PMID- 35756632 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2234-943X (Print) IS - 2234-943X (Electronic) IS - 2234-943X (Linking) VI - 12 DP - 2022 TI - Targeting ALK in Neuroendocrine Tumors of the Lung. PG - 911294 LID - 10.3389/fonc.2022.911294 [doi] LID - 911294 AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements. METHODS: To illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases. RESULTS: Within the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases. CONCLUSIONS: ALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations. CI - Copyright (c) 2022 Akhoundova, Haberecker, Fritsch, Holler, Kiessling, Rechsteiner, Ruschoff and Curioni-Fontecedro. FAU - Akhoundova, Dilara AU - Akhoundova D AD - Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. AD - Department of Medical Oncology, Inselspital, University Hospital of Bern, Bern, Switzerland. AD - Department for BioMedical Research, University of Bern, Bern, Switzerland. FAU - Haberecker, Martina AU - Haberecker M AD - Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. FAU - Fritsch, Ralph AU - Fritsch R AD - Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. FAU - Holler, Sylvia AU - Holler S AD - Institute of Pathology, Stadtspital Zurich Triemli, Zurich, Switzerland. FAU - Kiessling, Michael K AU - Kiessling MK AD - Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. AD - Department of Internal Medicine-Oncology, See Spital Horgen, Horgen, Switzerland. FAU - Rechsteiner, Markus AU - Rechsteiner M AD - Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. FAU - Ruschoff, Jan H AU - Ruschoff JH AD - Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. FAU - Curioni-Fontecedro, Alessandra AU - Curioni-Fontecedro A AD - Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. LA - eng PT - Journal Article DEP - 20220607 PL - Switzerland TA - Front Oncol JT - Frontiers in oncology JID - 101568867 PMC - PMC9214311 OTO - NOTNLM OT - ALK inhibitors OT - ALK rearrangements OT - large cell neuroendocrine carcinoma OT - neuroendocrine tumors of the lung OT - targeted treatment COIS- SH reports consulting and advisory fees from Bayer outside the submitted work. RF reports grants and consulting and advisory fees from Pierre Fabre, Bayer, Merck, MSD, Astra Zeneca, Novartis, and BMS outside the submitted work. MK reports ownership relationship with Novavax, Biontech, and Mol. Partners outside the submitted work. AC-F reports patent relationship with Astra Zeneca, Bristol Meyer Squibb, Boehringer Ingelheim, Pfizer, Roche, Takeda, MSD, and Janssen-Cilag outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/06/28 06:00 MHDA- 2022/06/28 06:01 PMCR- 2022/01/01 CRDT- 2022/06/27 04:08 PHST- 2022/04/02 00:00 [received] PHST- 2022/05/02 00:00 [accepted] PHST- 2022/06/27 04:08 [entrez] PHST- 2022/06/28 06:00 [pubmed] PHST- 2022/06/28 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fonc.2022.911294 [doi] PST - epublish SO - Front Oncol. 2022 Jun 7;12:911294. doi: 10.3389/fonc.2022.911294. eCollection 2022.