631 LID - 10.21037/tlcr-22-202 [doi] AB - BACKGROUND: Rearranged during transfection (RET) rearrangement has been identified as one of the crucial oncogenic drivers in non-small cell lung cancer (NSCLC). Recently, two highly selective RET inhibitors have been approved by the US Food and Drug Administration and demonstrated remarkable responses. However, the clinical characteristics, outcomes and optimal diagnostic method of RET-rearrangements are not well understood. This study sought to evaluate the prevalence and characteristics of RET rearrangement, identify an effective diagnostic method for it, and correlate its presence with outcomes. METHODS: A total of 9,431 Chinese NSCLCs from two cancer centers who have undertaken targeted DNA-NGS were enrolled and 167 RET-positive cases were screened. Non-canonical RET rearrangements were confirmed by targeted RNA-NGS. If material was sufficient, positive cases were analyzed by fluorescence in situ hybridization (FISH) (n=30) and immunohistochemistry (IHC) (n=57). Clinicopathologic characteristics, molecular profiling and treatment outcomes of RET rearrangement were evaluated. RESULTS: The prevalence of RET rearrangement was 1.52% (138/9,101) in unfiltered cases and 8.79% (29/330) in EGFR/KRAS/BRAF/ALK-negative cases. RET rearrangement was common in females, never smokers, and lung adenocarcinoma patients. Additionally, 40.3% of stage IV RET-rearranged NSCLC patients developed brain metastases. TP53 was the most common concurrent mutation, and 8 patients harbored concurrent driver oncogenic alterations, including EGFR (N=5), KRAS (N=2), and ALK (N=1). Non-canonical fusion partners were identified in 13.8% (23/167) of cases by DNA-based NGS, and RNA-based NGS identified 3 new partners (EPS8, GOLGA5, and TNIP1). The concordance of FISH and NGS was 83.3% (25/30), while the concordance of IHC and NGS was only 28.1% (16/57). Both IHC and FISH demonstrated lower sensitivity for NCOA4-/other-RET fusions. The CCDC6-RET subgroup had significantly longer progression-free survival than the KIF5B-RET subgroup, both after chemotherapy (23 vs. 9.7 months; P=0.014). CONCLUSIONS: RET rearrangement occurs in 1.52% of Chinese NSCLCs and has identifiable clinicopathologic characteristics. RET IHC has a low sensitivity, disavowing its use in routine practice. While NGS and FISH has good performance in identifying RET rearrangement. Both IHC and FISH demonstrated lower sensitivity for NCOA4-/others-RET fusions. Clinical benefit with chemotherapy is different between CCDC6-RET and KIF5B-RET fusion patients, optimal treatment should be considered when selecting therapies for patients with RET-rearranged lung cancers. CI - 2022 Translational Lung Cancer Research. All rights reserved. FAU - Feng, Junnan AU - Feng J AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Li, Yan AU - Li Y AD - Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Wei, Bing AU - Wei B AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Guo, Lei AU - Guo L AD - Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Li, Weihua AU - Li W AD - Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Xia, Qingxin AU - Xia Q AD - Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. FAU - Zhao, Chengzhi AU - Zhao C AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Zheng, Jiawen AU - Zheng J AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Zhao, Jiuzhou AU - Zhao J AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Sun, Rui AU - Sun R AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Guo, Yongjun AU - Guo Y AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. FAU - Brcic, Luka AU - Brcic L AD - Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Hakozaki, Taiki AU - Hakozaki T AD - Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center of Komagome Hospital, Tokyo, Japan. FAU - Ying, Jianming AU - Ying J AD - Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Ma, Jie AU - Ma J AD - Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. AD - Henan Key Laboratory of Molecular Pathology, Zhengzhou, China. LA - eng PT - Journal Article PL - China TA - Transl Lung Cancer Res JT - Translational lung cancer research JID - 101646875 PMC - PMC9073740 OTO - NOTNLM OT - Chinese patients OT - Rearranged during transfection (RET) OT - gene rearrangement OT - next-generation sequencing (NGS) OT - non-small cell lung cancer (NSCLC) COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-202/coif). LB reports that he has received grants from Takeda, Roche, BMS; payment or honoraria for lectures, presentations, speakers bureaus from Amgen, AstraZeneca, BMS, Eli Lilly, Janssen, MSD, Merck, Novartis; participation on an Advisory Boards of Eli Lilly, Janssen, MSD, Merck, Novartis. He is an International Secretary of the Austrian Society of Pathology, Member of Pulmonary Pathology Society Membership and Awards Committee, and Member of IASLC Mesothelioma Committee. TH has received payment for speakers bureaus from Chugai Pharmaceutical, outside the submitted work. The other authors have no conflicts of interest to declare. EDAT- 2022/05/10 06:00 MHDA- 2022/05/10 06:01 PMCR- 2022/04/01 CRDT- 2022/05/09 04:15 PHST- 2022/01/13 00:00 [received] PHST- 2022/04/15 00:00 [accepted] PHST- 2022/05/09 04:15 [entrez] PHST- 2022/05/10 06:00 [pubmed] PHST- 2022/05/10 06:01 [medline] PHST- 2022/04/01 00:00 [pmc-release] AID - tlcr-11-04-617 [pii] AID - 10.21037/tlcr-22-202 [doi] PST - ppublish SO - Transl Lung Cancer Res. 2022 Apr;11(4):617-631. doi: 10.21037/tlcr-22-202.