Lung cancer in never smokers: The role of different risk factors other than tobacco smoking

Lung cancer (LC), the leading cause of cancer-related deaths worldwide, is a complex and highly heterogeneous disease. Additional to its biological complexity, LC patients are often confronted with a high degree of stigma, mostly from the association of the disease with tobacco. Nonetheless, a proportion of LC patients are never-smokers, a population which we are beginning to comprehensively explore. Several risk factors have been linked to LC in never-smokers. Studies have consistently shown that radon exposure and domestic fuel smoke increase LC risk. Additionally, infections such as Mycobacterium tuberculosis, and Human Papilloma Virus are also risk factors. Other less conclusive associations include inflammatory diseases such as asthma and sarcoidosis. Moreover, we are now aware that molecular characteristics of LC vary widely according to smoking history, with important therapeutic implications. This review comprehensively assesses the current knowledge in terms of risk factors an..... READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102895

Authors: Luis Corrales, Rafael Rosell, Andrés F. Cardona, Claudio Martín, Zyanya Lucia Zatarain-Barrón, Oscar Arrieta

EditorialKirk SmithApril 1, 2020Never-smoker, Tobacco, Wood-smoke, RadonTuberculosis, HPV

Is there a place for crizotinib in c-MET alterations? A case of efficacy in ALK positive NSCLC patient with secondary c-MET amplification

Recently, Moro-Sibilot et al.1 presented the results of the AcSé study that evaluated the efficacy of crizotinib in non-small-cell lung cancer (NSCLC) with ROS1 fusions and c-MET mutations or overexpressions. The excellent performance of crizotinib in ROS1 fusions was confirmed. Nevertheless, in the c-MET cohort there was a lack of activity which was not sufficient to justify its use as targeted therapy in this population. Similar results were found in the analogous METROS trial.2
Despite this evidence, we present a case where crizotinib showed clinical activity, even in a life-threatening condition, thanks to double anaplastic lymphoma kinase (ALK) and c-MET inhibition. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2019.11.016

Authors: M.Mazzotta, M.Filetti, A.Rossi, M.Roberto, M.Occhipinti, A.Pernazza, A.Di Napoli, S.Scarpino, A.Vecchione, R.Giusti, P.Marchetti

Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer

Lung cancer is the leading cause of cancer
mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non–small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy. READ ARTICLE

Surgical Pathology Clinics DOI:10.1016/j.path.2019.11.002

Authors: Roberto Ruiz-Cordero, Walter Patrick Devine

Tumor-educated platelet as liquid biopsy in lung cancer patients

Lung cancer is the most frequent cancer for males and third most frequent cancer for females. Targeted therapy drugs based on molecular alterations, such as angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors are important part of treatment of NSCLC. However, the quality of the available tumor biopsy and/or cytology material is sometimes not adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of tumor-educated platelet (TEP) as a liquid biopsy in lung cancer patients. The development of sensitive and accurate techniques have made it possible to detect the specific genetic alterations for which targeted therapies are already available. Liquid biopsy offers opportunities to detect resistance mechanisms at an early stage. To conclude, tumor-educated platelet has the potential to be used as liquid biopsy for a variety of clinical and investigational applications. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102863

Authors: Lian Liua, Fang Lin, Xiaoting Ma, Zhaoxin Chen, Jing Yu

EditorialKirk SmithFebruary 1, 2020Tumor educated platelets, Liquid biopsy, Lung cancer, Methodologies

B01 Active YAP as a Functional Marker of Drug-Tolerant Persister Cells in EGFR-Mutant and ALK Fusion-Positive NSCLC

... Using RNA sequencing, we show a clear evolutionary path from drug-sensitive parental cells to drug-tolerant persisters and long-term derived drug-acquired resistant cells. We are currently profiling vulnerabilities of drug-tolerant EGFR-mutant and EML4-ALK fusion persisters using genetic and pharmacologic approaches. In conclusion, YAP activation is a functional marker of EGFR-mutant and EML4-ALK fusion persisters derived under high-dose drug treatment with third-generation TKIs. Targeting YAP activation either on the level of upstream signaling input, its relocalization between cytoplasm and nucleus, or its action as transcriptional coactivator may represent a promising combinatorial treatment approach to limit resistance development and improve patient survival in lung adenocarcinoma. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.12.070

Authors: F. Haderk, C. Fernández-Méndez, K. N. Shah, W. Wu, J. Guan, J. Rotow, D. Allegakoen, V. Olivas, S. Bandyopadhyay, C. Kuo, T. Bivona

Sequential blinded treatment decisions in ALK-positive non-small cell lung cancers in the era of precision medicine

Next-generation ALK TKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, sequential strategies at progression are relevant, as may have an impact on patients’ outcome. In this commentary we discuss whether genomic-tailored strategies at progression would be more suitable for improving outcome of ALK-positive NSCLC patients. READ ARTICLE

Clinical and Translational Oncology. DOI: 10.1007/s12094-020-02290-1

Authors: J. Remon, F. Tabbò, B. Jimenez, A. Collazo, J. de Castro, S. Novello

Next-generation ALK inhibitors: is the median the message?

In The Lancet Respiratory Medicine, Yunpeng Yang and colleagues3 provide phase 2 activity data for yet another ALK inhibitor, ensartinib, in the post-crizotinib setting. In the absence of direct head-to-head comparisons of this crowded field of next-generation drugs, how can these new data for ensartinib and, by extension, the potential usefulness of the drug be assessed? In most situations, cross-trial comparisons are frowned upon because of the effect that differences in trial design, inclusion and exclusion criteria, and inherent heterogeneity among patients can have on outcomes with apparently similar interventions.

READ ARTICLE

The Lancet Respiratory Medicine DOI: 10.1016/S2213-2600(19)30362-5

AUTHORS: Ross Camidge

EditorialKirk SmithJanuary 1, 2020

Precision Medicine in Lung Cancer Treatment

Summary: Over the past decade, tremendous progress has been made in understanding the molecular and biologic drivers of lung cancer. Testing for various biomarkers in lung cancer is improving our ability to understand the behavior of different cancers, so we can identify the optimal treatment strategy for each clinical subset of patients. This progress has helped us to deliver individualized precision therapy options for our patients with lung cancer. Ongoing clinical trials will help to improve our... READ ARTICLE

Surgical Oncology Clinics of North America DOI:Precision Medicine in Lung Cancer Treatment

Authors: Dhaval R. Shah, Gregory A. Masters

EditorialKirk SmithJanuary 1, 2020Precision Medicine, Lung Cancer

Identification of EML4-ALK fusion in a sporadic case of cholangiocarcinoma

•Patients with cholangiocarcinoma have extremely poor prognoses.
•No molecular targeted agents have been still approved for cholangiocarcinoma treatment.
•RNA sequencing disclosed the fusion transcript EML4-ALK in a patient with cholangiocarcinoma.
•Cholangiocarcinoma share some driver targetable mutations with other solid tumors. READ ARTICLE

European Journal of Internal Medicine DOI:10.1016/j.ejim.2019.10.030

Authors: Domenico Trombetta, Paola Parente, Tiziana Pia Latiano, Federico Pio Fabrizio, Lucia Anna Muscarella

EditorialKirk SmithNovember 9, 2019Cholangiocarcinoma, EML4-ALK, Gene fusion

A Compound L1196M/G1202R ALK Mutation in a Patient with ALK-Positive Lung Cancer with Acquired Resistance to Brigatinib Also Confers Primary Resistance to Lorlatinib

We report here the case of a 70-year-old patient with ALK-positive NSCLC treated with crizotinib as part of the ALTA-1L trial.4 The patient relapsed after a partial response. After crizotinib failure, the patient was crossed over to brigatinib, which led to a second partial response lasting 9 months. After progression, the patient was shifted to lorlatinib but the clinical conditions worsened and the patient died. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.06.028

Authors: Geeta G. Sharma, Diego Cortinovis, Francesco Agustoni, Giulia Arosio, Matteo Villa, Nicoletta Cordani, Paolo Bidoli, William H. Bisson, Fabio Pagni, Rocco Piazza, Carlo Gambacorti-Passerini, Luca Mologni

Early Onset Pulmonary Toxicity With Lorlatinib in a Patient With Previous Pulmonary Toxicity From Brigatinib

"A 53-year-old female ex-smoker (10 pack-years) presented with progressive dyspnea in February 2014. Her performance status was 1. She was diagnosed with stage IV lung adenocarcinoma with lung, lymph node, and bone involvement. Molecular testing revealed an ALK receptor tyrosine kinase (ALK) translocation with no other concomitant alterations. Our case describes a patient with ALK-rearranged NSCLC who developed pulmonary toxicity on brigatinib that recurred after exposure to lorlatinib at early onset. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.06.013

Authors: Xavier Monzonís, Edurne Arriola"

EditorialKirk SmithNovember 1, 2019Pulmonary Toxicity, Lorlatinib, Brigatinib

Ensartinib (X-396): what does it add for patients with ALK-rearranged NSCLC

Ensartinib is a unique, potent ALK inhibitor that has promising clinical activity and low toxicity in patients with ALK-rearranged NSCLC, most of whom had CNS metastases and had previous ALK-TKI treatment. Further study is needed to determine its role as either an initial or post-resistance therapy in ALK-rearranged NSCLC or other types of cancers. READ ARTICLE

Chinese Clinical Oncology DOI: 10.21037/cco.2018.10.12

Author: Tianhong Li, Weijie Ma, Eddie C. Tian

EditorialKirk SmithOctober 1, 2019ensartinib (X396)

Rapid Postoperative Relapse in ALK-Positive Locally Advanced NSCLC Patient with Complete Pathological Response to Neoadjuvant Crizotinib

In the April 2019 issue of the Journal of Thoracic Oncology, we reported cases of ALK-positive locally advanced NSCLC from two institutions in which neoadjuvant crizotinib showed quite acceptable efficacy and tolerability.1
Herein, we further describe the pathological evaluation and dynamic detection of circulating tumor DNA (ctDNA) in one patient receiving neoadjuvant crizotinib. Figure 1 summarizes the details of the entire therapeutic process. The patient is a 34-year-old male patient in whom lung adenocarcinoma and metastatic mediastinal lymph nodes were diagnosed and who received neoadjuvant crizotinib for 2 months. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.05.036

Authors: Chao Zhang, Yi-Long Wu, Wen-Zhao Zhong

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

The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies. READ ARTICLE

Cancers (Basel) DOI:10.3390/cancers11081074

Authors: Stephen P Ducray, Karthikraj Natarajan, Gavin D Garland, Suzanne D Turner, Gerda Egger

EditorialKirk SmithJuly 30, 2019ALCL, ALK, ALK-translocation proteins, EML4-ALK, NPM-ALK, NSCLC, epigenetics

Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed. READ ARTICLE

Organic Process Research & Development DOI:10.1021/acs.oprd.8b00427

Authors: Yuji Takahama, Kazuyoshi Obitsu, Kazuhiro Takeguchi, Shun Hirasawa, Koji Kobayashi, Takahiro Akiba, Norihiro Ueda, Ryoki Orii, Atsushi Ohigashi, Takumi Takahashi, Minoru Okada, Shigeru Ieda

EditorialKirk SmithJuly 11, 2019ALK inhibitor, SNAr reaction, 1, 3, 5-triazine, polymorph

MPRIP-ALK, a Novel ALK Rearrangement That Responds to ALK Inhibition in NSCLC

Oncogenic rearrangements of the ALK receptor tyrosine kinase (ALK) gene are detected in approximately 7% of NSCLC patients.1 However, novel partner genes for ALK fusion and their clinical significance are not fully defined. Herein we describe the first case of ALK fusion with the myosin phosphatase Rho interacting protein gene (MPRIP) via next-generation sequencing (NGS), whose oncogenicity was further validated in vitro. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.030

Authors: Wenfeng Fang, Jiadi Gan, Shaodong Hong, Feng Lu, Li Zhang.

EditorialKirk SmithJuly 1, 2019MPRIP-ALK, ALK, Inhibition, NSCLC

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