Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Introduction: Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated... Conclusions: Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

Deep RNA sequencing revealed fusion junctional heterogeneity may predict crizotinib treatment efficacy in ALK-rearranged non-small cell lung cancer

Gene fusion variants in ALK-rearranged non-small cell lung cancer (NSCLC) may predict patient outcomes but previous results have been inconclusive. Fusion isoforms co-existing in the same tumor may affect targeted therapy efficacy but have not been investigated. Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Song Z, Lian S, Mak S, Chow MZ, Xu C, Wang W, Keung HY, Lu C, Kebede FT, Gao Y, Cheuk W, Cho WCS, Yang M, Zheng Z.

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated.
Patients with ALK-rearranged NSCLC who received crizotinib treatments were recruited. Precrizotinib tumor tissues were analyzed by the anchored multiplex polymerase chain reaction for targeted RNA sequencing. Kaplan-Meier and Cox regression were used to compare overall and progression-free survivals.
It was concluded that intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

RNA sequencing effectively identifies gene fusions undetected by DNA sequencing in lung adenocarcinomas

Background: Next-generation sequencing of DNA, which can provide valid information for clinical therapeutic decision-making, has been widely used in the management of lung cancer especially adenocarcinoma. However, due to its technical limitations for detecting certain alterations such as gene rearrangement, the DNA-based sequencing (DNA-seq) may miss the actionable alteration in some cases, who would have benefited from targeted therapy. The study aimed to evaluate the capability of RNA sequencing (RNA-seq) in identifying DNA-seq undetectable gene alterations in lung adenocarcinomas. Conclusions: Targeted RNA-seq can effectively identify genomic rearrangements that are undetectable by DNA-seq and provide lung adenocarcinoma patients with more opportunities for targeted therapy. Therefore, it should be recommended for all patients, in whom DNA-seq fails to detect driver alteration. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.3052

Authors: Ruiying Zhao, Yuchen Han, Chan Xiang, Shengnan Chen, Jikai Zhao, Lianying Guo, Anbo Yu, Jinchen Shao, Lei Zhu, Yue Tian, Fan Yang, Lin Shao, Xuejing Li, Lu Zhang

Conference PaperKirk SmithMay 28, 2021RNA sequencing, DNA sequencing, lung adenocarcinoma

Optimizing Mutation and Fusion Detection in NSCLC by Sequential DNA and RNA Sequencing

Introduction: Frequently, patients with locally advanced or metastatic NSCLC are screened for mutations and fusions. In most laboratories, molecular workup includes a multitude of tests: immunohistochemistry (ALK, ROS1, and programmed death-ligand 1 testing), DNA sequencing, in situ hybridization for fusion, and amplification detection. With the fast-emerging new drugs targeting specific fusions and exon-skipping events, this procedure harbors a growing risk of tissue exhaustion... Conclusions: We conclude that sequentially combining DNA NGS and RNA NGS is the most efficient strategy for mutation and fusion detection in smoking-associated NSCLC, whereas for never smokers we recommend a parallel approach. This approach was shown to be feasible on small tissue samples including for cytology tests, can drastically reduce the complexity and cost of molecular workup, and also provides flexibility in the constantly evolving landscape of actionable targets in NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.01.019

Authors: Danielle Cohen, Liesbeth M. Hondelink, Nienke Solleveld-Westerink, Sandra M. Uljee, Dina Ruano, Anne-Marie Cleton-Jansen, Jan H. von der Thüsen, S. Rajen S. Ramai, Pieter E. Postmus, Jacob F. Graadt van Roggen, Bart P. C. Hoppe, Pieter C. Clahsen, Klaartje W. Maas, Els J. M. Ahsmann, Alexandraten Heuvel, Frank Smedts, Ronald N. van Rossem,Tomvan Wezel