The histological classification of non-small-cell lung cancer (NSCLC) and identification of possible therapeutic targets are important for disease management. However, as biopsies are often small, with a limited amount of tumor cells, it can be challenging to obtain enough tissue for the needed number of diagnostic immunohistochemical stains and molecular analyses. In this study, we combined a small custom designed targeted expression panel with a commercial fusion transcript assay by which we were able to perform both a histological classification (transcribing the expression of the genes encoding TTF1, Napsin A, CK5/6, and the truncated P63 isoform ΔNp63 (p40) into either adenocarcinoma or squamous cell carcinoma) and an identification of fusion genes involving ALK, RET, and ROS1. The expression panel also included the PD-L1 encoding gene, CD274, in order to evaluate the PD-L1 mRNA potential for identification of patients who will benefit from immune checkpoint inhibitor treatment. We evaluated the panel using 42 NSCLC patient samples. The molecular profiling agreed with the original immunohistochemistry (IHC)-based classification in 93% of the cases. For ten of the patients, being fusion gene positive, the fusion transcripts were detected in 100%. The molecular assessment of PD-L1 also showed agreement with the original assessment made by IHC. In conclusion, this study presents a small, targeted expression panel with the potential to perform both a molecularly based histological classification and a fusion gene identification in NSCLC patients as well as identifying PD-L1 status from a very limited amount of starting material. READ ARTICLE
Experimental and Molecular Pathology DOI:10.1016/j.yexmp.2022.104749
Authors: Anita Tranberg Simonsen, Amalie Utke, Johanne Lade-Keller, Lasse Westphal Thomsen, Torben Steiniche, Magnus Stougaard
Anaplastic lymphoma kinase (ALK) fusion is a well-defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC). Alectinib, a second-generation ALK-TKI, has been shown to have significantly longer progression-free survival (PFS) than first-generation ALK inhibitors in untreated ALK-rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first-line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next-generation sequencing (NGS) further revealed a striatin (STRN)-ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)-ALK fusion in another patient without any other known oncogenic alterations. Both patients d..... READ ARTICLE
Wiley DOI:10.1111/jcmm.16897
Authors: Mengnan Li, Zhou An, Qiusu Tang, Yutong Ma, Junrong Yan, Songan Chen, Yina Wang
Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene. READ ARTICLE
Current Oncology DOI: 10.3390/curroncol28030180
Authors: Sugiyama K., Izumika A., Iwakoshi A., Nishibori R., Sato M., Shiraishi K., Hattori H., Nishimura R. and Kitagawa C.
Read MoreTo assess EBUS-TBNA biopsy adequacy for ALK, EGFR and PD-L1 testing, we conducted a prospective study of 279 consecutive NSCLC patients referred to a tertiary EBUS-TBNA centre in South West England. One hundred eight-four (62.6%) patients were found to have adenocarcinoma, 83 (28.2%) had squamous cell carcinoma, and 27 (9.2%) were identified as NSCLC-not otherwise specified. EGFR testing was successful in 166 of 168 patients (98.8%), ALK testing in all 115 and PD-L1 testing in 43 of 49 patients (88.2%). Previous EGFR and ALK testing did not affect biopsy PD-L1 testing success. PD-L1 testing failures occurred in three of five (60.0%) of 22G needle biopsies, one of five (20.0%) of 21G needle biopsies and two of 39 (5.1%) of 19G needle biopsies, P = .016. EBUS-TBNA biopsies are mostly suitable for PD-L1 testing. Larger needle size may improve PD-L1 (but not EGFR and ALK) testing success but requires further study in a controlled trial...... READ ARTICLE
Asia-Pacific Journal of Clinical Oncology DOI:10.1111/ajco.13549
Authors: Joanna Hardy, Nidhi Bhatt, Andrew R L Medford
Comprehensive genomic profiling is needed to know and then target the genes causing resistance in ALK rearranged patients [ [9] ]. We report one such novel deletion p.(Q1188_L1190del) in the ALK tyrosine kinase domain which responded to Lorlatinib. READ ARTICLE
Cancer Genetics DOI:10.1016/j.cancergen.2021.03.006
Authors: Moushumi Suryavanshi, Krushna Chaudhari, Shrinidhi Nathany, Vineet Talwar
ALK (Anaplastic lymphoma kinase) fusion proteins are oncogenic and have been seen in various tumors. PPP1CB-ALK fusions are rare but have been reported in a few patients with low- or high-grade gliomas. However, little is known regarding the mechanism of fusion formation and genomic break points of this fusion. We performed genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma. The PPP1CB-ALK consists of exons 1–5 of PPP1CB and exons 20–29 of ALK. The genomic translocation breakpoints were determined by real-time quantitative PCR (RT-qPCR) and Sanger sequencing of genomic DNA. Next generation sequencing, RT-qPCR and fluorescence in situ hybridization analyses demonstrated PPP1CB-ALK amplification. Copy number analyses of genes between PPP1CB and ALK using RT-qPCR suggest that the PPP1CB-ALK is likely the result of local chromothripsis followed by episomal amplification. Transcriptome sequencing demonstrated high-level SOX2 expression and predicted WNT/β-catenin pathway activation, suggesting possible therapeutic approaches. READ ARTICLE
Cancer Genetics DOI:10.1016/j.cancergen.2020.12.005
Authors: Yiming Zhong, Fumin Lin, Feng Xu, Jeff Schubert, Jinhua Wu, Luanne Wainwright, Xiaonan Zhao, Kajia Cao, Zhiqian Fan, Jiani Chen, Shih-Shan Lang, Benjamin C. Kennedy, Angela N. Viaene, Mariarita Santi, Adam C. Resnick, Phillip B. Storm and Marilyn M. Li
Case report of a 19-year-old boy with an ALK-positive IMT of the bladder, proximal osteolytic and multiple bilateral lung lesions, who received ALK inhibitor entrectinib postoperatively and underwent longitudinal CTC analysis during treatment. Antitumor activity of entrectinib was demonstrated and was accompanied by regression of lung lesions, elimination of CTCs from the blood and no development of relapses afterwards. Therapy continued without any clinical sign of progression and 24 months since the initiation of treatment the patient remains symptom-free and disease-free. READ ARTICLE
Frontiers in Pediatrics DOI:10.3389/fped.2021.652583
Authors: Paolo Bonvini, Elisabetta Rossi, Angelica Zin, Mariangela Manicone, Riccardo Vidotto, Antonella Facchinetti, Lucia Tombolan, Maria C. Affinita, Luisa Santoro, Zamarchi Rita, Gianni Bisogno.
Concurrent genetic alterations, including loss-of-function mutations in FBXW7 and MLL3, may mainly contribute to poor prognosis in the patient. It highlighted the molecular profiling by using NGS can be useful in identifying the heterogeneity across lesions and the resistance mechanism of targeted treatments. READ ARTICLE
Translational Cancer Research DOI:10.21037/tcr-20-3473
Authors: Xiang Long, Hao Wu, Chenglin Yang, Fang Li, Min Zhang, Xuan Wu
Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.02.010
Authors: D. Ross Camidge, Gregory A. Otterson, Jeffrey W. Clark, Sai-Hong Ignatius Ou, Jared Weiss, Steven Ades, Geoffrey I. Shapiro, Mark A. Socinski, Danielle A. Murphy, Umberto Conte, Yiyun Tang, Sherry C. Wang, Keith D. Wilner, Liza C. Villaruz
The spectrum of ALK-fusion variants and the landscape of concomitant genomic alterations were delineated in 96 NSCLC patients. Our study also demonstrated the prognostic value of concomitant alterations in crizotinib-treated patients, which could facilitate improved stratification of ALK-rearranged NSCLC patients in the selection of candidates who could optimally benefit from therapy. READ ARTICLE
Translational Lung Cancer Research DOI:10.21037/tlcr-21-160
Authors: Jingjing Li, Bin Zhang, Yu Zhang, Feng Xu, Zhenfa Zhang, Lin Shao, Chunhe Yan, Paola Ulivi, Marc G Denis, Petros Christopoulos, Vincent Thomas de Montpréville, Eric H Bernicker, Anthonie J van der Wekken, Changli Wang, Dongsheng Yue
Review discusses technical aspects of plasma genotyping strategies and summarize findings from studies exploring plasma genotyping (including ctDNA analysis and profiling of nucleic acids contained in other plasma components) in two rearrangement-driven NSCLC subsets (ALK-rearranged and ROS1-rearranged). READ ARTICLE
Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-09
Authors: Dagogo-Jack I, Ritterhouse LL.
Read MoreObjectives: ... Here, we reported a case of lung adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)–ALK fusion which the breakpoints was (S6,A20). To our knowledge, this case is the first report showed clinical evidence of SRBD1-ALK fusion responding to crizotinib. Conclusion: To our knowledge, our case is the first case of SRBD1-ALK fusion with excellent response to crizotinib. This case merits further follow-up and provides valuable information on the response to crizotinib of NSCLC patients with SRBD1-ALK fusion. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.04.031
Authors: Yao, Chen, Xiaochen Zhang, Qi Jiang, Bo Wang, Yina Wang, Yan Junrong
ALK (Anaplastic lymphoma kinase) rearrangement is the second most common targetable oncogene-dirven gene in NSCLC (non-small cell lung cancer). It is identified in approximately 3–7% of NSCLC patients [ [1] ], and is highly sensitive to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib, ceritinib, brigatinib [ [2] ]. EML4-ALK rearrangement was firstly identified by Soda et al. in 2007 [ [3] ]. With the development of NGS (Next Generation Sequencing), more and more novel ALK fusion partners have been identified, such as KIF5B, STRN, KLC1, TPR, HIP1, DCTN1, CMTR1, GCC2, SEC31A and so on. A liquid biopsy by amplicon-based NGS analysis has been considered as an accurate and reliable tool to detect and monitor clinically relevant molecular alterations. Herein, using NGS and malignant pleural effusion (MPE) cfDNA, we report a novel latent transforming growth factor β binding protein 1 (LTBP1)-ALK fusion in a patient with NSCLC. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.03.025
Authors: HuiWen Qian, Juan Li, LiRong Zou, Cheng Ji, Hayen Li, YuShuang Zheng, LingChuan Guo, WeiDong Zhu, Yi Zhang
Introduction: Precision therapy for cancer drug resistance requires detection of resistance mutations and treatment with appropriate targeted therapies. This paradigm is well established in EGFR-mutant NSCLC, yet our understanding of drug resistance in ALK-positive NSCLC is limited. Next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) now permits noninvasive interrogation of drug resistance. To facilitate improved understanding of ALK drug resistance and the effectiveness of treatment strategies, we launched this remote participation study. Conclusions: Plasma NGS permits the detection of targetable resistance mechanisms in patients with ALK-positive NSCLC and drug resistance. Sensitivity of different plasma NGS assays for ALK fusions varies. This assay may help guide oncologists across the country to select best treatment options after resistance. Such remote-participation studies may offer a new mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations. READ ARTICLE
Clinical Cancer Research DOI:10.1158/1557-3265.LiqBiop20-A28
Authors: Marissa N. Lawrence, Rubii M. Tamen, Alicia Sable-Hunt, Seyed Ali Hosseini, George R. Simon, Jonathan W. Riess, Geoffrey R. Oxnard.
Objectives: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rearranged SCLC responding to ALK inhibitors. Conclusion: This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion mutations. This case also provides valuable information on the response to ALK inhibitors of patients with PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a routine test to explore more treatment opportunities for tumor SCLC patients. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2019.11.002
Authors: Tao Li, Fan Zhang, Zhaozhen Wu, Longgang Cui, Xiaochen Zhao, Jinliang Wang, Yi Hu
Objectives: Anaplastic lymphoma kinase (ALK) has been proven to be another driver oncogene that accounts for 3%–7% of non-small-cell lung cancer, and it is more common in young patients and nonsmokers. ALK rearrangements have been previously identified in about 5.1% of lung adenocarcinoma, including EML4-ALK fusion variants, KIF5B-ALK and TFG-ALK. However, a TNIP2-ALK fusion has not been reported in lung adenocarcinoma. Herein, we described a rare case of ALK-rearranged lung adenocarcinoma responding to crizotinib. Conclusion: This case provides valuable information on the response to crizotinib of patients with TNIP2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS is a new method that can offer effective detection of gene fusion and gene mutations. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2019.08.032
Authors: Tingting Feng, Zhongzhong Chen, Jianjun Gu, Yuxiu Wang, Jun Zhang, Lingfeng Min
Second- and third-generation ALK inhibitors each have diverse mechanisms of resistance. Only a fraction of resistance is due to secondary mutations of the ALK gene. Altered bypass tracts are likely the case in some other instances. Genomic alterations of other genes and pathways may be a third mechanism of resistance. Repeat liquid biopsies during the course of patients’ treatments can provide a minimally invasive method for sampling cancer-specific genomic information that leads to improved treatment selection. In the Lung Cancer Clinic of the Princess Margaret Cancer Centre, serial plasma samples were collected from six lung cancer patients with ALK rearrangement at multiple serial clinic visits pre- and post- progression on next-generation ALK inhibitors. We focused on next generation agents, as there has been previous focus on crizotinib resistance mechanisms already.The study found that broad panel-based NGS of plasma cfDNA enabled noninvasive detection of systemic (but not CNS-pr..... READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1158
Authors: E. Stewart, A. Wang, J. Huang, H. Bao, X. Wu, D. Patel, Z. Chen, J. Law, P. Bradbury, F. Shepherd, A. Sacher, M. Tsao, S. Bratman, N. Leighl, T. Pugh, G. Liu
Background: Anaplastic lymphoma kinase (ALK) rearrangements is an important molecular subtype of non-small cell lung cancer (NSCLC), and patients with this variant are sensitive to ALK inhibitors. Since the discovery of the EML4-ALK fusion ten years ago, several fusion partners of ALK in NSCLC have been reported, including KIF5B, KLC1, HIP1, TPR and so on. According to previous reports, different fusion partner lead to various function and activity of the fusion product. Here, we identified a novel fusion partner for ALK in a lung adenocarcinoma patient. Conclusion: The novel ALK fusion gene probably served as oncogenic driver of the patient’s tumor. This case is the first report of ATAD2B-ALK fusion in clinical tumor samples and could provide a new diagnostic and therapeutic candidate target for patients with lung cancer. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1823
Authors: H. Bai, W. Jia, X. Jin, H. Mao, D. Wu, R. Chen, X. Xia, H. Wu
Introduction: Chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene are detected in approximately 5% of non–small-cell lung cancers (NSCLCs) and function as oncogenic driver genes.1 First- and second-generation ALK-tyrosine kinase inhibitors (TKIs) were developed and showed clinical response for ALK-rearranged NSCLC.2, 3, 4 However, resistance to those ALK-TKIs almost develops, resulting in clinical relapse.5, 6 Lorlatinib is a third-generation ALK-TKI and has demonstrated significant antitumor activity against ALK-rearranged NSCLC with previous ALK-TKI resistance.7, 8 Although lorlatinib response was observed, relapse on lorlatinib ultimately developed.9, 10, 11 Mechanisms of lorlatinib resistance were reported,9, 10, 11 but remained unknown. Moreover, post-lorlatinib treatment has not been determined. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.021
Authors: Jun Sakakibara-Konishi, Hidenori Kitai, Yasuyuki Ikezawa, Yutaka Hatanaka, Takaaki Sasaki, Ryohei Yoshida, Shinichi Chiba, Shingo Matsumoto, Koichi Goto, Hidenori Mizugaki, Naofumi Shinagawa
Objectives: Patients harboring rearrangements of the ROS1 gene are eligible for first-line therapy with Crizotinib, which represents the best available treatment option. Diagnostic criteria, based on break-apart fluorescence in situ hybridization, were mirrored from ALK by analogy and include tumors with 5' deletions. However, the probability of response to Crizotinib in patients with 5' deletion in ROS1 is unknown given the rarity of this condition. Conclusion: 5' ROS1 deletions detected by FISH are associated with a high chance of response to Crizotinib in NSCLC, similarly to canonical ROS1 split-apart FISH rearrangements. However, the confirmation of the ROS1 gene fusion with at least another method, such as NGS, seems beneficial in order to define the ROS1 fusion partner and to avoid possible false positive results. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2019.07.017
Authors: Elisa Capizzi, Filippo Gustavo, Dall’Olio, Elisa Gruppioni, Francesca Sperandi, Annalisa Altimari, Francesca Giunchi, Michelangelo Fiorentino, Andrea Ardizzoni