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 Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment

2020 ◽  
Vol 12 ◽  
pp. 175883592097419
Author(s):  
Julie A. Vendrell ◽  
Xavier Quantin ◽  
Isabelle Serre ◽  
Jérôme Solassol
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Liquid Biopsies ◽  
Cell Lung Carcinoma ◽  
Histological Transformation

Background: Histological transformation of advanced non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the mechanisms of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib. This acquired TKI resistance is linked to the high degree of tumor heterogeneity and adaptive cellular signaling pathways, including epidermal growth factor receptor ( EGFR)-dependent pathways, observed in NSCLC. Methods: Here, we investigated a series of paired pre- and post-histological transformation biopsies obtained from three patients initially having a NSCLC with an EGFRactivating mutation treated with first-generation TKI, who then received osimertinib as second-line after EGFRT790M resistance and, lastly, developed a histological transformation to SCLC. Both tissue and liquid biopsies were analyzed using large panel sequencing approaches at various time points to reconstruct the clonal evolutionary history of the tumor. Results: Our complementary analysis of tumor tissue and circulating tumor DNA samples allowed us to better characterize the histological and molecular alterations associated with resistance to osimertinib. SCLC transformation was linked to the presence of several concomitant gene alterations, including EGFR, TP53 and RB1, but also to specific signal bypass, such as EGFR and MET amplifications and activation of the PI3K/AKT/mTOR pathway. Conclusion: Our report emphasizes the mutational landscape of SCLC histological transformation and highlights the importance of combining tissue and liquid biopsy profiling before and during osimertinib treatment to predict such histological transformation.

scholarly journals Liquid Biopsy for Biomarker Testing in Non-Small Cell Lung Cancer: A European Perspective

2021 ◽  
Vol 2 (3) ◽  
pp. 255-273
Author(s):  
Umberto Malapelle ◽  
Marcello Tiseo ◽  
Ana Vivancos ◽  
Joshua Kapp ◽  
M. Josè Serrano ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Molecular Diagnosis ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Liquid Biopsy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tissue Biopsy ◽  
Biomarker Testing

The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging biomarkers with available targeted treatments highlights the challenges associated with sequential single-gene testing and limited tissue availability. Multiplex next-generation sequencing (NGS) offers an attractive alternative and represents a logical next step, and in cases where the tumour is inaccessible, tissue biopsy yields insufficient tumour content, or when the patient’s performance status does not allow a tissue biopsy, liquid biopsy can provide valuable material for molecular diagnosis. Here, we explore the role of liquid biopsy (i.e., circulating cell-free DNA analysis) in Europe. Liquid biopsies could be used as a complementary approach to increase rates of molecular diagnosis, with the ultimate aim of improving patient access to appropriate targeted therapies. Expert opinion is also provided on potential future applications of liquid biopsy in NSCLC, including for cancer prevention, detection of early stage and minimum residual disease, monitoring of response to therapy, selection of patients for immunotherapy, and monitoring of tumour evolution to enable optimal adaptation/combination of drug therapies.

scholarly journals Complementing Tissue Testing with Plasma mutation Profiling Improves Therapeutic Decision Making for Lung Cancer Patients

2021 ◽  
Author(s):  
Yukti Choudhury ◽  
Min-Han Tan ◽  
Jun Li Shi ◽  
Augustine Tee ◽  
Kao Chin Ngeow ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Small Cell Lung Carcinoma ◽  
Egfr Mutations ◽  
P Value ◽  
Liquid Biopsies ◽  
Cell Lung Carcinoma ◽  
Lung Cancer Patients ◽  
Tissue Biopsy ◽  
Mutation Profiling

Background: Tissue biopsy is an integral part of the diagnostic approach to lung cancer. It is however invasive and associated with limitations of tissue heterogeneity. Liquid biopsies may complement tissue testing by providing additional molecular information and may be particularly helpful in patients from whom obtaining sufficient tissue for genomic profiling is challenging. Methods: Patients with suspected lung cancer (n=71) were prospectively recruited. Blood and diagnostic tissue samples were collected within 48 hrs of each other. Plasma cell-free DNA (cfDNA) testing was done using an ultrasensitive amplicon-based next-generation sequencing (NGS) panel (plasma NGS testing). For cases diagnosed as non-small cell lung carcinoma (NSCLC) via histology or cytology, targeted testing for epidermal growth factor receptor (EGFR) mutations was performed using tissue biopsy samples, where available (tissue EGFR testing). Concordance of clinically actionable mutations between methods and sample types were assessed. Results: For confirmed NSCLC cases (n = 54), tissue EGFR test results were available only for 70.3% (38/54) due to sample inadequacies, compared to blood samples for 98.1% (53/54) cases. Tissue EGFR testing identified sensitizing EGFR (L858R or exon 19 deletion) mutation in 31.6% (12/38) of cases. Plasma NGS identified clinically actionable mutations in 37.7% (20/53) of cases, including EGFR mutations in two cases with no tissue EGFR results, and mutations in KRAS, BRAF and MET. Overall sensitivity of EGFR sensitizing mutation detection by plasma NGS was 75% (9/12), and specificity was 100% (25/25) in patients tested in both tissue EGFR and plasma NGS (n=37). In this cohort of patients, tissue EGFR testing alone informed clinical decisions in 22.2% (12/54) of cases. Adding plasma NGS to tissue EGFR testing increased the detection rate of actionable mutations to 42.6% (23/54), representing a near doubling (1.9-fold increase) of clinically relevant findings. The average turnaround time (TAT) of plasma NGS was shorter than standard tissue testing (10 days vs. 29.9 days, p-value <0.05). Conclusions: In the first-line setting, plasma NGS was highly concordant with tissue EGFR testing. Plasma NGS increases the detection of actionable findings with shorter time to results. This study outlines the clinical utility of a complementary plasma mutation profiling in the routine management of lung cancer patients.

Liquid biopsy: Safety and efficacy in a tool for molecular profiling of advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21506-e21506
Author(s):  
Saleha Rizwan ◽  
Zachary Otaibi ◽  
Herman Lo ◽  
Talal Khan ◽  
Rodney E. Wegner ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Liquid Biopsy ◽  
Small Cell ◽  
Molecular Testing ◽  
Small Cell Lung ◽  
Liquid Biopsies ◽  
Nsclc Patients

e21506 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a broad spectrum of targeted therapies already available or in clinical trials. Among the NSCLC patients, 23% to 25% harbor a mutation in a gene associated with approved or emerging targeted therapy. These therapies have changed the therapeutic landscape of NSCLC with significantly improved clinical outcomes in advanced metastatic NSCLC patients. It is imperative to test for these gene alterations in order to identify patients who could potentially benefit from these efficacious targeted therapies and to avoid therapies unlikely to provide clinical benefit. A major limitation in obtaining molecular testing occurs when minimally invasive techniques are used to obtain tissue sample resulting in insufficient yield for testing. In such cases, the utilization of circulating tumor DNA (ctDNA), commonly known as liquid biopsy, has proven very beneficial. In a study utilizing ctDNA, increased detection rates were found when using ctDNA in addition to tissue testing and a > 98.2% concordance rate was found. We report results of 40 NSCLC patients from our institute who had liquid biopsy with or without tissue profiling done. Methods: We molecularly profiled 40 newly diagnosed advanced NSCLC patients using both tissue and liquid biopsies. Tissue was assayed using the John Hopkins university molecular panel and liquid biopsies were performed by Biocept. Results: 14 out of 40 (35%) patients had insufficient or no tissue for molecular testing. Concordant results were found in 17 out of the 26 (65.4%) patients who had both tissue and liquid molecular testing done. Liquid Biopsy detected additional mutations in 5 (19.2%) patients which were not picked up on tissue and led to change in management in 4 patients. 12 out of 40 (30%) patients had repeat liquid biopsies done at progression of disease with new mutations detected on 4 patients revealing resistance to current treatment and change in treatment. Conclusions: Liquid Biopsy reveals high concordance rates with tissue genotyping and increases rate of detection of targetable mutations in NSCLC. It offers a safe and effective alternative when additional tissue is needed to identify genetic mutations.

Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 247-254 ◽  
Author(s):  
Jason Sheehan ◽  
Douglas Kondziolka ◽  
John Flickinger ◽  
L. Dade Lunsford
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Content Type ◽  
The Brain ◽  
Fine Print

Object. Lung carcinoma is the leading cause of death from cancer. More than 50% of those with small cell lung cancer develop a brain metastasis. Corticosteroid agents, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, median survival for patients with small cell lung carcinoma metastasis is approximately 4 to 5 months after cranial irradiation. In this study the authors examine the efficacy of gamma knife surgery for treating recurrent small cell lung carcinoma metastases to the brain following tumor growth in patients who have previously undergone radiation therapy, and they evaluate factors affecting survival. Methods. A retrospective review of 27 patients (47 recurrent small cell lung cancer brain metastases) undergoing radiosurgery was performed. Clinical and radiographic data obtained during a 14-year treatment period were collected. Multivariate analysis was utilized to determine significant prognostic factors influencing survival. The overall median survival was 18 months after the diagnosis of brain metastases. In multivariate analysis, factors significantly affecting survival included: 1) tumor volume (p = 0.0042); 2) preoperative Karnofsky Performance Scale score (p = 0.0035); and 3) time between initial lung cancer diagnosis and development of brain metastasis (p = 0.0127). Postradiosurgical imaging of the brain metastases revealed that 62% decreased, 19% remained stable, and 19% eventually increased in size. One patient later underwent a craniotomy and tumor resection for a tumor refractory to radiosurgery and radiation therapy. In three patients new brain metastases were demonstrating on follow-up imaging. Conclusions. Stereotactic radiosurgery for recurrent small cell lung carcinoma metastases provided effective local tumor control in the majority of patients. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can extend survival.

New lung cancer treatment strategy with molecular target of PKCeta

Impact ◽  
2019 ◽  
Vol 2019 (8) ◽  
pp. 56-58
Author(s):  
Motoi Ohba
Keyword(s):  
Lung Cancer ◽  
Cancer Treatment ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Surgical Removal ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Nucleotide Mutation

Lung cancer is one of the most prevalent and lethal forms of the disease accounting for almost 20 per cent of all deaths from cancer. It is therefore the leading cause of cancer death in men and second most fatal in women. There are between 1.5 and 2 million new cases of cancer globally every year. A similar number die from the disease annually. There are two forms of lung cancer – small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). SCLC is the more aggressive form being faster growing and more metastatic, however it also responds more effectively to treatments such as chemotherapy. NSCLC is the more common form of the disease, accounting for 85 per cent of cases. They develop more slowly than SCLCs, however they are largely unresponsive to chemotherapy and require precise surgical removal. Both present a huge medical problem in terms of diagnosis and treatment. Due to its far higher prevalence, NSCLC is the most studied of the two forms. A chemotherapeutic treatment has been developed that targets the epidermal growth factor receptor (EGFR). EGFR is majorly upregulated in most cases and plays a key role in the tumour's growth and survival. The treatment blocks the receptor and is usually very effective in the first instances. However, it is typically unable to clear the cancer as a single nucleotide mutation is capable of rendering the inhibitor unable to act on the receptor. Therefore, the cancer returns and continues to develop. New treatments are also required. This is the work of Dr Motoi Ohba of the Advanced Cancer Translational Research Institute, Showa University, Japan. His work is aimed at both uncovering novel targets for cancer treatment and finding and developing molecules that could effectively manipulate these targets.

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.

Targeted therapeutics for non small cell lung carcinoma

2019 ◽  
Author(s):  
◽  
Soumavo Mukherjee
Keyword(s):  
Lung Cancer ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Environmental Pollutants ◽  
Ether Linkage ◽  
University Of Missouri ◽  
Cell Lung Carcinoma ◽  
Age Of Diagnosis ◽  
The University ◽  
Gene Expression Levels

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] "Lung carcinoma, also known as lung cancer, is a malignant tumor of lungs characterized by uncontrolled call growth in lung tissue. Tobacco smoking is the reason for nearly 85% of cases of lung cancer. The rest 10-15% are usually a combination of genetic factors, secondhand smoke, environmental pollutants, asbestos and radon gas exposure. Chest radiography and CT scan with confirmation by biopsy are the ways to detect the cancer. The type of cancer, degree of spread and the overall health weigh in on the outcome and eventual possible cure. Still now, most cases are not curable. Surgery, chemotherapy and radiotherapy are the treatments of choice for all types of lung cancer. Being the most common form of cancer in men and second most common form in women, after breast, data of the year 2012 showed 1.8 million incidences of lung cancer resulting to 1.6 million deaths worldwide, with the most common age of diagnosis being 70 years. 5-year survival rate in USA is 17.4%. ... Studies has been done to unravel the downstream effect after knocking down the oncogene via siRNA(42). Malignant cells have a number of secondary pathways, along with the primary pathway, which remain dormant till the disruption of the primary pathway(43). A complex mechanism controls this function which is triggered by the change in downstream protein and gene expression levels. This makes the cancer cells develop drug resistance(44). In this project, we developed a gelatin-based nanoparticle (GelNP) that will act as a vehicle to deliver targeted siRNAs against NSCLC cells in combination with Cisplatin. The cetuximab (Ab), an EGFR targeting antibody, shall be attached to the surface. The AXL and FN14 SiRNAs shall be conjugated to the antibody by the thio-ether linkage. The cetuximab antibody shall be used to specifically target the cell and also to protect the siRNAs from degradation. We predict that 146kDa cetuximab antibody will shield the 15kDa siRNAs and prevent it from exposure to environment. Since AXL and FN14 has been observed to be related to EGFR, we hypothesize that knocking down AXL and FN14 will block EGFR and thus allow the TKI to continue its course of therapeutic action."--Introduction.

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