Concomitant novel ALK-SSH2, EML4-ALK and ARID2-ALK, EML4-ALK double-fusion variants and confer sensitivity to crizotinib in two lung adenocarcinoma patients, respectively

Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements, have been identified in approximately 2-7% of patients with lung adenocarcinoma (LUAD). However, co-occurrence of double ALK fusions in one patient was rare. Herein, we reported two Chinese female LUAD patients with confirmed double ALK fusion variants by next generation sequencing.
Case presentation

Case 1, a 38-year-old female was diagnosed as peripheral LUAD in left upper lobe with synchronous multiple intrapulmonary metastases (pT2N0M1b, stage IVa). And case 2, a 58-year-old female had left lower lobe primary LUAD and synchronous multiple lung metastases (pT4N2M1b, stage IVa). In both patients, tumor cells displayed strong expression of ALK protein. Genetic profiling by next generation sequencing showed both patients concurrently harbored two types of ALK rearrangements. Case 1 had an unreported ALK-SSH2/EML4-ALK double fusions, and case 2 had an another novel ARID2-ALK/EML4‐ALK double fusions. Both of these patients responded to ALK inhibitor crizotinib.
Conclusions

Our study reported two novel ALK fusion partners never reported, which expands the knowledge of ALK fusion spectrum and provides insight into therapeutic options for patients with double ALK fusions. READ ARTICLE

Diagnostic Pathology DOI:10.1186/s13000-022-01212-9

Authors: Tao H, Liu Z, Mu J, Gai F, Huang Z, Shi L.

Multiplex fluorescence in situ hybridization testing for anaplastic lymphoma kinase and c-ros oncogene 1 gene rearrangements on cytology smears in lung adenocarcinomas:..

Introduction: Multiplex anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) fluorescence in situ hybridization (FISH) probes conserve tissue by analyzing both ALK and ROS1 gene rearrangements (ALK-R/ROS1-R) in a single test. The positivity cutoffs have been validated on formalin-fixed, paraffin-embedded (FFPE) tissue sections and not tested on non–cell block (CB) cytology preparations. We sought to validate non-CB cytology preparations for the detection of ALK-R/ROS1-R using multiplex ALK/ROS1 FISH probes by comparing the results with matched FFPE results... Conclusions: Non-CB cytology smears are highly suitable for multiplex FISH analysis with 100% concordance with FFPE FISH and/or ALK D5F3 companion diagnostics assay results. READ ARTICLE

Journal of the American Society of Cytopathology DOI:10.1016/j.jasc.2022.01.001

Authors: Aruna Nambirajan, Deeksha Rana, Komal Samant, Aswini Prabakaran, Prabhat Malik, Deepali Jain

Review PaperKirk SmithJanuary 13, 2022ALK, ROS1, Multiplex FISH, Cytology smear, Lung adenocarcinoma

Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform

Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are slow and technically demanding. In contrast, cell line transplant models are fast and flexible, but are often derived from clonal idiosyncratic tumors that fail to capture the full spectrum of clinical disease. Organoid technologies provide a means to create next-generation cancer models that integrate the most relevant features of autochthonous and transplant-based systems, yet robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 cells (AT2), a prominent cell-of-origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expre..... READ ARTICLE

bioRxiv DOI:10.1101/2021.12.07.471632

Authors: Santiago Naranjo, Christina M. Cabana, Lindsay M. LaFave, Peter M.K. Westcott, Rodrigo Romero, Arkopravo Ghosh, Laura Z. Liao, Jason M. Schenkel, Isabella Del Priore, Arjun Bhutkar, Dian Yang, Tyler Jacks

Pre-Clinical, Pre-Print, group1Kirk SmithDecember 7, 2021Lung adenocarcinoma, organoid culture

68-months progression-free survival with crizotinib treatment in a patient with metastatic ALK positive lung adenocarcinoma and sarcoidosis: A case report

Lung cancer still ranks first among the most common and most lethal cancers today. The most common subtype is non-small cell lung cancer, and in this group, adenocarcinoma has the worst prognosis. EGFR, ROS1 and ALK-EML4 gene fusion mutations are common in non-small cell lung cancer.In this article, we wanted to share our experience of crizotinib in a 68-months progression-free survival in a 62-years old non-smoking female patient with metastatic lung adenocarcinoma who is also diagnosed with sarcoidosis. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220951242

Authors: Ozgur Tanriverdi, Mehmet L Tarimer, Ceren D Pak, Selcuk Uylas, Ali Alkan, Ozgur Ilhan Celik, Rabia M Kilic, Arife Zeybek

Comparison of solid tissue sequencing and liquid biopsy accuracy in identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas

Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. “Liquid biopsies” are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a ..... READ ARTICLE

Modern Pathology DOI:10.1038/s41379-021-00880-0

Authors: Lawrence Hsu Lin, Douglas H. R. Allison, Yang Feng, George Jour, Kyung Park, Fang Zhou, Andre L. Moreira, Guomiao Shen, Xiaojun Feng, Joshua Sabari, Vamsidhar Velcheti, Matija Snuderl, Paolo Cotzia

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

Immune checkpoint inhibitors in oncogene-addicted non-small cell lung cancer: a systematic review and meta-analysis

Eighty-seven studies were included in the qualitative analysis. EGFR mutation may be a biomarker of poor response to single-agent ICIs (7% of EGFR-mutant NSCLC patients achieved disease response in prospective trials), while encouraging results have been shown with combination strategies. KRAS-mutated disease (response rate, RR, 22%) has different clinical and pathological characteristics, and the co-existence of additional mutations (e.g., STK11 or TP53) influence tumor microenvironment and response to immunotherapy. Other molecular alterations have been marginally considered prospectively, and data from clinical practice are variegated, given poor effectiveness of ICIs in ALK-rearranged disease (RR 9.5%, pooling the data of retrospective studies) or some encouraging results in BRAF-(RR 25%, retrospective data) or MET-driven one (with estimations conditioned by the presence of both exon 14 skipping mutations and gene amplification in reported series). In oncogene-addicted NSCLC (with ..... READ ARTICLE

Translational lung Cancer Research DOI:10.21037/tlcr-20-941

Authors: Giorgia Guaitoli, Marcello Tiseo, Massimo Di Maio, Luc Friboulet and Francesco Facchinetti

Successful management of a lung cancer patient harbouring both EGFR mutation and EML4-ALK fusion gene with disseminated intravascular coagulation

Lung cancer patients harbouring driver oncogene alterations are markedly responsive to molecular target agents, such as epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor (TKI), and echinoderm microtubule-associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK)-TKI. We encountered an exceptionally rare case, harbouring both EGFR mutation and EML4-ALK fusion gene, and suffering from severe disseminated intravascular coagulation. In this case report, we present two notable points. First, our patient was successfully treated with a third-generation EGFR-TKI, osimertinib. Second, osimertinib could manage severe conditions, such as disseminated intravascular coagulation. Third-generation EGFR-TKIs may be a viable option for patients harbouring both EGFR mutations and EML4-ALK fusion genes, even in severe conditions. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2021.101393

Authors: Kohei Fujita, Megumi Naka, Takanori Ito, Osamu Kanai, Koichi Maekawa, Koichi Nakatani, Tadashi Mio

Analysis of multigene detection in patients with advanced lung adenocarcinoma using cytological specimens

Objective: To investigate the mutation status and clinical characteristics of multigene detection in advanced lung adenocarcinoma using cytological specimens... Conclusions: In the study, cytological specimens and biopsy samples have a very high coincidence rate of gene detection. EGFR, ALK and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations respectively and the treatment of advanced lung adenocarcinoma patients with concomitant mutations deserves further study. The rate of KRAS, NRAS, BRAF, PIK3CA, RET and MET exon14 skipping mutation were low but may had a significant impact on the targeted therapy of patients with advanced lung adenocarcinoma. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2020.153036

Authors: Yang Ma, Yun Du, Rui Wang, Xiaokun Ji, Juan Wu, Ying Liu, Xiao Guo, Yan Zhang

Review PaperKirk SmithAugust 1, 2020Lung adenocarcinoma, Cytological, Specimen, ARMS, Driver mutations

BRAF V600E mutation and MET amplification as resistance pathways of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in lung cancer

Background: Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. However, patients inevitably develop resistance to such therapies. To investigate novel mechanisms of resistance to second generation ALK inhibitors, we characterized and modeled ALK inhibitor resistance of ALK-positive patient-derived xenograft (PDX) models established from advanced-stage lung adenocarcinoma patients who have progressed on one or more ALK inhibitors. Conclusions: Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.018

Authors: Ruoshi Shi, Sebastiao N. Martins Filho, Ming Li, Aline Fares, Jessica Weiss, Nhu-An Pham, Olga Ludkovski, Vibha Raghavan, Quan Li, Deepti Ravi, Michael Cabanero, Nadeem Moghal, Natasha B. Leighl, Penelope Bradbury, Adrian Sacher, Frances A. Shepherd, Kazuhiro Yasufuku, Ming-Sound Tsao, Geoffrey Liu

HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model

Objectives: Somatic chromosomal rearrangements resulting in ALK fusion oncogenes are observed in 3–7 % of lung adenocarcinomas. ALK tyrosine kinase inhibitors (ALKi) induce initially response, however, various resistance mechanisms limit their efficacy. Novel therapeutic approaches are of utmost importance to tailor these targeted therapies... Conclusion: Using a patient-derived ALKi resistant lung cancer model we demonstrated the synergism of HDAC and ALK inhibition. Furthermore, our findings provide strong evidence for intratumoral heterogeneity under targeted therapy and highlight the importance of site-specific mutational analysis. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.002

Authors: Paul Stockhammer, Cassandra Su Lyn Ho, Luca Hegedus, Gabor Lotz, Eszter Molnár, Agnes Bankfalvi, Thomas Herold, Stavros Kalbourtzis, Till Ploenes, Wilfried E. E. Eberhardt, Martin Schuler, Clemens Aigner, Alexander Schramm, Balazs Hegedus

Serial liquid biopsies for detection of treatment failure and profiling of resistance mechanisms in KLC1–ALK-rearranged lung cancer

Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene confer sensitivity to ALK tyrosine kinase inhibitors (TKIs) and superior outcome in non-small-cell lung cancer (NSCLC). However, clinical courses vary widely, and recent studies suggest that molecular profiling of ALK+ NSCLC can provide additional predictors of therapy response that could assist further individualization of patient management. In summary, our findings illustrate the utility of noninvasive longitudinal molecular profiling for assessing remission status, exploring mechanisms of treatment failure, predicting subsequent clinical course, and dissecting dynamics of drug-resistant clones in ALK+ lung cancer. READ ARTICLE

Cold Spring Harbor Molecular Case Studies DOI:10.1101/mcs.a004630

Authors: Steffen Dietz, Petros Christopoulos, Lisa Gu, Anna-Lena Volckmar, Volker Endris, Zhao Yuan, Simon J. Ogrodnik, Tomasz Zemojtel, Claus-Peter Heussel, Marc A. Schneider, Michael Meister, Thomas Muley, Martin Reck, Matthias Schlesner, Michael Thomas, Albrecht Stenzinger, Holger Sültmann

Case StudyKirk SmithSeptember 4, 2019Lung adenocarcinoma

Targeting SLMAP-ALK—a novel gene fusion in lung adenocarcinoma

Assessment of ALK gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non-small-cell lung cancer (NSCLC) with ALK gene rearrangements or the resulting fusion proteins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4. Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs. Additionally, non-EML4-ALK fusions that result from ALK rearrangements with diverse 5′ partners could possibly have varied biologic and clinical implications in their therapeutic responses and outcomes of patients with NSCLC. Existing literature documents at least 20 non-EML4 fusion partners for ALK, and the clinical responsiveness to c..... READ ARTICLE

Cold Spring Harbor Molecular Case Studies DOI:10.1101/mcs.a003939

Authors: Carlos Pagan, Subit Barua, Susan J. Hsiao, Mahesh Mansukhani, Anjali Saqi, Vundavalli Murty, and Helen Fernandes

Case StudyKirk SmithJune 1, 2019Lung adenocarcinoma, SLMAP-ALK fusion

Lung adenocarcinoma with concurrent ALK and ROS1 rearrangement: A case report and review of the literatures

ALK and ROS1 are prognostic and predictive tumor markers in non-small cell lung carcinoma (NSCLC), which are more often found in lung adenocarcinomas as with other oncogenes such as EGFR, KRAS, or C-MET. Their positivity is 2.6% and 1.3%, respectively, and patients who have mutations in both genes are extremely rare. Here, we report a 61-year-old male diagnosed with acinar adenocarcinoma, who was shown to have both ALK and ROS1 rearrangements but was EGFR- and C-MET mutation-negative. He was treated surgically and received targeted therapy. Our review of the literature revealed that few such cases of concurrent ALK and ROS1 rearrangements have been reported. This information furthers our understanding of the molecular biology underlying NSCLC which will aid the selection of optimal treatment for patients with more than one driver mutation. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2018.09.028

Authors: Huiyan Deng, Chang Liu, Guoliang Zhang, Xiaoling
Wang, Yueping Liu

Case StudyKirk SmithDecember 1, 2018Lung adenocarcinoma, ALK, ROS1, Co-mutation