Malignant pleural mesothelioma with an EML4-ALK fusion: Expect the unexpected!

Case report of malignant pleural mesothelioma with an ALK gene rearrangement, detected by FISH and confirmed by RNA-based next-generation sequencing. The co-occurrence of ALK gene fusions with the more common genetic alterations in CDKN2A, NF2 and BAP1 has, to our best knowledge, not yet been described in malignant mesothelioma. Furthermore, this unexpected finding could suggest a potential target for therapy in this subset of malignant mesotheliomas. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2022.153772

Authors: Fleur Cordier, Joni Van der Meulen, Nadinevan Roy, Jilke De Wilde, Herwigvan Dijck, Filip Vanhoenacker, Marc Lambrechts, Valentin Noyez, Koen Van de Vijver, Liesbeth Ferdinande, Amélie Dendooven, Jo Van Dorpe, David Creytens

Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions

Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%–99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%–74%) were concordant with p..... READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2021.06.018

Authors: Sebastian Mondaca, Emily S. Lebow, Azadeh Namakydoust, Pedram Razav, Jorge S. Reis-Filho, Ronglai Shen, Michael Offin, Hai-Yan Tu, Yonina Murciano-Goroff, Chongrui Xu, Alex Makhnin, Andres Martinez, Nick Pavlakis, Stephen Clarke, Malinda Itchins, Adrian Lee, Andreas Rimner, Daniel Gomez and Bob T. Li

The impact of the ALK fusion variant on clinical outcomes in EML4-ALK patients with NSCLC: a systematic review and meta-analysis

Background: Recent studies showed that ALK-fusion variants are associated with heterogeneous clinical outcomes. However, contradictory conclusions have been drawn in other studies showing no correlation between ALK variants and prognoses. Methods: A systematic review and meta-analysis was performed to evaluate the prognostic value of EML4-ALK fusion variants for patient outcomes. Results: 28 studies were included in the analysis. According to the pooled results, patients harboring variant 1 showed equivalent progression-free survival (PFS) and overall survival (OS) with non-v1 patients (hazard ratio [HR] for PFS: 0.91 [0.68–1.21]; p = 0.499; OS: 1.12 [0.73–1.72]; p = 0.610). Similarly, patients with v3 showed the same disease progress as non-v3 patients (pooled HR for PFS = 1.07 [0.72–1.58]; p = 0.741). However, pooled results for OS suggested that patients with v3 had worse survival than non-v3 patients (HR = 3.44 [1.42–8.35]; p = 0.006). Conclusion: Results suggest that patients with..... READ ARTICLE

Future Oncology DOI:10.2217/fon-2021-0945

Authors: Wang S, Luo R, Shi Y, Han X.

Review Paper, group2Kirk SmithNovember 16, 2021ALK fusion, ALK rearrangement, ALK variant, NSCLC, prognosis

Case Report: Identification of Two Rare Fusions, PDK1-ALK and STRN-ALK, That Coexist in a Lung Adenocarcinoma Patient and the Response to Alectinib

Several double ALK fusions coexisting in one patient have been reported. However, few studies have reported the clinical efficacy of ALK inhibitors in rare double ALK fusions. Here, we described a rare PDK1-ALK, STRN-ALK double-fusion variant in a patient with metastatic lung adenocarcinoma. The patient responded well to alectinib (600 mg) twice daily. This case shows a promising treatment option for patients with rare ALK double-fusion variants. READ ARTICLE

Frontiers in oncology DOI:10.3389/fonc.2021.722843

Authors: Zeng H, Li Y, Wang Y, Huang M, Zhang Y, Tian P, Li W.

One-Step Polymerase Chain Reaction-Free Nanowire-Based Plasma Cell-Free DNA Assay to Detect EML4-ALK Fusion and to Monitor Resistance in Lung Cancer

Background: Next-generation sequencing has mostly been used for genotyping cell-free DNA (cfDNA) in plasma. However, this assay has several clinical limitations. We evaluated the clinical utility of a novel polymerase chain reaction–free nanowire (NW)-based plasma cfDNA assay for detecting ALK fusion and mutations. Conclusion: The newly developed simple NW-based cfDNA assay may be clinically applicable for rapid diagnosis of ALK fusion with its variant forms and early detection of resistance. READ ARTICLE

The Oncologist DOI:10.1002/onco.13902

Authors: Youngjoo Lee, Youngnam Cho, Eun Young Park, Seong-Yun Park, Kum Hui Hwang, Ji-Youn Han

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. Results:While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = − 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = − 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine–cytokine receptor signaling, were differentially expressed be..... READ ARTICLE

Cancer Immunology, Immunotherapy DOI:doi.org/10.1007/s00262-021-02981-w

Authors: Jan Budczies, Martina Kirchner, Klaus Kluck, Daniel Kazdal, Julia Glade, Michael Allgäuer, Mark Kriegsmann, Claus-Peter Heußel, Felix J. Herth, Hauke Winter, Michael Meister, Thomas Muley, Torsten Goldmann, Stefan Fröhling, Martin Wermke, Cornelius F. Waller, Amanda Tufman, Martin Reck, Solange Peters, Peter Schirmacher, Michael Thomas, Petros Christopoulos, & Albrecht Stenzinger

Crizotinib in Patients With MET-Amplified NSCLC

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

Concomitant mutation status of ALK-rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib

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

Clinical Utility of Reflex Ordered Testing for Molecular Biomarkers in Lung Adenocarcinoma

Introduction: In order to standardize and expedite molecular biomarker testing, we implemented reflex ordered testing of targeted gene alterations in newly diagnosed lung adenocarcinomas within our hospital system... Conclusions: Reflex ordered testing of molecular biomarkers in lung adenocarcinoma led to significantly decreased TAT within our hospital system and higher detection rates of targeted gene alterations. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.007

Authors: Kartik Anand, Thuy L. Phung, Eric H. Bernicker, Philip T. Cagle, Randall J. Olsen, Jessica S. Thomas

Review PaperKirk SmithSeptember 1, 2020ALK fusion, EGFR mutation, NSCLC, ROS1 fusion, Turnaround time

Investigation on the prognostic impact of concurrent genomic alterations in crizotinib-treated EML4-ALK-rearranged advanced non-small cell lung cancer patients

Background: ... In our study, we investigated concurrent molecular factors that could contribute to the heterogeneity of their clinical outcomes to crizotinib therapy... Conclusion: Our study revealed that concurrent deleterious mutations, particularly copy number amplifications in oncogenic genes have prognostic implications in patients with EML4-ALK-rearranged NSCLC receiving crizotinib therapy. These observations advance the understanding of the heterogeneity of treatment responses among patients with EML4-ALK-rearranged tumors. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.026

Authors: Jing Zheng, Yanping Zhu, Ke Sun, Qian Shen, Yuehong Wang, He Cao, Analyn Lizaso, Bing Yu, Jing Lin, Songan Chen, Jianya Zhou, Jianying Zhou

Case StudyKirk SmithAugust 1, 2020ALK fusion, ALK rearrangements, EML4-ALK, Crizotinib, Lung cancer

The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma

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

Case StudyKirk SmithNovember 1, 2019NSCLC, ALK fusion, TNIP2-ALK, crizotinib, NGS

Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer

ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated.
Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17).
Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.024

Authors: Yongfeng Yu, Qiuxiang Ou, Xue Wu, Hairong Bao,
Yan Ding, Yang W. Shao, Shun Lu