Leal Jose Luis, Peters Geoffrey, Szaumkessel Marcin, Leong Trishe, Asadi Khashayar, Rivalland Gareth, Do Hongdo, Senko Clare, Mitchell Paul L, Quing Chai Zi, Dobrovic Alexander, Thapa Bibhusal, John Thomas
Department of Medical Oncology, Austin Health, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria, Australia; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
ANU Medical School, Australian National University, Australian Capital Territory, Australia; Department of Medical Oncology, The Canberra Hospital, Australian Capital Territory, Australia.
Lung Cancer. 2020 Aug;146:154-159. doi: 10.1016/j.lungcan.2020.05.019. Epub 2020 May 24.
Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC.
Archival tumor tissue from patients with MPM, lung NETs, SCLC and NSCLC were used to create tissue microarrays. Immunohistochemistry (IHC) was performed using a cocktail of antibodies against TRK, ROS1 and ALK. IHC positive samples underwent RNA sequencing using the ArcherDX FusionPlex CTL diagnostic assay. Clinical data were obtained through retrospective chart review.
We performed IHC on 1116 samples: 335 MPMs, 522 NSCLCs, 105 SCLCs and 154 lung NETs. There were 23 IHC positive cases (2.1%) including eight MPMs (2.4%), eight NETs (5.2%), five SCLC (4.8%) and two NSCLC (0.4%). The following fusions were detected: one MPM with an NTRK ex10-TPM3 ex8, another MPM with an ALK ex20-EML4ex13, one lung intermediate-grade NET (atypical carcinoid) with an ALK ex20-EML4 ex6/intron6, and two NSCLCs with an ALK ex20-EML4 ex6/intron6 rearrangement. None of the patients received targeted treatment.
To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized.
在包括非小细胞肺癌（NSCLC）在内的多种癌症中已发现涉及NTRK1、NTRK2、NTRK3、ROS1和ALK的基因重排。恶性胸膜间皮瘤（MPM）、肺神经内分泌肿瘤（NETs）和小细胞肺癌（SCLC）的数据尚缺乏。鉴于NTRK、ROS-1和ALK抑制剂在具有基因融合的肿瘤中的活性，我们试图在这些除NSCLC外的较少见肿瘤中探索此类重排。
使用来自MPM、肺NETs、SCLC和NSCLC患者的存档肿瘤组织制作组织微阵列。使用针对TRK、ROS1和ALK的抗体混合物进行免疫组织化学（IHC）。IHC阳性样本使用ArcherDX FusionPlex CTL诊断检测法进行RNA测序。通过回顾性病历审查获得临床数据。
我们对1116个样本进行了IHC检测：335个MPM、522个NSCLC、105个SCLC和154个肺NETs。有23例IHC阳性病例（2.1%），包括8例MPM（2.4%）、8例NETs（5.2%）、5例SCLC（4.8%）和2例NSCLC（0.4%）。检测到以下融合：1例MPM具有NTRK外显子10-TPM3外显子8，另1例MPM具有ALK外显子20-EML4外显子13，1例肺中级NET（非典型类癌）具有ALK外显子20-EML4外显子6/内含子6，以及2例NSCLC具有ALK外显子20-EML4外显子6/内含子6重排。所有患者均未接受靶向治疗。
据我们所知，我们首次报道了一小部分MPM中的NTRK和ALK重排。在肺中级NET（或非典型类癌）中也检测到ALK重排。我们的数据表明，IHC可能是对此类患者有用的筛查检测，以确保利用包括靶向治疗在内的所有治疗策略。
