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

ALK-rearranged lung adenocarcinoma transformation into high-grade large cell neuroendocrine carcinoma: Clinical and molecular description of two cases

Highlights: • First two cases of ALK-rearranged LUAD that transformed to high-grade LCNEC after ALK-TKI treatment. • Development of on-target ALK G1202R mutation, showing unique dual mechanisms of resistance in both cases. • Different RB1 status in both cases, with worse outcome in the case with RB1 loss. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.06.005

Authors: Aline F. Fares, Benjamin H. Lok, Tong Zhang, Michael Cabanero, Sally C. M. Lau, Tracy Stockley, Devalben Patel, Penelope A. Bradbury, Adrian Sacher, Kazuhiro Yasufuku, Barbara A. Morash, Peter J. B. Sabatini, Lananhn N. Nguyen, Natasha B. Leighl, Ming-Sound Tsao, Frances A. Shepherd, Geoffrey Liu, Sebastiao N. Martins-Filho, Prodipto Pal

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

Lung Adenocarcinoma during Pregnancy: 11-Year Follow-Up

The incidence of lung cancer during pregnancy is rising due to the high rate of smokers in young women and the late mean age of pregnancy; in addition, considering that the patients are young women with a higher incidence of molecular alterations, molecular testing in lung adenocarcinoma should always be performed, even in pregnancy. Here, we report the case of a lung adenocarcinoma diagnosed during pregnancy with a long survival who benefitted from brain radiotherapy, conventional chemotherapy, and ALK TKI-targeted treatment. It reveals the safety of whole brain radiotherapy during pregnancy and consideration of other brain radiation techniques even in palliative cases, which should be personalized and managed by a multidisciplinary team. However, upfront management of brain metastasis in ALK-positive patients remains unresolved. READ ARTICLE

Case Reports in Oncology DOI:10.1159/000508360

Authors: Acosta Rojas A., Collazo-Lorduy A., Remon J., Hernando Requejo O., Jiménez-Munarriz B., Rubio Rodríguez M.C., De Castro J.

Novel MRPL13-ALK and PPP1CB-ALK Double Fusion As a Potential Mechanism of Acquired Resistance to First-Line Osimertinib in EGFR-Mutant HighGrade Neuroendocrine Tumor of the Lung

To our knowledge, this is the first report to state that that EGFR L858R and ALK double fusion were found in a high-grade neuroendocrine tumor of the lung. The rare ALK double fusion may be the potential reason for osimertinib resistance. Serine/threonine-PPP1CB (PPP1CBALK) fusion has already been reported in individual cases in glioma of infancy and leiomyosarcoma, but none in lung cancer. MRPL13-ALK is a novel fusion, which has never been reported yet. READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100079

Authors: Yuyan Jiao, MM, Ming Liu, MM, Ningning Luo, MS, Hao Guo, PhD, Jianzhe Li, PhD

Case StudyKirk SmithJuly 23, 2020osimertinib, EGFR, yrosine kinase inhibitor, NSCLC, ALK

Salivary Intraductal Carcinoma Arising within Intraparotid Lymph Node: A Report of 4 Cases with Identification of a Novel STRN-ALK Fusion

Intraductal carcinoma (IDC) is a rare salivary gland tumor that is considered analogous to ductal carcinoma in-situ of the breast, demonstrating a complex neoplastic epithelial proliferation surrounded by a continuous layer of presumed non-neoplastic myoepithelial cells. It is subcategorized into intercalated duct, apocrine, and hybrid subtypes based on morphologic and immunohistochemical features, with frequent NCOA4-RET and TRIM27-RET fusions, respectively, seen in intercalated duct and hybrid tumors. However, as an expanding clinicopathologic spectrum of IDC has been documented, controversy has emerged as to whether this tumor type is best defined by its intraductal growth pattern or distinctive molecular and immunophenotypic differentiation. Here, we further explore the nature of IDC by evaluating four cases that arose within intraparotid lymph nodes. These intercalated-duct phenotype tumors with diffuse S100 protein expression demonstrated a crowded and complex epithelial prolifer..... READ ARTICLE

Head and Neck Pathology DOI:10.1007/s12105-020-01198-0

Authors: Lisa M. Rooper, Lester D. R. Thompson, Jeffrey Gagan, Bahram R. Oliai, Ilan Weinreb & Justin A. Bishop

A novel EML4-ALK BIRC6-ALK double fusion variant in lung adenocarcinoma confers sensitivity to alectinib

ALK receptor tyrosine kinase gene (ALK) rearrangement is a common driver mutation for patients with NSCLC. At present, more than 20 fusion partners for ALK in NSCLC have been reported. The most common partner of ALK rearrangement is echinoderm microtubule-associated protein-like 4 gene (EML4). But ALK double fusion is rare. ALK inhibitors are widely used in cancer-targeted therapy now. The progression-free survival of patients with ALK-positive NSCLC treated with alectinib as a first-line treatment is varied due to different fusion forms of ALK [ [1] ]. Therefore, it is of great clinical significance to continuously explore new forms of ALK fusion and study its correlation with drug sensitivity. With the development of next-generation sequencing (NGS) technology, ALK detection is becoming more and more precise, Herein we described a patient with advanced lung adenocarcinoma who presented simultaneously with two novel fusions, EML4-ALK and BIRC6-ALK, and with sensitivity to alectinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.030

Authors: Jiang-Ming Zhong, Gui-Feng Zhang, Li Lin, De-Yu Li, Zhen-Hua Liu

Intergenic Breakpoints Identified by DNA Sequencing Confound Targetable Kinase Fusion Detection in NSCLC

Introduction: Next-generation sequencing (NGS) based on genomic DNA has been widely applied for gene rearrangement detection in patients with NSCLC. However, intergenic-breakpoint fusions, in which one or both genomic breakpoints localize to intergenic regions, confound kinase fusion detection. We evaluated the function of intergenic-breakpoint fusions with multiplex molecular testing approaches... Conclusions: Intergenic-breakpoint fusions detected by DNA sequencing confound kinase fusion detection in NSCLC, as functional fusion transcripts may be generated or not. Additional validation testing using RNA/protein assay should be performed in intergenic-breakpoint fusion cases to guide optimal treatment. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.02.023

Authors: Weihua Li, Yutao Liu, Wenbin Li, Li Chen, Jianming Ying

Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both a..... READ ARTICLE

Therapeutic Advances in Respiratory Disease DOI:10.1177/1753466620935770

Authors: Jia Hu, Baoshi Zhang, Fangfang Yao, Yan Fu, Dianjun Chen, Donghui Li, Nan Du, Analyn Lizaso, Jinlei Song, Lu Zhang, Xiaosong Li

Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insul..... READ ARTICLE

Diabetology International DOI:10.1007/s13340-020-00442-w

Authors: Miyoshi, Y., Ogawa, O., Nishida, A. et al.

Epithelioid fibrous histiocytoma of the vulva: Report of a case with next-generation sequencing analysis

Epithelioid fibrous histiocytoma (EFH), also known as epithelioid cell histiocytoma (ECH), is an uncommon benign cutaneous mesenchymal neoplasm that typically occurs in the limbs and consistently harbors ALK gene rearrangements. In this study, we report a unique case of EFH that arose in the labia majora, an unusual site which has been rarely described. The tumor occurred in a 41-year-old woman who presented with a slowly growing painless nodule in the vulva. Histological examination revealed a circumscribed lesion located within the dermis, which was composed of sheets or nests of large polygonal epithelioid cells with abundant eosinophilic cytoplasm. Nuclear atypia was minimal and mitotic figures were rare. Immunohistochemically, the neoplastic cells showed diffuse cytoplasmic staining of ALK protein. Subsequent fluorescence in situ hybridization (FISH) assessment demonstrated a balanced rearrangement of ALK gene. Further next-generation sequencing (NGS) analysis identified SQSTM1-AL..... READ ARTICLE

Human Pathology: Case Reports DOI:10.1016/j.ehpc.2020.200378

Authors: Lu Zhao, Jiahan Liu, Meng Sun, I. Weng Lao, Lin Yu, Jian Wang

Clinical Benefit From a Combination of Brigatinib and Camrelizumab in Sarcomatoid Transformation of ALK-Rearranged Squamous Cell Lung Cancer Resistant to Crizotinib

A 27-year-old nonsmoking Chinese man was referred to the hospital owing to chest pain in May 2015. He had a diagnosis of stage IV lung squamous cell carcinoma (SCC), (cT2aN3M1b). Computed tomography displayed a 3-cm dense mass in the left superior lung (Fig. 1A, baseline), and immunohistochemistry (IHC) staining of the tumor biopsy reported positive for pulmonary SCC marker p40 (Fig. 1B, baseline). READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100009

Authors: Wei Jiang, Ruting Guan, Yang W. Shao, Bo Wang, Yina Wang

Feasibility and Safety of Neoadjuvant Alectinib in a Patient With ALK-Positive Locally Advanced NSCLC

A 46-year-old man, a nonsmoker, was hospitalized owing to complaints of repeated cough and hemoptysis. Enhanced computed tomography scan revealed a large mass with a diameter of 66 mm located in the left lower lobe. Enlarged mediastinal lymph nodes were also identified with bulky station 7... Herein, we have first reported a clinically successful case involving neoadjuvant alectinib... Collectively, neoadjuvant alectinib may be clinically feasible and a registered real-world study will be set to further assess its clinical implication. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.12.133

Authors: Chao Zhang, Li-Xu Yan, Ben-Yuan Jiang, Yi-Long Wu, Wen-Zhao Zhong

Case StudyKirk SmithJune 1, 2020Neoadjuvant, Alectinib, ALK, NSCLC

A Novel Linc00308/D21S2088E Intergenic Region ALK Fusion and Its Enduring Clinical Responses to Crizotinib

... Herein we report a novel ALK fusion partner, the Linc00308/D21S2088E intergenic region, that conferred responsiveness to crizotinib in a patient with lung adenocarcinoma (LUAD)... Thus, we have provided proof that patients with advanced NSCLC harboring a Linc00308/D21S2088E intergenic region ALK may benefit from crizotinib, expanding the spectrum of ALK fusion variants to optimize treated strategy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.03.009

Authors: Jian Zhang, Chang Zou, Chenzhi Zhou, Yifeng Luo, Qiong He, Yu Sun, Jianwen Zhou, Zunfu Ke

Case StudyKirk SmithJune 1, 2020Linc00308/D21S2088E, Intergenic Region, ALK Fusion, Crizotinib

Successful alectinib desensitization in a patient with anaplastic lymphoma kinase-positive adenocarcinoma of the lung and alectinib-induced drug rash

Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220918644

Authors: Anderson BE, Luczak TS, Ries LM, Hoefs GE, Silva-Benedict AC.

Case StudyKirk SmithMay 31, 2020Alectinib, desensitization, hypersensitivity, ALK-positive

Treatment Sequencing in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in Japan: A Real-World Observational Study

Introduction The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan. Results A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who ..... READ ARTICLE

Advances in Therapy DOI:10.1007/s12325-020-01392-0

Authors: Yasushi Goto, Nobuyuki Yamamoto, Elizabeth T. Masters, Hironori Kikkawa, Jack Mardekian, Robin Wiltshire, Kanae Togo and Yuichiro Ohe

Primary Resistance to Brigatinib in a Patient with Lung Adenocarcinoma Harboring ALK G1202R Mutation and LIPI-NTRK1 Rearrangement

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors have transformed the management of non-small-cell lung cancer (NSCLC) patients with ALK gene rearrangement. This paper reports a new resistance mechanism to a second-generation ALK inhibitor, brigatinib. Case Report: A 43-year-old woman who had no history of smoking was diagnosed with stage IVa (T2bN2M1b) lung adenocarcinoma. After the first-line chemotherapy failed, the patient received crizotinib due to the presence of EML4-ALK fusion by next-generation sequencing (NGS). The patient had disease progression after 8 months on crizotinib, and a second NGS identified the ALK G1202R resistance mutation. Therefore, she was switched to brigatinib. After only 53 days of treatment with brigatinib, the patient developed a new 1.6× 1.2 cm lesion in the mediastinal lymph node. A third NGS testing revealed a new form of NTRK rearrangement (LIPI-NTRK1). The patient died 16 months after diagnosis.Conclusion: This paper provides new insights into ..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S249652

Authors: Xiao Z, Huang X, Xie B, Xie W, Huang M, Lin L.

Case StudyKirk SmithMay 22, 2020LIPI-NTRK1, ALK, primary resistance, brigatinib, NSCLC

Responses to ALK Inhibitor Treatments in a Patient with Non-Small Cell Lung Cancer Harboring a Novel HPCAL1-ALK Fusion Variant: A Case Report

Anaplastic lymphoma kinase (ALK) fusion is present in approximately 2–7% of patients with lung adenocarcinoma. ALK fusion-positive patients can benefit from targeted therapy. We herein report a 53-year-old Chinese male patient diagnosed as lung adenocarcinoma with a smoking history. Next-generation sequencing was performed to detect somatic mutations of oncogenic drivers and tumor suppressor genes in plasma-derived circulating tumor DNA using an ultra-deep 160-gene panel. A novel HPCAL1-ALK fusion variant was identified in the patient responding to ALK inhibitor treatments, and the fusion variant was also confirmed by fluorescence in situ hybridization and immunohistochemical. Our study expands the mutational spectrum of ALK fusion variants and provides options for the precise treatment of such patients. READ ARTICLE

OncoTargets and therapy DOI:10.2147/OTT.S252210

Authors: Wang R, Qin J, Fan Y, Li Z, Chen C, Su W.

The Genomic Characteristics of ALK Fusion Positive Tumors in Chinese NSCLC Patients

Anaplastic lymphoma kinase (ALK) fusion events account for ~3–7% genetic alterations in patients with non-small cell lung cancer (NSCLC). In this study, we identified the ALK fusion patterns and a novel ALK fusion partner in 44 ALK positive NSCLC patients using a customized HapOncoCDx panel, and identified ALK fusion partners. The most common partner is EML4, forming the variant 1 (v1, E13:A20, 18/44), variant 2 (v2, E20:A20, 5/44), and variant 3 (v3, E6:A20, 13/44). Moreover, we detected a new ALK fusion partner HMBOX1. At the mutation level, TP53 is the most frequently mutated gene (24%), followed by ALK (12%) and STED2 (12%). The median tumor mutation burden (TMB) of these samples is 2.29 mutations/Mb, ranging from 0.76 mut/Mb to 16.79 muts/Mb. We further elaborately portrayed the TP53 mutation sites on the peptide sequence of the encoded protein by lollipop. The mutational signature and copy number alterations (CNAs) of the samples were also analyzed. The CNA events were found in 1..... READ ARTICLE

Frontiers in oncology DOI:10.3389/fonc.2020.00726

Authors: Shaokun Liu, Tanxiao Huang, Ming Liu, Wenlong He, YingShen Zhao, Lizhen Yang, Yingjiao Long, Dandan Zong, Huihui Zeng, Yuanyuan Liu, Wenting Liao, Jingxian Duan, Subo Gong and Shifu Chen

Anaplastic lymphoma kinase inhibitor-associated myositis

Anaplastic lymphoma kinase (ALK) inhibitors have been used in patients with non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion gene.1 Severe skeletal muscle adverse events of ALK inhibitors, such as muscle weakness, have seldom been reported.2,3 Herein, we describe a patient who showed a severe skeletal muscle deficit after the administration of the ALK inhibitor, alectinib, and was successfully treated by corticosteroids without withdrawal from the cancer therapy READ ARTICLE

Neurology: Neuroimmunology & Neuroinflammation DOI:10.1212/NXI.0000000000000735

Authors: Akinori Uruha, Stefan Kliesch, Simone Schmid, Carsten Dittmayer, Hans-Hilmar Goebel, Alexander Dressel, Werner Stenzel, Robert Handreka

Case StudyKirk SmithMay 6, 2020Alk, inhibitor, myositis, corticosteroids