Lung cancer is one of the most common types of cancer and the leading cause of cancer-related deaths worldwide. A major factor related with the high mortality rate of lung cancer patients is the late diagnosis of the disease. So, the identification and characterization of new epigenetic marks and mechanisms may contribute to better diagnose and treat lung cancer. In this chapter we review the epigenetic mechanisms involved in lung cancer, including DNA methylation, histone posttranslational modification and noncoding RNAs. The chapter focuses on biomarkers for diagnostic, prognostic and response to treatment. Finally, thanks to the reversible nature of epigenetic marks, we provide not only information about the therapeutic targets identified in preclinical studies but also drugs which are being evaluated for lung cancer in clinical trials. Epigenetics translated to personalized medicine will help to develop new tools to guide decisions made by the oncologist regarding the proper treatment of lung cancer. READ ARTICLE
Epigenetics in Precision Medicine DOI:10.1016/B978-0-12-823008-4.00007-X
Authors: Alejandro Cardona-Monzonís, Ángel L. Ortega, Julian Carretero, José Luis García-Giménez, Salvador Mena-Mollá
Objectives: Next-generation sequencing (NGS) is able to identify targetable mutations to guide therapy and endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) offers a potential route to routinely obtain specimens for analysis. However, the suitability of EBUS-TBNA samples for NGS remains uncertain... Conclusion: EBUS-TBNA was associated with a high yield for NGS and the success of EBUS-TBNA sampling for NGS was proportional to the number of passes. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2022.01.018
Authors: Joseph J Zhao, Hiang Ping Chan, Yu Yang Soon, Yiqing Huang, Ross A Soo, Adrian C L Kee
In the past decades, great progress has been made for the prevention and treatment of lung cancer. Yet, lung cancer remains as the leading cause of cancer death worldwide. In this manuscript, we describe the current genetic and molecular characterization of lung cancer subtypes, review up-to-date treatment options for lung cancer patients, summarize the antibodies and small molecule drugs under clinical development, and elaborate on the expression and characteristics of important RTK primary targets and representative preclinical agents which may provide new opportunities for lung cancer treatment. Since gefitinib was first introduced to non-small-cell lung carcinoma (NSCLC) patients in 2002, remarkable progress has been made in targeted therapy for NSCLC patients with the development of multiple generations of small molecule inhibitors targeting relevant driver mutations. However, very little achievement has been made in the development of targeted drugs for small-cell lung carcinoma (SCLC). The successful harness of immune checkpoint inhibitors against PD-1/PD-L1 has marked a major advancement in recent lung cancer treatment. Looking forward, therapeutic strategies that tackle brain metastasis are highly desirable, the combination of molecular testing and strategies tailored to tackle tumor heterogeneity and resistance mechanisms is the key direction for future development. READ ARTICLE
Cell Insight DOI:10.1016/j.cellin.2022.100015
Authors: Zilai Wang, Jiyeon Kim, Pin Zhang, Jazmin M. Galvan Achi, Yuwei Jiang, Lijun Rong
Lung cancer remains the leading cause of cancer death world-wide. This is in part due patients presenting late with disseminated disease and despite recent advances, a limited therapeutic landscape... Despite these advances there remains a significant unmet clinical need with much research needed to elucidate the optimal treatment paradigm to improve response rates, mortality and quality of life for patients with advanced NSCLC. READ ARTICLE
Encyclopedia of Respiratory Medicine (Second Edition) DOI:10.1016/B978-0-08-102723-3.00265-1
Authors: Alice Davies, Martin Forster
The therapeutic arsenal for advanced ALK positive non-small cell lung cancer has been enriched by specific treatments targeting this molecular abnormality, with five molecules available, including lorlatinib, approved since July 2020. This treatment can have side effects common to other tyrosine kinase inhibitors, as well as other less common disorders affecting the central nervous system such as impaired cognitive function, speech or mood. The prevalence of neuro-psychiatric effects under treatment with lorlatinib reported in studies is nearly 40 % with a mild to moderate intensity in most cases. Given the potential impact on patients’ quality of life and even on compliance with treatment, it is essential to include their detection during consultations. The main problem is still to have simple screening tools adapted to clinical practice. A multidisciplinary expert panel (pulmonologist, medical oncologist, psychiatrist, neurologist, pharmacist, nurse) therefore met to propose, based on data from the literature and their clinical experience, elements of management in order to detect these cognitive disorders at an early stage and optimize treatment tolerance. The subjects discussed concern screening and assessment tools, the management of side effects, and their prevention. The use of the practical elements proposed by the group could help optimize the identification and management of central nervous system disorders occurring on lorlatinib. READ ARTICLE
Bulletin du Cancer DOI:10.1016/j.bulcan.2022.01.011
Authors: Vincent Fallet, Pascal Rouby, Guido Ahle, Jennifer Arrondeau, Charles Naltet, Adeline Duflot-Boukobza, Françoise De Crozals, Hervé Lena, Alexis Cortot
Introduction: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic... Conclusion: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2022.01.009
Authors: Wanyuan Cui, Charlotte Milner-Watts, Terri P. McVeigh, Anna Minchom, Jaishree Bholse, Michael Davidson, Nadia Yousaf, Suzanne MacMahon, Hood Mugalaasi, Ranga Gunapala, Richard Lee, Angela George, Sanjay Popat, MaryO'Brien
Clinical Practice Points:
• HER2 amplification is an acquired resistance mechanism in ALK-rearranged non–small cell lung cancer.
• FISH analysis revealed a minor subclone of HER2-amplified cells before becoming the dominant resistance mechanism.
• Combination of HER2 and ALK therapies may be an effective treatment approach for ALK-rearranged NSCLC with acquired HER2 amplification. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2021.06.012
Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter, D. Ross Camidge
Currently, early detection of lung cancer relies on the characterisation of images generated from computed tomography (CT). However, lung tissue biopsy, a highly invasive surgical procedure, is required to confirm CT-derived diagnostic results with very high false-positive rates. Hence, a non-invasive or minimally invasive biomarkers is essential to complement the existing low-dose CT (LDCT) for early detection, improve responses to a certain treatment, predict cancer recurrence, and to evaluate prognosis. In the past decade, liquid biopsies (e.g., blood) have been demonstrated to be highly effective for lung cancer biomarker discovery. In this review, the roles of emerging liquid biopsy-derived biomarkers such as circulating nucleic acids, circulating tumour cells (CTCs), long non-coding RNA (lncRNA), and microRNA (miRNA), as well as exosomes, have been highlighted. The advantages and limitations of these blood-based minimally invasive biomarkers have been discussed. Furthermore, the current progress of the identified biomarkers for clinical management of lung cancer has been summarised. Finally, a potential strategy for the early detection of lung cancer, using a combination of LDCT scans and well-validated biomarkers, has been discussed. READ ARTICLE
Cancer Letters DOI:10.1016/j.canlet.2021.10.013
Authors: Cuiliu Liu, Xiaoqiang Xiang, Shuangqing Han, Hannah Ying Lim, Lingrui Li, Xing Zhang, Zhaowu Ma, Li Yang, Shuliang Guo, Ross Soo, Boxu Ren, Lingzhi Wang, Boon Cher Goh
Lung cancer associated with pregnancy is rare but on the increase. The use of tyrosine kinase inhibitor (TKI) therapy for advanced oncogenic-driven non-small cell lung carcinoma (NSCLC) has improved overall survival. Oncological and obstetric outcomes of patients diagnosed with NSCLC and treated by TKIs during pregnancy have been poorly evaluated. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2021.09.001
Authors: Anne-Sophie Boudy, Noémie Grausz, Lise Selleret, Cyril Touboul, Emile Daraï, Jacques Cadranel
Background: Next-generation sequencing has mostly been used for genotyping cell-free DNA (cfDNA) in plasma. However, this assay has several clinical limitations. We evaluated the clinical utility of a novel polymerase chain reaction–free nanowire (NW)-based plasma cfDNA assay for detecting ALK fusion and mutations. Conclusion: The newly developed simple NW-based cfDNA assay may be clinically applicable for rapid diagnosis of ALK fusion with its variant forms and early detection of resistance. READ ARTICLE
The Oncologist DOI:10.1002/onco.13902
Authors: Youngjoo Lee, Youngnam Cho, Eun Young Park, Seong-Yun Park, Kum Hui Hwang, Ji-Youn Han
Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patient..... READ ARTICLE
Journal of Hematology & Oncology DOI:10.1186/s13045-021-01121-2
Authors: Umair Majeed, Rami Manochakian, Yujie Zhao & Yanyan Lou
Here, we present a lung adenocarcinoma with two ALK fusions, a novel RMDN2-ALK fusion accompanied by an EML4-ALK fusion, detected by a targeted next generation sequencing assay. The genomic translocation breakpoints of the RMDN2-ALK fusion were mapped to intron 2 for RMDN2 and exon 15 for ALK, and EML4-ALK breakpoints were mapped to intron 13 for EML4 and intron 19 for ALK. ALK break-apart FISH detected multiple ALK rearrangements, a gene fusion panel (NanoString) test confirmed the EML4-ALK fusion, and RNA-sequencing revealed two ALK fusions. The RMDN2 gene locates at the short arm of chromosome 2 between ALK and EML4 genes. The intact ALK kinase domain fused to RMDN2. Genome-wide copy number variants were found in multiple chromosome arms and the short arm of chromosome 2, suggestive of complex rearrangements. Further detailed analyses of breakpoints and copy number variants may shed light on mechanisms of their formation and pathogenesis in lung malignancies. READ ARTICLE
Cancer Genetics DOI: 10.1016/j.cancergen.2021.06.004
Authors: Liqun Jiang, Suping Chen, Victoria Stinnett, Lisa Haley, Laura Morsberger, Alison Shane, Melanie Hardy, Kirstin Smith, Christopher D. Gocke, Ming-Tseh Lin and Ying S. Zou,
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Brigatinib is a novel potent tyrosine kinase inhibitor as third-generation therapy for anaplastic lymphoma kinase (ALK) rearrangement positive non-small cell lung cancer (NSCLC). Clinical trials show that brigatinib is potent choice of treatment for the first line and further lines of treatment of ALK rearranged NSCLC with highly potent anti-tumor effect on brain metastasis. The adverse effects of brigatinib are tolerable and managable. However, there is limited data about effects on immune system. The most possible serious adverse effect of brigatinib on immune system might be brigatinib associated grade 3-4 lymphopenia. Here we report a brigatinib-induced tuberculosis reactivation patient who is using third-line brigatinib for metastatic NSCLC and have partial response. READ ARTICLE
Current Problems in Cancer DOI:10.1016/j.currproblcancer.2021.100738
Authors: Volkan Keş, Osman Sütcüoğlu, Fatih Gürler, Ozan Yazıcı, Ahmet Özet
This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient’s preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.02.005
Authors: Giovanna Scarfone, Monica Fumagalli, Martina Imbimbo, Tommaso Ceruti, Fulvia Milena Cribiù, Eugenia Di Loreto, Maurizio D’Incalci, Federica Facchin, Camilla Fontana, Marina C. Garassino, Fedro A. Peccatori, Nicola Persico, Diego Signorelli, Massimo Zucchetti
This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient’s preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.02.005
Authors: GiovannaScarfone, Monica Fumagalli, Martina Imbimbo, Tommaso Ceruti, Fulvia Milena Cribiù, Eugenia Di Loreto, Maurizio D’Incalci, Federica Facchin, Camilla Fontana, Marina C. Garassino, Fedro A. Peccatori, Nicola Persico, Diego Signorelli and Massimo Zucchetti
We demonstrated that IHC positive test, in these cases, must be interpreted with caution. FISH analysis has to be recommended to confirm IHC results in case of unusual phenotype, such as smoker or lung cancer other than adenocarcinoma. Although lung carcinoma with ALK rearrangement seems to be not sensitive to ICI, further investigations should be conducted on other types of ALK molecular alterations. ALK amplifications, as observed in the present case, should not be an impediment to taking into account the PD-L1 marking for the initiation of treatment by immunotherapy. READ ARTICLE
Lung Cancer DOI: 10.1016/j.lungcan.2020.12.022.
Authors: Gendarme S, Matton L, Antoine M, Kerrou K, Ruppert AM, Epaud C, Cadranel J, Fallet V.
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This descriptive, retrospective observational study used the Japan Medical Data Vision Co., Ltd. (MDV), database (June 2017–November 2018) and covered data for EGFR, ALK, ROS1, and PD-L1; records on BRAF testing were not yet available. This real-world evidence revealed variations in diagnostic testing patterns, which could affect time to treatment in Japan. Variations are likely influenced by individual biomarker prioritization considering limited tissue samples in clinical practice. READ ARTICLE
Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2020.100136
Authors: Yasushi Yatabe, Yasumasa Yoshiki, MPH, Koichi Matsumura, Kanae Togo, MSc, Hironori Kikkawa, Laura Iadeluca, MPH, Benjamin Li, Kazuto Nishio,
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Herein, we report the case of a non-smoking 36-year-old female patient who was diagnosed with right lung adenocarcinoma in 2005 (cT1N3M0, IIIB) and received definitive chemoradiotherapy. The patient achieved a partial response, and her disease remained under control for 8 years. However, in May 2013, the patient was diagnosed with brain metastasis and underwent subsequent surgical resection, followed by postoperative brain radiotherapy and chemotherapy. Postoperative pathology confirmed ALK gene rearrangement, and next-generation sequencing performed in 2020 identified the EML4-ALK variant as variant 1. After progression-free survival lasting 4 years, new metastatic lesions were found in the patient’s right lung, and she was administered crizotinib for 20 months. Due to a suspicious recurrence in the intracranial surgical margin area, as well as an unbearable gastrointestinal reaction to crizotinib, alectinib was later adopted. At the 7-month follow-up, positron emission tomography/com..... READ ARTICLE
Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1212
Authors: Xu X, Liu D, Wen J, Chen J, Fan M.
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In recent years, serious changes have been observed in the treatment algorithms of especially lung cancer patients. The start-up phase of treatment planning of metastatic lung adenocarcinoma patients is comprised of driver mutation research. Among the pretreatment options of patients diagnosed with EML4-ALK rearrangement, is crizotinib. The group disgnosed with EML4-ALK rearrangement, composes a little part of metastatic non-small cell lung cancer. In this case presented, I will focus on the start of crizotinib treatment and 53-month follow-up in remission in a patient, who has been operated twice and received cisplatin-based adjuvant chemotherapy twice, and relapsed for the second time as Stage-4. READ ARTICLE
Cancer Treatment and Research Communications DOI: 10.1016/j.ctarc.2020.100259
Author: Gulmez A Dr.
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... Garlic is used in the treatment of various ailments such as cancer, diabetes and cardiovascular diseases. The present study aims to explore the plausible mechanisms of the selected phytocompounds as potential inhibitors against the known drug targets of non-small-cell lung cancer (NSCLC)... The result of this study suggest that these identified phytocompounds from garlic would serve as promising leads for the development of lead molecules to design new multi-targeting drugs to address the different clinical forms of NSCLC. READ ARTICLE
Saudi Journal of Biological Sciences DOI:10.1016/j.sjbs.2020.09.041
Authors: R. Padmini, V. Uma Maheshwari, P.Saravanan, Keun Woo Lee, M. Razia, Mona S. Alwahibi, B. Ravindran, Mohamed Soliman Elshikh, Young Ock Kim, Hyungsuk Kim, Hak-Jae Kim