scholarly journals Liquid Biopsy to Identify Actionable Genomic Alterations

2018 ◽  
pp. 978-997 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Misako Nagasaka ◽  
Viola W. Zhu
Keyword(s):  
Liquid Biopsy ◽  
Residual Disease ◽  
Single Gene ◽  
Prognostic Significance ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Braf Mutations ◽  
Clinicopathologic Characteristics ◽  
Pik3ca Mutations

Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify resistance mechanisms, and to prognosticate outcome. Although many liquid biopsy sequencing platforms are being used, only five test kits have received government approval. We review representative literature on these government-approved liquid biopsy kits, which are primarily used to detect EGFR mutation in lung cancer and RAS ( KRAS, NRAS, BRAF) mutations in colorectal carcinoma. Another emerging use of single-gene liquid biopsy is to detect PIK3CA mutations and to understand resistance to hormonal blockade in breast and prostate cancers. The two most commonly used next-generation sequencing (NGS) liquid biopsy tests (Guardant 360, Guardant Health; FoundationACT, Foundation Medicine Inc.) are discussed. The ability and the applicability of NGS platform to detect tumor mutation burden are also addressed. Finally, the use of circulating tumor DNA (ctDNA) to detect minimal residual disease may be the most important use of ctDNA in the setting of tumor heterogeneity. The ability to identify “shedders” and “nonshedders” of ctDNA may provide important insight into the clinicopathologic characteristics of the tumor and portend important prognostic significance regarding survival.

scholarly journals Liquid Biopsy in Breast Cancer: A Focused Review

2020 ◽  
Author(s):  
Timothy Kwang Yong Tay ◽  
Puay Hoon Tan
Keyword(s):  
Breast Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Breast Cancers ◽  
Liquid Biopsies ◽  
Disease Response ◽  
Pik3ca Mutations ◽  
Cancer Management

Context.— The role of liquid biopsy in cancer management has been gaining increased prominence in the past decade, with well-defined clinical applications now being established in lung cancer. Recently, the US Food and Drug Administration also approved the Therascreen PIK3CA RGQ polymerase chain reaction assay as a companion diagnostic assay to detect PIK3CA mutations in breast cancer for both tissue and liquid biopsies, bringing the role of liquid biopsy in breast cancer management to the fore. Its utility in other aspects of breast cancer, however, is yet to be clearly defined. Objective.— To review the studies that looked at liquid biopsies in breast cancer and examine their potential for clinical application in the areas of early diagnosis, prognostication, monitoring disease response, detecting minimal residual disease, and predicting risk of progression or relapse. We focus mainly on circulating tumor cells and circulating tumor DNA. Data sources.— Peer-reviewed articles in PubMed. Conclusions.— Liquid biopsies in breast cancers have yielded promising results, especially in the areas of monitoring treatment response and predicting disease progression or relapse. With further study, and hopefully coupled with continued improvements in technologies that isolate tumor-derived materials, liquid biopsies may go on to play a greater role in the breast cancer clinic.

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.

scholarly journals Diving into the Pleural Fluid: Liquid Biopsy for Metastatic Malignant Pleural Effusions

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2798
Author(s):  
Maria Alba Sorolla ◽  
Anabel Sorolla ◽  
Eva Parisi ◽  
Antonieta Salud ◽  
José M. Porcel
Keyword(s):  
Pleural Fluid ◽  
Liquid Biopsy ◽  
Cell Types ◽  
Circulating Tumor Dna ◽  
Therapeutic Interventions ◽  
Driver Mutations ◽  
Pleural Effusions ◽  
Malignant Pleural Effusions ◽  
Micro Rnas ◽  
Low Sensitivity

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

Multigene Combined Detection by RT-qPCR Using Cytological Specimens

2021 ◽  
pp. 1-10
Author(s):  
Yang Ma ◽  
Jingxia Zhao ◽  
Yun Du ◽  
Rui Wang ◽  
Xiaokun Ji ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Smoking Status ◽  
Single Gene ◽  
Rna Extraction ◽  
Pcr Amplification ◽  
Driver Mutations ◽  
Amplification Refractory Mutation System ◽  
Driver Genes ◽  
Mutation Status ◽  
Pik3ca Mutations

<b><i>Objective:</i></b> The aim of the study was to investigate the mutation status of multiple driver genes by RT-qPCR and their significance in advanced lung adenocarcinoma using cytological specimens. <b><i>Materials and Methods:</i></b> 155 cytological specimens that had been diagnosed with lung adenocarcinoma in the Fourth Hospital of Hebei Medical University were selected from April to November 2019. The cytological specimens included serous cavity effusion and fine-needle aspiration biopsies. Among cytological specimens, 108 cases were processed by using the cell block method (CBM), and 47 cases were processed by the disposable membrane cell collector method (MCM) before DNA/RNA extraction. Ten drive genes of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA, and MET were combined detected at one step by the amplification refractory mutation system and ABI 7500 RT-qPCR. <b><i>Results:</i></b> The purity of RNA (<i>p</i> = 0.005) and DNA (<i>p</i> = 0.001) extracted by using the MCM was both significantly higher than that extracted by using the CBM. Forty-seven cases of fresh cell specimens processed by the MCM all succeeded in multigene detections, while of 108 specimens processed by the CBM, 6 cases failed in multigene detections. Among 149 specimens, single-gene mutation rates of EGFR, ALK, ROS1, RET, HER2, MET, KRAS, NRAS, BRAF, and PIK3CA mutations were 57.71%, 6.04%, 3.36%, 2.68%, 2.01%, 2.01%, 1.34%, 0.67%, 0% and 0% respectively, and 6 cases including 2 coexistence mutations. We found that mutation status was correlated with gender (<i>p</i> = 0.047), but not correlated with age (<i>p</i> = 0.141) and smoking status (<i>p</i> = 0.083). We found that the EGFR mutation status was correlated with gender (<i>p</i> = 0.003), age (<i>p</i> = 0.015) and smoking habits (<i>p</i> = 0.007), and ALK mutation status was correlated with age (<i>p</i> = 0.002). <b><i>Conclusion:</i></b> Compared with the CBM, the MCM can improve the efficiency of DNA/RNA extraction and PCR amplification by removing impurities and enriching tumor cells. And we speculate that the successful detection rate of fresh cytological specimens was higher than that of paraffin-embedded specimens. EGFR, ALK, and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations, respectively. Targeted therapies for patients with coexisting mutations need further study.

scholarly journals Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1740
Author(s):  
John J. Park ◽  
Russell J. Diefenbach ◽  
Natalie Byrne ◽  
Georgina V. Long ◽  
Richard A. Scolyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Benefit ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Roc Curves ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Targeted Next Generation Sequencing

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) (p < 0.001) and baseline disease burden (p = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65–1.0, p = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.

scholarly journals Liquid biopsy in NSCLC: a new challenge in radiation therapy

2021 ◽  
Author(s):  
Annarita Perillo ◽  
Mohamed Vincenzo Agbaje Olufemi ◽  
Jacopo De Robbio ◽  
Rossella Margherita Mancuso ◽  
Anna Roscigno ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Biological Fluids ◽  
Circulating Tumor Dna ◽  
Minimum Residual ◽  
Nsclc Patients ◽  
Choice Of Therapy ◽  
Tumor Dna

Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide. To date, tissue biopsy has been the gold standard for the diagnosis and the identification of specific molecular mutations, to guide choice of therapy. However, this procedure has several limitations. Liquid biopsy could represent a solution to the intrinsic limits of traditional biopsy. It can detect cancer markers such as circulating tumor DNA or RNA (ctDNA, ctRNA), and circulating tumor cells, in plasma, serum or other biological fluids. This procedure is minimally invasive, reproducible and can be used repeatedly. The main clinical applications of liquid biopsy in non-small cell lung cancer (NSCLC) patients are the early diagnosis, stratification of the risk of relapse, identification of mutations to guide application of targeted therapy and the evaluation of the minimum residual disease. In this review, the current role of liquid biopsy and associated markers in the management of NSCLC patients was analyzed, with emphasis on ctDNA and CTCs, and radiotherapy.

scholarly journals Translational Application of Circulating DNA in Oncology: Review of the Last Decades Achievements

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1251 ◽  
Author(s):  
Tuaeva ◽  
Falzone ◽  
Porozov ◽  
Nosyrev ◽  
Trukhan ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Liquid Biopsy ◽  
Prognostic Significance ◽  
Circulating Tumor Dna ◽  
Molecular Techniques ◽  
Unknown Primary ◽  
Diagnostic Strategies ◽  
Early Diagnosis Of Cancer ◽  
Mutational Status ◽  
Ctdna Analysis

In recent years, the introduction of new molecular techniques in experimental and clinical settings has allowed researchers and clinicians to propose circulating-tumor DNA (ctDNA) analysis and liquid biopsy as novel promising strategies for the early diagnosis of cancer and for the definition of patients’ prognosis. It was widely demonstrated that through the non-invasive analysis of ctDNA, it is possible to identify and characterize the mutational status of tumors while avoiding invasive diagnostic strategies. Although a number of studies on ctDNA in patients’ samples significantly contributed to the improvement of oncology practice, some investigations generated conflicting data about the diagnostic and prognostic significance of ctDNA. Hence, to highlight the relevant achievements obtained so far in this field, a clearer description of the current methodologies used, as well as the obtained results, are strongly needed. On these bases, this review discusses the most relevant studies on ctDNA analysis in cancer, as well as the future directions and applications of liquid biopsy. In particular, special attention was paid to the early diagnosis of primary cancer, to the diagnosis of tumors with an unknown primary location, and finally to the prognosis of cancer patients. Furthermore, the current limitations of ctDNA-based approaches and possible strategies to overcome these limitations are presented.

Genomic architecture of gallbladder cancer: Results of a first prospective study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16628-e16628
Author(s):  
Amol Patel ◽  
H P Singh ◽  
Suresh Pandalanghat ◽  
Manish Kumar ◽  
Bhupesh Guleria ◽  
...  
Keyword(s):  
Prospective Study ◽  
Gallbladder Cancer ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Genomic Profiling ◽  
Female Ratio ◽  
Pik3ca Mutations ◽  
Phase 2 Trial ◽  
Comprehensive Genomic Profiling

e16628 Background: Rarity in western countries precluded Gallbladder cancer (GBC) from prospective research. Comprehensive Genomic profiling carries potential to determine oncogenic pathways, driver mutations and possible resistance mechanisms. This study is evaluating the role of comprehensive genomic profiling and role of targeted therapies therein. Methods: This is a single center, prospective, study conducted from Aug2018-Dec2019. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture based comprehensive genomic profiling was performed by Foundation Medicine CDx. Microsatellite instability and PDL1 expression were studied. Results: Median age was 56 years (range:26-83) with male to female ratio of 1:1.6. NGS information was available for 50 patients. ERBB pathway was aberrated in 44% of patients. ERBB2 & ERBB3 amplification was seen in 9(18%) and 2(4%) patients respectively. ERBB2 mutations were present concurrently with amplification in 3 patients. MET amplification was present in 3 (6%) PIK3CA mutations were seen in 14% of cases. PIK3CA mutations were independent of ERBB aberrations. FGFR2 mutation, FGFR2 and FGFR3 amplification was present in one patient each. NF1 and NF2 mutations were seen in three and two patients respectively. Median TMB (n = 39) was 5 mut/Mb with range of 1-14 mut/Mb. PDL1 (n = 31) of ≥ 1% was present in 32% of cases and it ranged from 1-100%. MSI (n = 39) was stable in all cases. Other somatic mutations and/or amplifications are shown in Table. Conclusions: GBC is enriched in 28% of patients with ERBB2 & ERBB3 amplifications and/or mutations. FGFR2 mutation is rare in GBC. PIK3CA aberrations are common. Phase 2 trial of frontline Trastuzumab combined with chemotherapy is ongoing. [Table: see text]

scholarly journals Circulating Tumor DNA Testing Opens New Perspectives in Melanoma Management

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2914 ◽  
Author(s):  
Alessandra Sacco ◽  
Laura Forgione ◽  
Marianeve Carotenuto ◽  
Antonella De Luca ◽  
Paolo A. Ascierto ◽  
...  
Keyword(s):  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Prognostic Information ◽  
Skin Cancers ◽  
Highly Sensitive ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna

Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease.

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