scholarly journals Serial liquid biopsies for detection of treatment failure and profiling of resistance mechanisms in KLC1–ALK-rearranged lung cancer

2019 ◽  
Vol 5 (6) ◽  
pp. a004630 ◽  
Author(s):  
Steffen Dietz ◽  
Petros Christopoulos ◽  
Lisa Gu ◽  
Anna-Lena Volckmar ◽  
Volker Endris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Failure ◽  
Resistance Mechanisms ◽  
Liquid Biopsies

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

ESMO Open ◽  
2019 ◽  
Vol 4 (5) ◽  
pp. e000561 ◽  
Author(s):  
Anastasia Kougioumtzi ◽  
Panagiotis Ntellas ◽  
Eirini Papadopoulou ◽  
George Nasioulas ◽  
Eleftherios Kampletsas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Molecular Testing ◽  
Liquid Biopsies ◽  
Disease Biology ◽  
Remarkable Progress

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.Method: Here, we present the case of a patient with NSCLC treated with TKIs, in which molecular profiling of the tumour was performed with different methods of tissue and plasma testing at each disease progression. A review of the literature was further conducted to offer insights into the resistance mechanisms of ALK-rearranged NSCLC.Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional ALK mutations were later detected in the tissue and plasma and are likely to have caused resistance to the administered TKIs. Continued research into the mechanisms of acquired resistance is required in order to increase the benefit of the patients treated with targeted ALK TKIs.

scholarly journals The Liquid Biopsy for Lung Cancer: State of the Art, Limitations and Future Developments

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3923
Author(s):  
Daniel Di Capua ◽  
Dara Bracken-Clarke ◽  
Karine Ronan ◽  
Anne-Marie Baird ◽  
Stephen Finn
Keyword(s):  
Lung Cancer ◽  
Lung Carcinoma ◽  
Targeted Therapies ◽  
Liquid Biopsy ◽  
Genetic Alterations ◽  
Rapid Progression ◽  
Liquid Biopsies ◽  
Cell Lung Carcinoma ◽  
Genetic Sequencing ◽  
Tissue Biopsy

Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.

scholarly journals Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2101
Author(s):  
Ângela Carvalho ◽  
Gabriela Ferreira ◽  
Duarte Seixas ◽  
Catarina Guimarães-Teixeira ◽  
Rui Henrique ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Lab On A Chip ◽  
Microfluidic Devices ◽  
Early Recurrence ◽  
Circulating Tumor Dna ◽  
Clinical Validation ◽  
Liquid Biopsies ◽  
Lung Cancer Patients

Despite the intensive efforts dedicated to cancer diagnosis and treatment, lung cancer (LCa) remains the leading cause of cancer-related mortality, worldwide. The poor survival rate among lung cancer patients commonly results from diagnosis at late-stage, limitations in characterizing tumor heterogeneity and the lack of non-invasive tools for detection of residual disease and early recurrence. Henceforth, research on liquid biopsies has been increasingly devoted to overcoming these major limitations and improving management of LCa patients. Liquid biopsy is an emerging field that has evolved significantly in recent years due its minimally invasive nature and potential to assess various disease biomarkers. Several strategies for characterization of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been developed. With the aim of standardizing diagnostic and follow-up practices, microfluidic devices have been introduced to improve biomarkers isolation efficiency and specificity. Nonetheless, implementation of lab-on-a-chip platforms in clinical practice may face some challenges, considering its recent application to liquid biopsies. In this review, recent advances and strategies for the use of liquid biopsies in LCa management are discussed, focusing on high-throughput microfluidic devices applied for CTCs and ctDNA isolation and detection, current clinical validation studies and potential clinical utility.

Proteomic analysis of multidrug-resistance mechanisms in adriamycin-resistant variants of DLKP, a squamous lung cancer cell line

PROTEOMICS ◽  
2009 ◽  
Vol 9 (6) ◽  
pp. 1556-1566 ◽  
Author(s):  
Joanne Keenan ◽  
Lisa Murphy ◽  
Michael Henry ◽  
Paula Meleady ◽  
Martin Clynes
Keyword(s):  
Lung Cancer ◽  
Multidrug Resistance ◽  
Cell Line ◽  
Cancer Cell ◽  
Proteomic Analysis ◽  
Cancer Cell Line ◽  
Resistance Mechanisms ◽  
Lung Cancer Cell Line ◽  
Lung Cancer Cell ◽  
Squamous Lung Cancer

scholarly journals Exosomal Proteins in Lung Cancer: The Last Frontier in Liquid Biopsies

2016 ◽  
Vol 11 (10) ◽  
pp. 1609-1611 ◽  
Author(s):  
Christian Rolfo
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsies

Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and overcome Resistance Mechanisms

2017 ◽  
Vol 103 (4) ◽  
pp. 325-337 ◽  
Author(s):  
Claudia Proto ◽  
Giuseppe Lo Russo ◽  
Giulia Corrao ◽  
Monica Ganzinelli ◽  
Francesco Facchinetti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Exon 20 ◽  
Egfr Mutated ◽  
Egfr Tkis

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

scholarly journals Extensive Disease Small Cell Lung Cancer Dose-Response Relationships: Implications for Resistance Mechanisms

2010 ◽  
Vol 5 (11) ◽  
pp. 1826-1834 ◽  
Author(s):  
David J. Stewart ◽  
Constance Johnson ◽  
Adriana Lopez ◽  
Bonnie Glisson ◽  
Jay M. Rhee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Dose Response ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Small Cell Lung ◽  
Extensive Disease

Residual ctDNA after treatment predicts early relapse in patients with early-stage NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8517-8517
Author(s):  
Davina Gale ◽  
Katrin Heider ◽  
Malcolm Perry ◽  
Giovanni Marsico ◽  
Andrea Ruiz-Valdepeñas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Deep Sequencing ◽  
Early Stage ◽  
Post Treatment ◽  
Disease Stage ◽  
Analytical Sensitivity ◽  
Disease Relapse ◽  
Clinical Progression ◽  
Liquid Biopsies ◽  
Early Stage Disease

8517 Background: Liquid biopsies based on circulating tumor DNA (ctDNA) analysis are being investigated for detection of residual disease and recurrence. Conclusive evidence for utility of ctDNA in early-stage non-small cell lung cancer (NSCLC) is awaited. Due to low ctDNA levels in early-stage disease or post-treatment, effective methods require high analytical sensitivity to detect mutant allele fractions (MAF) below 0.01%. Methods: We analysed 363 plasma samples from 88 patients with NSCLC recruited to the LUng cancer CIrculating tumour DNA (LUCID) study, with disease stage I (49%), II (28%) and III (23%). 62% were adenocarcinomas. Plasma was collected before and after treatment, and at 3, 6 and 9 months after surgery (N = 69) or chemoradiotherapy (N = 19). Additional plasma was collected at disease relapse for 17 patients. Median follow-up was 3 years, and 40 patients progressed or died of any cause. We employed the RaDaR™ assay, a highly sensitive personalized assay using deep sequencing of up to 48 tumor-specific variants. Variants identified by tumor exome analysis were tested by deep sequencing of tumor tissue and buffy coat DNA to verify somatic mutations and exclude clonal hematopoiesis. The RaDaR assay demonstrated 90% sensitivity at 0.001% MAF in analytical validation studies. Results: ctDNA was detected in 26% of samples, at median MAF of 0.047% (range: 0.0007% to > 2%), and prior to treatment in 87%, 77% and 24% for disease stage III, II and I respectively. For 62 patients, plasma was collected at a landmark timepoint, between 2 weeks and 4 months after initial treatment. ctDNA detection at the landmark timepoint was strongly predictive of clinical disease relapse, with Hazard Ratio of 20.7 (CI: 7.7-55.5, p-value < 0.0001). All 11 cases with ctDNA detected at landmark had disease progression, a median of 121 days after detection, and these included all 8 patients that relapsed within 300 days of treatment. Across 27 patients whose disease progressed during the study, ctDNA was detected at any timepoint post-treatment in 17 cases, with a median lead time of 203 days, and up to 741 days prior to clinical progression. ctDNA was detected post-treatment, in 13 of the 15 patients that progressed and had ctDNA detected prior to treatment. Conclusions: Our results support an emerging paradigm shift, by demonstrating that liquid biopsies can reliably detect recurrence of NSCLC at a preclinical stage, many months before clinical progression, thereby offering the opportunity for earlier therapeutic intervention. Clinical trial information: NCT04153526.

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