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,

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

Coexistence of a Novel PRKCB-ALK, EML4-ALK Double-Fusion in a Lung Adenocarcinoma Patient and Response to Crizotinib

ALK receptor tyrosine kinase (ALK) rearrangement is a common driver mutation for patients with NSCLC. More than 20 other fusion partners for ALK in NSCLC have been reported.1 However, one patient with double ALK fusions simultaneously is still rare, and the double ALK fusions changing after treatment is also rarely reported. Here, a lung adenocarcinoma patient with EMAP like 4 (EML4)-ALK and protein kinase C beta (PRKCB)–ALK double fusion variant was presented who responded to crizotinib and showed the changes of two ALK fusions before and after treatment... In summary, this study is the first to describe a novel EML4-ALK, PRKCB-ALK double-ALK fusion lung adenocarcinoma patient who is sensitive to crizotinib. This is also the first study to describe a novel PRKCB-ALK fusion that may have promising efficacy by crizotinib treatment. In addition, the case also shows that liquid biopsy can provide more information of mutation to guide treatment and multiple liquid biopsy procedures can a..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.07.021

Authors: Jing Luo, Dejian Gu, Huasong Lu, Si Liu, Jinliang Kong

Case StudyKirk SmithDecember 1, 2019PRKCB-ALK, EML4-ALK Double-Fusion, Lung Adenocarcinoma, Crizotinib

Two Cases of Krukenberg Tumors from ALK-Rearranged Lung Adenocarcinoma: An Uncommon Site of Metastasis

Approximately 5% of all NSCLCs harbor ALK receptor tyrosine kinase gene (ALK) rearrangements.1 ALK-rearranged NSCLC is more commonly associated with younger individuals and those without a smoking history. The most common ALK rearrangement is a fusion between the ALK gene and gene echinoderm microtubule associated protein like 4 gene (EML4).1 Several drugs targeting ALK-rearranged NSCLC are currently available. Unfortunately, almost all ALK-positive NSCLCs will eventually progress during treatment with ALK inhibitors. This is mainly due to ALK point mutations, most commonly a L1196M mutation and the G1269A mutation, although several others have been identified.2 NSCLC tends to spread to the bones, brain, liver, lungs, and adrenal glands. ALK-positive NSCLCs have an increased tendency to metastasize to the pericardium, pleura, and liver compared with other NSCLCs.3 Rarely, tumors can metastasize to the ovaries; such tumors are known as Krukenberg tumors. Typically, Krukenberg tumors ori..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.05.028

Authors: John (Jack) Ogden, Hao Xie, Randolph S. Marks, Konstantinos Leventakos

EditorialKirk SmithOctober 1, 2019Krukenberg Tumors, ALK-Rearranged, Lung Adenocarcinoma, Metastasis

A Novel Intergenic Region between CENPA and DPYSL5-ALK Exon 20 Fusion Variant Responding to Crizotinib Treatment in a Patient with Lung Adenocarcinoma

Herein, we report a novel intergenic region between centromere protein A gene (CENPA) and dihydropyridiminase like 5 (DPYSL5)-ALK fusion in a patient with lung adenocarcinoma... To our knowledge, the shortcoming of traditional FISH and IHC was that the precise ALK fusion variants could not be identified, and the application of next-generation sequencing might be used as an optional and supplementary method. Because this patient received a remarkable tumor response after crizotinib therapy, our case report has expanded the spectrum of ALK fusion and provided useful information for precise ALK inhibitor administration in the future. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.04.012

Authors: Xiaodong Fei, Liqun Zhu, Hongxuan Zhou, Chuang Qi, Chun Wang

Identification of a Novel EML4-ALK, BCL11A-ALK Double-Fusion Variant in Lung Adenocarcinoma Using Next-Generation Sequencing and Response to Crizotinib

ALK receptor tyrosine kinase gene (ALK) fusion is an important driving oncogene in NSCLC, and echinoderm microtubule associated protein like 4 gene (EML4)-ALK fusion is the most prevalent type. With the rapid development and popularity of tumor genomic sequencing, more and more uncommon ALK fusion partners have been discovered, including kinesin family member 5B gene (KIF5B), baculoviral IAP repeat containing 6 gene (BIRC6), and striatin gene (STRN). However, two ALK fusions detected simultaneously in one patient with NSCLC is still rare. Here we present a novel EML4-ALK, B-cell CLL/lymphoma 11A gene (BCL11A)-ALK double-fusion variant in a patient with lung adenocarcinoma who responded well to crizotinib and describe the dynamic change in these two ALK fusions after crizotinib treatment. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.01.032

Authors: Bao-Dong Qin, Xiao-Dong Jiao, Ke Liu, Ying Wu, Yuan-Sheng Zang

ALK-Positive Lung Adenocarcinoma Arising in an Adolescent Treated for Relapsed Neuroblastoma

Pediatric lung adenocarcinoma is rare, but has been reported in patients with nonpulmonary childhood cancers.1, 2, 3 We report a case of a 17-year-old male who developed pulmonary adenocarcinoma with ALK receptor tyrosine kinase (ALK) rearrangement following neuroblastoma therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.010

Authors: Yazeed Alwelaie, Rebecca J. Deyell, Helen R. Nadel, Tracy Tucker, Janessa Laskin, S. Rod Rassekh, Chen Zhou, John C. English, Anna F. Lee

EditorialKirk SmithJune 1, 2019ALK-Positive, Lung Adenocarcinoma, Adolescent, Relapsed, Neuroblastoma

Concurrent Presence of ALK Rearrangement and MET Mutation in Lung Adenocarcinoma

During recent years, many gene mutations have been reported in lung adenocarcinoma, and target agents against driver mutations have been explored. MNNG HOS transforming gene (MET) exon 14 mutation and ALK receptor tyrosine kinase (ALK) translocation were usually mutually exclusive. However, here, we describe a case that had intratumor heterogeneity on both genetic and pathologic characteristics. Patients whose tumors harbored MET exon 14 splice site mutations or ALK rearrangement derived meaningful clinical benefit from crizotinib.4, 5 Our findings may have profound clinical implications for potential therapeutic targeting during disease progression. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.10.149

Authors: Tian Qiu, Fanshuang Zhang, Weihua Li, Lei Guo, Jianming Ying

Case StudyKirk SmithFebruary 1, 2019ALK Rearrangement, MET Mutation, Lung Adenocarcinoma