Rapid Progression of Metastatic Panspinal Epidural Non−Small Cell Lung Cancer After Discontinuation of Alectinib

Rapid progression of metastatic non−small cell lung cancer (NSCLC) after discontinuation of tyrosine kinase inhibitors or anaplastic lymphoma kinase (ALK) inhibitors has been described and is associated with a poor prognosis. We describe the first reported case of accelerated NSCLC tumor extension throughout the entire spinal epidural space
The differential diagnosis when evaluating presumed spine epidural abscess should include tumor and metastatic disease, even in cases of rapid development. Recent termination of tyrosine kinase inhibitors or ALK inhibitors may result in severe disease flares, and a history of such should raise clinical suspicion for metastatic progression. In addition to cultures, biopsy for pathologic diagnosis should be collected during decompressive surgery. READ ARTICLE

World Neurosurgery DOI:10.1016/j.wneu.2018.11.118

Authors: Carole S.L. Spake, Daniel B.C. Reid, Alan H. Daniels

$A Pilot Prospective Study of Refractory Solid Tumor Patients for NGS-Based Targeted Anticancer Therapy$

A Pilot Prospective Study of Refractory Solid Tumor Patients for NGS-Based Targeted Anticancer Therapy

With the advent of next-generation sequencing (NGS), targeted sequencing is now contributing to decision making for which chemotherapeutics to administer to cancer patients, especially in refractory and metastatic cancer. Given that most patients with refractory cancer develop resistance to chemotherapy and have few treatment options, we performed NGS test to evaluate the efficacy and clinical feasibility of NGS-based targeted anticancer therapy. We used a gene panel for capturing target regions covering 83 cancer-related genes. A total of 25 refractory metastatic solid tumor patients were enrolled in this study. Among the 25 patients, 7 had FDA-approved drug-responsive or -resistant alterations. However, the effectiveness of targeted therapy was assessed by follow-up in three patients (12%). These included crizotinib for ALK-EML4 fusion in a malignancy of undefined origin patient and everolimus for AKT3 amplification in a uterine sarcoma patient. In addition, we identified a KRAS codo..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2018.10.011

Authors: Young MiSeol, Chae Hwa Kwon, So Jeong Lee, Seon Jin Lee, Yuri Choi, Young Jin Choi, Hyojeong Kim, Do Youn Park

Case StudyKirk SmithFebruary 1, 2019Refractory Solid Tumor, NGS-Based Targeted Anticancer Therapy

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

Case report of unusual ALK gene rearrangement and review of 354 cases of ALK rearrangement study of lung non-small cell carcinoma

Background: Lung cancer is the leading cause of cancer-related death in Australia, accounting for 18.7% in 2017; and an estimated incidence of 43 cases per 100,000 persons in 2013, making it the 5th most common cancer. Many genetic abnormalities are essential in driving tumorigenesis. Anaplastic lymphoma kinase (ALK) gene rearrangement is responsible for 3–7% of all non-small cell lung cancers (NSCLC); which are responsive to tyrosine kinase inhibitors. Therefore, detection of such genetic abnormalities has become mainstay practice in the diagnostic workup for lung cancers. READ ARTICLE

Pathology DOI:10.1016/j.pathol.2018.09.044

Authors: M. Huang, A. Chou, D. Riley, Y. Kim, R. Lukeis, M. Qiu

Case StudyKirk SmithFebruary 1, 2019ALK gene rearrangement, lung non-small cell carcinoma

Carcinoma of Unknown Primary with EML4‐ALK Fusion Response to ALK Inhibitors

With the advent of next‐generation sequencing (NGS) and precision medicine, investigators have determined that tumors from different tissue sources that have the same types of genetic mutations will have a positive response to the same targeted therapy. This finding has prompted us to seek potential therapeutic targets for patients with carcinoma of unknown primary (CUP) using NGS technology. Here, we reported a case of a woman with CUP resistance to chemotherapy. We detected 450 cancer‐related gene alterations using three metastatic tumor specimens and found the presence of EML4 exon13 and ALK exon20 fusion. The tumor did respond to crizotinib, a first‐generation ALK inhibitor. When her tumor progressed, circulating tumor DNA detection revealed ALK L1196 M and G1269A mutation resistance to crizotinib, but she had a response to brigatinib. This case revealed that NGS technology used to detect the genetic alterations in patients with CUP might be a reliable method to find potential ther..... READ ARTICLE

The Oncologist DOI:10.1634/theoncologist.2018-0439

Authors: Peng Zhao, Ling Peng, Wei Wu, Yi Zheng, Weiqin Jiang, Hangyu Zhang, Zhou Tong, Lulu Liu, Ruobing Ma, Liping Wang, Ming Yao, Kai Wang, Weijia Fang, Liming Wu

Diffuse Atypical Cystic Brain Metastases in ALK+ NSCLC Treated With Whole Brain Radiation and Second-Generation ALK-Targeted Therapy

A 53-year-old African American man who had never smoked was initially diagnosed with clinical stage cT2pN3 (contralateral mediastinal node) M0, IIIB EML4-anaplastic lymphoma kinase translocation–positive (ALK+) adenocarcinoma of the right lung. He was treated with concurrent chemotherapy using pemetrexed/carboplatin and 60 Gy of radiation to the lung and mediastinum. The patient tolerated these treatments well with complete response in the chest, but he developed biopsy-proven solitary metastatic recurrence in the liver 1 year later. He underwent stereotactic radiation therapy with 30 Gy in 3 fractions, followed by crizotinib at this time. READ ARTICLE

Practical Radiation Oncology DOI:10.1016/j.prro.2018.11.002

Authors: William R. Grubb, Mitchell Machtay, Afshin Dowlati, Tithi Biswas

Case StudyKirk SmithJanuary 18, 2019

ALK inhibition in two emblematic cases of pediatric inflammatory myofibroblastic tumor: Efficacy and side effects

There is an increasing interest for anaplastic lymphoma kinase (ALK) inhibitors in pediatric oncology for specific entities such as ALK-driven inflammatory myofibroblastic tumor (IMT). IMTtreatment can be challenging due to localization of the tumor and in rare cases of metastasis.When standard surgical treatment is not feasible, ALK inhibitors may play an important role,as recently reported for the first-generation ALK inhibitors (crizotinib). However, data on thesecond-generation ALK inhibitors are limited. We report two emblematic cases of IMT in pediatric patients, treated with the second-generation ALK inhibitor ceritinib in the context of a clinical trial(NCT01742286). READ ARTICLE

Pediatric Blood & Cancer DOI: 10.1002/pbc.27645

Authors: Erica Brivio and C. Michel Zwaan

Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable. Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional..... READ ARTICLE

ESMO Open, Cancer Horizons DOI:10.1136/esmoopen-2019-000561

Authors: Anastasia Kougioumtzi, Panagiotis Ntellas, Eirini Papadopoulou, George Nasioulas, Eleftherios Kampletsas, George Pentheroudakis

Histologic transformation of ALK-rearranged adenocarcinoma to squamous cell carcinoma after treatment with ALK inhibitor

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) treated with ALK tyrosine kinase inhibitor (TKI) eventually acquires resistance to the treatment. However, our current knowledge regarding the resistance mechanisms is based on non-synonymous mutation and amplification in ALK, with the reasons still unknown for nearly half of all such cases. Other than genomic alteration as a resistance mechanism, up to 10% of NSCLC with activating epithelial growth factor receptor (EGFR) mutation showed resistance to EGFR TKI through histologic transformation. Although limited in number, there are cases showing transformed samples retaining the initial genomic alteration, which support lineage transition as a novel resistance mechanism. In this report, we described the first case of squamous cell carcinoma (SCC) transformation from adenocarcinoma (ADC) in NSCLC with ALK rearrangement after treatment with ALK TKI. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.027

Authors: Sehhoon Park, Joungho Han, Jong-Mu Sun

A Novel CAMKMT Exon3-ALK Exon20 Fusion Variant was Identified in a Primary Pulmonary Mucinous Adenocarcinoma

... Here, we reported a novel calmodulin-lysine N-methyltransferase (CAMKMT)–ALK fusion in a patient with PPMA... This first report of a CAMKMT-ALK fusion expands the spectrum of ALK fusion variants and supports comprehensive genomic profiling in PPMA to optimize therapeutic options. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.09.020

Authors: Xueting Hu, Qiang Cui, Minghui Wang

MYC Amplification as a Potential Mechanism of Primary Resistance to Crizotinib in ALK-Rearranged Non-Small Cell Lung Cancer: A Brief Report

Translocations of the anaplastic lymphoma kinase (ALK) can be effectively targeted in advanced non-small cell lung cancer by ALK-TKI inhibitors including Crizotinib. However, the development of acquired resistance often limits the duration of these therapies. While several mechanisms of secondary resistance have been already identified, little is known about molecular determinants of primary resistance. In our brief report we investigated the tumor molecular profile of a patient who failed to respond to Crizotinib.
We postulate that the MYC gene may be implicated in the mechanism of primary resistance to ALK inhibitors. We also suggest potential MYC-directed inhibition strategies to overcome primary resistance in advanced ALK-rearranged NSCLC. READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2018.09.013

Authors: Karim Rihawi, Roberta Alfieri, Michelangelo Fiorentino, Francesca Fontana, Elisa Capizzi, Andrea Cavazzoni, Mario Terracciano, Silvia La Monica, Alberto Ferrarini, Genny Buson, Pier Giorgio Petronini, Andrea Ardizzoni

Case StudyKirk SmithJanuary 1, 2019ALK, Crizotinib, Resistance, MYC Amplification

Ceritinib for an anaplastic lymphoma kinase rearrangement-positive patient previously treated with alectinib with poor performance status

ALK inhibitors are promising for treating ALK rearrangement non-small-cell lung cancer (NSCLC), but secondary mutations of ALK can sometimes inhibit their effectiveness. A 54-year-old woman with lung adenocarcinoma harboring ALK rearrangement previously treated with first-line alectinib and second-line cisplatin/pemetrexed showed poor performance status (PS) with rapid progression. She was treated with ceritinib as salvage treatment, upon which tumor shrinkage was demonstrated on CT and her PS gradually improved. The best supportive care is recommended for patients with advanced NSCLC with poor PS due to lower treatment efficacy and more toxicities than those with good PS. In this case, rapid progression led to a poor PS; however, ceritinib achieved a breakthrough in this case. The optimal treatment sequence and key drugs in ALK-positive NSCLC remain controversial. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S186213

Authors: Rui Kitadai, Yusuke Okuma, and Shoko Kawai

Molecular profile of non-small cell lung cancer in northeastern Brazil

Objective: To investigate the histological subtypes and mutational profiles of non-small cell lung cancer in Brazil, looking for correlations among histological subtypes, expression of anaplastic lymphoma kinase (ALK), EGFR mutation status, and programmed death-ligand 1 (PD-L1) expression. Conclusions: Our results suggest that the molecular profile of non-small cell lung cancer in northeastern Brazil differs from those of populations in other regions of the country, with ALK positivity being higher than the other biomarkers. Further studies including clinical and genetic information are required to confirm these differences, as well as studies focusing on populations living in different areas of the country. READ ARTICLE

Jornal Brasileiro de Pneumologia DOI:10.1590/1806-3713/e20180181

Authors: Ana Claudia da Silva Mendes de Oliveira, Antonio Vinicios Alves da Silva, Marclesson Alves, Eduardo Cronemberger, Benedito Arruda Carneiro, Juliana Carneiro Melo, Francisco Martins Neto

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

Neoadjuvant Crizotinib in Resectable Locally Advanced Non–Small Cell Lung Cancer with ALK Rearrangement

Background: Locally advanced NSCLC is one of the most heterogeneous conditions, with multidimensional treatments involved. Neoadjuvant therapy had been commonly considered an optimal management strategy for patients with operable locally advanced. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy has remained poorly explored in locally advanced disease. Conclusion: Neoadjuvant crizotinib may be feasible and well tolerated in locally advanced disease for complete resection. Crizotinib therapy before surgery may provide thorough elimination of circulating molecular residual disease and not influence the reuse of first-line crizotinib, but ongoing prospective trials are warranted to prove its efficacy in the neoadjuvant setting. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.10.161

Authors: Chao Zhang, Shao-lei Li, Qiang Nie, Song Dong, Yang Shao, Xue-ning Yang, Yi-long Wu, Yue Yang, Wen-zhao Zhong

Case StudyKirk SmithNovember 5, 2018Neoadjuvant, Locally advanced NSCLC, ALK, Crizotinib

Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC)

Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model. READ ARTICLE

Biochemical and Biophysical Research Communications DOI:10.1016/j.bbrc.2018.09.169

Authors: Chung Hyo Kanga, Dong Ho Lee, Chong Ock Lee, Jae Du Ha, Chi Hoon Park, Jong Yeon Hwang

Pitfalls in Oncology: Osteoblastic Response Mimicking Bone Progression during Ceritinib Treatment in ALK-Rearranged NSCLC

Bone metastases of non–small cell lung cancer (NSCLC) may present an osteolytic or osteoblastic pattern, and their occurrence during treatment qualifies as progressive disease. However, “osteoblastic responses” (the appearance of either new osteoblastic lesions or a sclerotic component within preexisting lytic lesions) have been described, particularly in epidermal growth factor receptor gene (EGFR)-addicted NSCLC READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2016.04.002

Authors: Francesco Gelsomino, Valentina Ambrosini, Barbara Melotti, Francesca Sperandi, Andrea Ardizzoni

Case StudyKirk SmithApril 11, 2016

SEC31A-ALK Fusion Gene in Lung Adenocarcinoma

Anaplastic lymphoma kinase (ALK) fusion is a common mechanism underlying pathogenesis of non-small cell lung carcinoma (NSCLC) where these rearrangements represent important diagnostic and therapeutic targets. In this study, we found a new ALK fusion gene, SEC31A-ALK, in lung carcinoma from a 53-year-old Korean man. The conjoined region in the fusion transcript was generated by the fusion of SEC31A exon 21 and ALK exon 20 by genomic rearrangement, which contributed to generation of an intact, in-frame open reading frame. SEC31A-ALK encodes a predicted fusion protein of 1,438 amino acids comprising the WD40 domain of SEC31A at the N-terminus and ALK kinase domain at the C-terminus. Fluorescence in situ hybridization studies suggested that SEC31A-ALK was generated by an unbalanced genomic rearrangement associated with loss of the 3′-end of SEC31A. This is the first report of SEC31A-ALK fusion transcript in clinical NSCLC, which could be a novel diagnostic and therapeutic target for patie..... READ ARTICLE

Cancer Research and Treatment DOI:10.4143/crt.2014.254

Authors: Ryong Nam Kim, Yoon-La Choi, Mi-Sook Lee, Maruja E. Lira, Mao Mao, Derrick Mann, Joshua Stahl, Abel Licon, So Jung Choi, Michael Van Vrancken, Joungho Han, Iwona Wlodarska and Jhingook Kim