Blood-based liquid biopsy: Insights into early detection and clinical management of lung cancer

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

EditorialKirk SmithJanuary 1, 2022Liquid biopsy, Biomarkers, Lung cancer, Early detection, Clinical management

Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions

Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%–99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%–74%) were concordant with p..... READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2021.06.018

Authors: Sebastian Mondaca, Emily S. Lebow, Azadeh Namakydoust, Pedram Razav, Jorge S. Reis-Filho, Ronglai Shen, Michael Offin, Hai-Yan Tu, Yonina Murciano-Goroff, Chongrui Xu, Alex Makhnin, Andres Martinez, Nick Pavlakis, Stephen Clarke, Malinda Itchins, Adrian Lee, Andreas Rimner, Daniel Gomez and Bob T. Li

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non–small-cell lung cancer: a multicenter study using targeted next-generation sequencing

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2021.06.043

Authors: Yen-Ting Lin, Chi-Lu Chiang, Jen-Yu Hung, Mei-Hsuan Lee, Wu-Chou Su, Shang-Yin Wu, Yu-Feng Wei, Kang-Yun Lee, Yen-Han Tseng, Jian Su, Hsin-Pei Chung, Chih-Bin Lin, Wen-Hui Ku, Tsai-Shin Chiang, Chao-Hua Chiu, Jin-Yuan Shih

Comparison of solid tissue sequencing and liquid biopsy accuracy in identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas

Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. “Liquid biopsies” are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a ..... READ ARTICLE

Modern Pathology DOI:10.1038/s41379-021-00880-0

Authors: Lawrence Hsu Lin, Douglas H. R. Allison, Yang Feng, George Jour, Kyung Park, Fang Zhou, Andre L. Moreira, Guomiao Shen, Xiaojun Feng, Joshua Sabari, Vamsidhar Velcheti, Matija Snuderl, Paolo Cotzia

Functional coding/non-coding variants in EGFR, ROS1 and ALK genes and their role in liquid biopsy as a personalized therapy

Personalized medicine holds promise to tailor the treatment options for patients’ unique genetic make-up, behavioral and environmental background. Liquid biopsy is non-invasive technique and precise diagnosis and treatment approach. Significantly, NGS technologies have revolutionized the genomic medicine by novel identifying SNPs, indel mutations in both coding and non-coding regions and also a promising technology to accelerate the early detection and finding new biomarkers for diagnosis and treatment. The number of the bioinformatics tools have been rapidly increasing with the aim of learning more about the detected mutations either they have a pathogenic role or not. EGFR, ROS1 and ALK genes are members of the RTK family. Until now, mutations within these genes have been associated with many cancers and involved in resistance formation to TKIs. This review article summarized the findings about the mostly investigated variations in EGFR, ROS1 and ALK genes and their potential role in..... READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.103113

Authors: Mahmut Cerkez Ergoren, Havva Cobanogulları, Sehime Gulsun Temel, Gamze Mocan

Review PaperKirk SmithDecember 1, 2020EGFR, ROS1, ALK, Tyrosine kinase inhibitors, Liquid biopsy, Personalized therapy

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression

Introduction: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown... Conclusions: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.024

Authors: Mihaela Aldea, Lizza Hendriks, Laura Mezquita, Cécile Jovelet, David Planchard, Edouard Auclin, Jordi Remon, Karen Howarth, Jose Carlos Benitez, Anas Gazzah, Pernelle Lavaud, Charles Naltet, Ludovic Lacroix, Frankde Kievit, Clive Morris, Emma Green, Maud Ngo-Camus, Etienne Rouleau, … , Benjamin Besse

Review PaperKirk SmithMarch 1, 2020Liquid biopsy, ctDNA, NSCLC, Brain, Leptomeningeal

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition

Background ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. Results Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, b..... READ ARTICLE

Clinical Proteomics DOI:10.1186/s12014-020-9269-6

Authors: Couëtoux du Tertre, M., Marques, M., McNamara, S. et al.

Clinical TrialsKirk SmithFebruary 7, 2020Protein signature, Crizotinib, Liquid biopsy, NSCLC, Prediction of response

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

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

Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions

Many advanced cases of cancer show central nervous system, pleural, or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE), and/or ascites (ASC) can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE, and ASC samples from advanced non-small-cell lung cancer and melanoma patients. Cell-free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA-Q-PCR or next-generation sequencing. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty-three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE, and ASC were used to guide treatm..... READ ARTICLE

Molecular Oncology DOI:10.1002/1878-0261.12574

Authors: Sergio Villatoro, Clara Mayo-de-las-Casas, Núria Jordana-Ariza, Santiago Viteri-Ramírez, Mónica Garzón-Ibañez, Irene Moya-Horno, Beatriz García-Peláez, María González-Cao, Umberto Malapelle, Ariadna Balada-Bel, Alejandro Martínez-Bueno, Raquel Campos, Noemí Reguart, Margarita Majem, Remei Blanco, Ana Blasco, María J. Catalán, Xavier González, Giancarlo Troncone, Niki Karachaliou, Rafael Rosell, Miguel A. Molina-Vila

Feasibility of liquid biopsy using plasma and platelets for detection of anaplastic lymphoma kinase rearrangements in non-small cell lung cancer

Purpose: Fluorescence in situ hybridization (FISH) using tumor tissue is the gold standard for detection of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC). However, this method often is not repeatable due to difficulties in the acquisition of tumor tissues. Blood-based liquid biopsy using reverse transcription polymerase chain reaction (RT-PCR) is expected to be useful to overcome this limitation. Here, we investigated the feasibility of liquid biopsy using plasma and platelets for detection of ALK rearrangement and prediction of ALK inhibitor treatment outcomes. Conclusion: Liquid biopsy could have applications in the diagnosis of ALK-positive NSCLC, even when using RT-PCR, and platelets can be useful for predicting treatment outcomes of ALK inhibitors. READ ARTICLE

Journal of Cancer Research and Clinical Oncology DOI:10.1007/s00432-019-02944-w

Authors: Cheol-Kyu Park, Ji-Eun Kim, Min-Seok Kim, Bo-Gun Kho, Ha-Young Park, Tae-Ok Kim, Hong-Joon Shin, Hyun-Joo Cho, Yoo-Duk Choi, In-Jae Oh, Young-Chul Kim

EML4-ALK TRANSLOCATION IDENTIFICATION IN RNA EXOSOMAL CARGO (EXOALK) IN NSCLC PATIENTS: A NOVEL ROLE FOR LIQUID BIOPSY

The introduction of druggable targets has significantly improved the outcomes of non-small cell lung cancer patients (NSCLC). EML4-ALK translocation represents 4–6% of the druggable alterations in NSCLC. With the approval of Crizotinib, first discovered drug for the EML4-ALK translocation, on first line treatment for patients with detected mutation meant a complete change on the treatment landscape. The current standard method for EML4-ALK identification is immunohistochemistry or FISH in a tumor biopsy. However, a big number of NSCLC patients have not tissue available for analysis and others are not suitable for biopsy due to their physical condition or the location of the tumor. Liquid biopsy seems the best alternative for identification in these patients that have no tissue available. Circulating free RNA has not been validated for the identification of this mutation. As a complementary tool, exosomes might represent a good tool for predictive biomarkers study, and due to their stab..... READ ARTICLE

Translational Cancer Research DOI:10.21037/tcr.2018.11.35

Authors: Reclusa, P. (Pablo), Laes, J.F. (Jean-François), Malapelle, U. (Umberto), Valentino, A. (Anna), Rocco, D. (Danilo), Gil-Bazo, I. (Ignacio), Rolfo, C. (Christian)