Concomitant EGFR mutation and ALK rearrangement in multifocal lung adenocarcinoma: a case report

Background The prevalence of EGFR/ALK co-alterations in patients with NSCLC was low. The several previous studies focused on the simultaneous occurrence of EGFR mutations and ALK rearrangements in a unifocal lung cancer. However, the incidence of multifocal pulmonary adenocarcinomas was increasingly encountered in clinical practice, due to the increased availability and improvement of the thoracic imaging. The clinical relevance of EGFR/ALK co-alterations in multifocal adenocarcinomas required detailed investigation as well. ConclusionsThe status of the oncogenic mutations in lymph node metastasis may provide some effective hints for metastasis lesion in other organ or tissue. Therefore, it is recommended to fully evaluate the driver genes in lymph node metastasis after radical resection. READ ARTICLE

Diagnostic Pathology DOI:10.1186/s13000-020-00969-1

Authors: Fan, J., Wu, J., Huang, B. et al.

Chr2 30297612-ALK, A Novel Intergenic Fusion With Exon18 of ALK, Responds to Crizotinib

Anaplastic lymphoma kinase (ALK) fusion is an important molecular subtype of non–small-cell lung cancer, and patients who have ALK fusion can be highly sensitive to ALK tyrosine kinase inhibitors. Different ALK fusions showed different sensitivities to ALK tyrosine kinase inhibitors. EML4-ALK (E6; A18) fusion showed resistance to crizotinib in a 48-year-old male patient with lung adenocarcinoma. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.04.014

Authors: Xiaofeng Chen, Guohong Zhao, Peilin Zhong, Min Zhang, Rongrong Chen, Derong Zhang

18F-FDG PET/CT Confirms a High Proportion of Advanced Disease at Baseline in ALK Gene Rearranged Non-Small Cell Lung Cancer: A Case Review and Comparison with Diagnostic CT

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Journal of Nuclear Medicine DOI:Print ISSN 0161-5505

Authors: Sally Ayesa, Malinda Itchins, Anthony Gill and Geoff Schembri

Case StudyKirk SmithMay 1, 2020PET/CT

SPECC1L-ALK: A novel gene fusion response to ALK inhibitors in non-small cell lung cancer

There was a case report showed that a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)- anaplastic lymphoma kinase (ALK) gene rearrangement in small cell lung cancer (SCLC) patient had long-term benefit from ALK inhibitors [ [1] ]. Actually, the case report demonstrated that next generation sequence (NGS) maybe a very useful method for detecting a new subtype of ALK fusion and it may provide a better understanding of ALK- tyrosine kinase inhibitors (TKIs) treatment. Here, we identified a novel type of ALK rearrangement responding to ALK inhibitors in non-small cell lung cancer (NSCLC) by NGS. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.03.017

Authors: Li Ma, Quan Zhang, Yujie Dong, Haoyang Li, Jinghui Wang

Case StudyKirk SmithMay 1, 2020SPECC1L-ALK, gene fusion, ALK, inhibitors, non-small cell lung cancer

A Naive Lung Adenocarcinoma Harboring G1269A ALK Resistance Mutation

Introduction ALK gene rearrangement in NSCLC results from fusion with another partner gene, mainly EML4 gene, and is observed in less than 5% of adenocarcinoma tumors. Patients usually manifest a response to ALK tyrosine kinase inhibitors. Unfortunately, acquired resistance ineluctably occurs and has been associated with the emergence of secondary mutations.1 Here, we report the identification of an ALK resistance mutation in a patient with ALK tyrosine kinase inhibitor–naive multimetastatic NSCLC. Conclusions ALK secondary resistance mutations can be present in naive tumors and may be associated with aggressive presentation. Baseline NGS screening is very important to identify uncommon mutations and improve first-line targeted therapeutic strategies. READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100047

Authors: Olfa Trabelsi-Grati, Elsy El-Alam, Samia Melaabi, Yves Allory, Ivan Bièche, Nicolas Girard, Céline Callens,

Complete response after ceritinib treatment in non-small cell lung cancer in an elderly patient

Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC) Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220919172

Authors: Nilay Sengul Samanci, Emir Celik, Burak Akovalı, Sait Sager, Fuat Hulusi Demirelli

Case StudyKirk SmithApril 27, 2020Non-small cell lung cancer, EML4-ALK, ceritinib

Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the ALK Gene Have Durable Responses to ALK Kinase Inhibitors

Background

ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.

Methods

Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.

Results

We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing i..... READ ARTICLE

Lung Cancer: Targets and Therapy DOI:10.2147/LCTT.S239675

Authors: Schrock AB, Madison R, Rosenzweig M, Allen JM, Erlich RL, Wang SY, Chidiac T, Reddy VS, Riess JW, Yassa AE, Shakir A, Miller VA, Alexander BM, Venstrom J, McGregor K, Ali SM

Case StudyKirk SmithApril 17, 2020ALK rearrangement, inversion, deletion, genomic profiling, targeted therapy

LTBP1-ALK: A novel fusion identified in malignant pleural effusions from a patient with advanced lung adenocarcinoma

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

A novel SOS1-ALK fusion variant in a patient with metastatic lung adenocarcinoma and a remarkable response to crizotinib

Objectives: Transforming anaplastic lymphoma kinase (ALK) gene rearrangements are well known as a unique subset of non-small cell lung cancer (NSCLC) with mutations other than EGFR. Currently, crizotinib is the standard first-line treatment for ALK-positive NSCLC. Conclusion: Considering this rare SOS1-ALK fusion and remarkable response to an ALK-inhibitor, it is important to be aware of the presence of SOS1-ALK fusions in patients with advanced NSCLC to better guide targeted therapy. Precision methods, such as NGS for oncogenic alteration detection, should also be encouraged in clinical practice. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.02.012

Authors: Hua-fei Chen, Wen-xian Wang, Chun-wei Xu, Li-chao Huang, Xiao-feng Li, Gang Lan, Zhan-qiang Zhai, You-cai Zhu, Kai-qi Du, Lei Lei, Mei-yu Fang

Case StudyKirk SmithApril 1, 2020Non-Small cell lung cancer, ALK, Fusion, TKI, Crizotinib

Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement

Objectives: Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Conclusions: Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.02.006

Authors: Giuseppe Bronte, Angelo Delmonte, Marco Angelo Burgio, Alberto Verlicchi, Maurizio Puccetti, Sara Bravaccini, Paola Cravero, Maria MaddalenaTumedei, Danila Diano, Giulio Rossi, Paola Ulivi, Giovanni Martinelli, Lucio Crinòa

Case StudyKirk SmithApril 1, 2020Mesothelioma, PD-L1, Immunotherapy, Immune checkpoint inhibitors, EML4-ALK

Next-generation sequencing to dynamically detect mechanisms of resistance to ALK inhibitors in ALK-positive NSCLC patients: a case report

Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an ALK translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an ALK-positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the ALK locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively...... READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr.2020.02.07

Authors: Sánchez-Herrero E, Blanco Clemente M, Calvo V, Provencio M, Romero A.

Tree-in-bud Pattern in ALK-positive Lung Adenocarcinoma

A 62-year-old woman presented with a 3-month history of cough and hemoptysis. CT revealed nodular shadows with centrilobular distribution in the left lung. Three sputum smears for acid-fast bacillus were negative. Based on the results of a transbronchial biopsy, she was diagnosed with stage IVA lung lepidic adenocarcinoma harboring ALK translocation. At this point, CT showed progressive shadows, and alectinib was immediately initiated. Acid-fast bacillus culture of bronchoscopic biopsy tissue was negative. One month later, marked remission was observed, providing definitive evidence to exclude mycobacterial infection. The tree-in-bud pattern occurs commonly in patients with mycobacterial infection. Central lung cancer is reportedly another common cause of the treein-bud pattern. Nevertheless, when encountering a treein-bud pattern, physicians tend to be anxious about the possibility of tuberculosis; even when mycobacterial tests are negative, the absence of evidence is not evidence of ..... READ ARTICLE

Internal Medicine (The Japanese Society of Internal Medicine) DOI:10.2169/internalmedicine.4076-19

Authors: Takayuki Shiroyama, Shingo Nasu, Ayako Tanaka and Tomonori Hirashima

Case StudyKirk SmithMarch 12, 2020tree-in-bud, lung adenocarcinoma, ALK, alectinib

Oncogenic Fusions May Be Frequently Present at Resistance of EGFR Tyrosine Kinase Inhibitors in Patients With NSCLC: A Brief Report

Introduction Despite initial benefit, virtually all patients suffering from EGFR-mutant NSCLC experience acquired resistance to tyrosine kinase inhibitors (TKIs), driven by multiple mechanisms. Recent reports have identified oncogenic kinase fusions as off-target resistance mechanisms; however, these alterations have been rarely investigated at EGFR TKIs progression. Results Six gene fusions were detected in tumor progression biopsies under an EGFR TKI from 62 consecutive patients (9.7%) with EGFR-mutated advanced NSCLC. Among 31 patients progressing to first- or second-generation EGFR TKIs, one (3%) had an Eukaryotic translation initiation factor 4 gamma 2–GRB2 associated binding protein 1 (EIF4G2-GAB1) fusion. Among 31 patients progressing to the third-generation osimertinib, five (16%) presented oncogene fusions of fibroblast growth factor receptor 3–transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3) (n = 2), kinesin family member 5B–Ret proto-oncogene (KIF5B-RET) (n..... READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100023

Authors: Diego Enrico, Ludovic Lacroix, Jeanne Chen, Etienne Rouleau, Jean-Yves Scoazec, Yohann Loriot, Lambros Tselikas, Cécile Jovelet, David Planchard, Anas Gazzah, Laura Mezquita, Maud Ngo-Camus, Stefan Michiels, Christophe Massard, Gonzalo Recondo, Francesco Facchinetti, Jordi Remon, Jean-Charles Soria, Fabrice André, Gilles Vassal, Luc Friboulet, Benjamin Besse

Melanoregulin-Anaplastic Lymphoma Kinase (ALK), a Novel ALK Rearrangement That Responds to Crizotinib in Lung Adenocarcinoma

Here, we report a novel melanoregulin (MREG)-ALK fusion, which is sensitive to crizotinib, in a patient with lung adenocarcinoma and brain metastasis. A 65-year-old nonsmoking Chinese woman was admitted to the local hospital with cough since 2 months. She had no fever, expectoration, or headache. Computed tomography scans of her chest reported an irregular nodular mass in the left main bronchial wall and the left lingual lobe, with a narrowing of the left lower lobe bronchi, Meanwhile, cranial computed tomography and magnetic resonance imaging revealed a space-occupying lesion in the frontal lobe, accompanied by bone destruction, which was considered a metastatic tumor. A biopsy through fiberoptic bronchoscopy was performed, and pathologic analysis reported a poorly differentiated lung adenocarcinoma with mucin production in cytoplasm. Formalin-fixed, paraffin-embedded specimens from bronchoscopy biopsy were sent for genomic testing by next-generation sequencing. Results revealed that ..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.019

Authors: Leiming Wang, Shuyang Yao, Lianghong Teng, Weiwei Zhang, Li Chen

Case StudyKirk SmithMarch 1, 2020Melanoregulin-ALK, Crizotinib, Lung Adenocarcinoma

$Complete Response of Primary Refractory ALK-Positive Large B-Cell Lymphoma Treated With Single-Agent Nivolumab$

Complete Response of Primary Refractory ALK-Positive Large B-Cell Lymphoma Treated With Single-Agent Nivolumab

... Here we report a case of relapsed/refractory (R/R) ALK-positive LBCL with a prolonged complete response to single-agent nivolumab... Case Report: Here we report a case of relapsed/refractory (R/R) ALK-positive LBCL with a prolonged complete response to single-agent nivolumab... Conclusion: This is to our knowledge the first report of a complete response in a patient with primary refractory ALK-positive LBCL after treatment with nivolumab. Although recent reports showing low single-agent activity of checkpoint inhibitors in R/R DLBCL have been disappointing, patients with disease exhibiting exceptional response to immunotherapy are still seen and need to be further characterized. New cellular therapies may prove to be effective in these uncommon and aggressive lymphomas... READ ARTICLE

Clinical Lymphoma Myeloma and Leukemia DOI:10.1016/j.clml.2019.08.015

Authors: Jose D. Sandoval-Sus, Amanda Brahim, Alina Khan, Yehuda Deutsch, Barbara Raphael, Ali Ansari-Lari, Hugo F. Fernandez, Luis E. Raez

Case StudyKirk SmithMarch 1, 2020ALK-Positive, Large B-Cell Lymphoma, Nivolumab

ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib

Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib. READ ARTICLE

OncoTargets and therapy DOI:10.2147/OTT.S236706

Authors: Kaiho T, Nakajima T, Iwasawa S, Yonemori Y, Yoshino I.

Life-threatening hypertriglyceridemia-induced pancreatitis related to alectinib successfully treated by plasmapheresis: A review of the literature on metabolic toxicities...

Case report A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis. Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, t..... READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220904141

Authors: Rao A, Reddy A, Dinunno C, Elali I.

Case StudyKirk SmithFebruary 13, 2020Alectinib, anaplastic lymphoma kinase mutation, pancreatitis, plasmapheresis

B07 Mechanisms of Alectinib Resistance in a Leptomeningeal Carcinomatosis of EML4-ALK Lung Cancer and Its Circumvention by EGR-TKIs

... This study aimed to clarify the mechanism of resistance to alectinib in LMC and seek a novel therapeutic strategy... Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.12.076

Authors: S. Yano, S. Arai, K. Fukuda, S. Takeuchi

Case StudyKirk SmithFebruary 1, 2020Alectinib, Leptomeningeal Carcinomatosis, EML4-ALK, Lung Cancer, EGR-TKIs

Multiplex fluorescence in situ hybridisation to detect anaplastic lymphoma kinase and ROS proto-oncogene 1 receptor tyrosine kinase rearrangements in lung cancer cytological samples

Aims: Several predictive biomarkers of response to specific inhibitors have become mandatory for the therapeutic choice in non-small-cell lung cancer (NSCLC). In most lung cancer patients, the biological materials available to morphological and molecular diagnosis are exclusively cytological samples and minimum tumour wastage is necessary. Multiplex fluorescence in situ hybridisation (mFISH) to detect simultaneously ALK-rearrangement and ROS1-rearrangement on a single slide could be useful in clinical practice to save cytological samples for further molecular analysis. In this study, we aim to validate diagnostic performance of multiplex ALK/ROS1 fluorescence in situ hybridisation (FISH) approach in lung adenocarcinoma cytological series compared with classic single break apart probes. Conclusion: Multiplex ALK/ROS1 FISH probe test is a useful tool to detect simultaneously ALK-rearrangement and ROS1-rearrangement on a single slide in cytological specimens with a small amount of biomaterial. READ ARTICLE

Clinical Pathology DOI:10.1136/jclinpath-2019-206152

Authors: Federica Zito Marino, Giulio Rossi, Immacolata Cozzolino, Marco Montella, Mariacarolina Micheli, Giuseppe Bogina, Enrico Munari, Matteo Brunelli, Renato Franco

Transformation of EML4-ALK fusion-positive adenocarcinoma into squamous cell carcinoma in association with acquired resistance to crizotinib

The development of targeted therapies has revolutionized the treatment of patients with lung cancer, especially non-small-cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) is a research hotspot of molecular targeted therapy for lung cancer. ALK tyrosine kinase inhibitors (TKIs) are highly effective for ALK-rearranged NSCLC-positive patients. These targeted therapies have significant clinical effects; however, they inevitably lead to acquired resistance. In previous studies, the histological transformation after ALK inhibitor treatment was mostly based on small-cell lung cancer (SCLC). The transformation from adenocarcinoma into squamous cell carcinoma in NSCLC after treatment with ALK TKI was extremely rare. This study aimed to report a case of lung cancer with a histological transformation from adenocarcinoma into squamous cell carcinoma after crizotinib treatment, still having the original ALK rearrangement at the molecular level. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.01.001

Authors: Fenfang Wang, Jing Qin, Fajun Xie, Qihuan Wu, Hongyang Lu