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 The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

2020 ◽  
Vol 9 (11) ◽  
pp. 3674
Author(s):  
D. Akhoundova ◽  
J. Mosquera Martinez ◽  
L. E. Musmann ◽  
C. Britschgi ◽  
C. Rütsche ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Practice ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Clinical Management ◽  
Circulating Tumor Dna ◽  
Precision Oncology ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Molecular Alterations

Liquid biopsy is a rapidly emerging tool of precision oncology enabling minimally invasive molecular diagnostics and longitudinal monitoring of treatment response. For the clinical management of advanced stage lung cancer patients, detection and quantification of circulating tumor DNA (ctDNA) is now widely adopted into clinical practice. Still, interpretation of results and validation of ctDNA-based treatment decisions remain challenging. We report here our experience implementing liquid biopsies into the clinical management of lung cancer. We discuss advantages and limitations of distinct ctDNA assay techniques and highlight our approach to the analysis of recurrent molecular alterations found in lung cancer. Moreover, we report three exemplary clinical cases illustrating the complexity of interpreting liquid biopsy results in clinical practice. These cases underscore the potential and current limitations of liquid biopsy, focusing on the difficulty of interpreting discordant findings. In our view, despite all current limitations, the analysis of ctDNA in lung cancer patients is an essential and highly versatile complementary diagnostic tool for the clinical management of lung cancer patients in the era of precision oncology.

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.

Real-world data on liquid biopsies utilization in lung cancer patients in the community setting: The Mount Sinai experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21502-e21502
Author(s):  
Kathrin Dvir ◽  
Gliceida Galarza Fortuna ◽  
Joel M. Haines ◽  
Leylah Drusbosky ◽  
Christopher Febres-Aldana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Real World ◽  
Community Setting ◽  
Circulating Tumor Dna ◽  
Liquid Biopsies ◽  
Real World Data ◽  
World Data ◽  
Lung Cancer Patients ◽  
Synonymous Mutations ◽  
Variants Of Unknown Significance

e21502 Background: Liquid biopsy describes the extraction of circulating tumor DNA (ctDNA) from peripheral blood via next-generation-sequencing (NGS). The yield of adding plasma-based NGS to tissue NGS for the detection of Actionable Mutations (AM) have been reported scarcely and additional “real world” data is needed. Methods: In this retrospective data review, we included patients with non-small cell lung cancer (NSCLC) who had plasma NGS genomic testing ordered between Nov 2014 and July 2019, as part of routine management. Plasma testing was performed using Guardant360 commercial platform and was analyzed for therapeutically AM in: EGFR, ALK, MET, BRCA1, BRCA2, KRAS, ROS1, RET, ERBB2, BRAF, and NTRK2. Results: Over a period of 5 years, 337 samples taken from 279 patients were sent for ctDNA NGS testing. The median age at diagnosis was 73 years [range 36-93, SD:10.4], 51% (N=141) were males and 49% (N=138) were females. Excluding synonymous mutations and variants of unknown significance, 239 samples (71%) and 201 patients (72%) had 705 somatic mutations. Of them, 36% (N=254) were therapeutically actionable and were detected in 139 samples (58%), taken from 106 patients (53%). Commonly detected AM were EGFR (N=127; 50%), KRAS (N=61; 24%), BRAF (N=24; 9.5%), MET (N=23; 9%), RET (N=5; 1.9%), BRCA1 (N=5; 1.9%), BRCA2 (N=4; 1.6%), ERBB2 (N=4; 1.6%) and ALK (N=1, 0.4%). None of the samples had mutations in ROS1, NTRK2. One patient had Microsatellite instability (MSI). Common co-occurring mutations were EGFR and BRAF (N=14), EGFR and MET (N=13) and MET and BRAF (N=10) (p<0.001). Common mutually exclusive mutations were KRAS and EGFR (p<0.001). Tissue NGS analysis was performed in 62/106 patients (58%), with AM found in 45 patients (72%). Concordance agreement in AM between plasma and tissue NGS modalities was detected in 39/45 patients (87%) and was demonstrated in EGFR (N=25), KRAS (N=11), BRAF (N=2) and MET (N=1). In the reminder 6 patients (13%), tissue NGS was discordant from their plasma NGS results. In 44/106 patients, for whom tissue sampling was not performed, utilizing plasma NGS increased AM detection yield by 41%. Conclusions: Integration of plasma NGS testing into the routine management of NSCLC patients demonstrated substantial yield of therapeutically targetable mutations detection rate, when tissue NGS was not available.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR -mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
First Line ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites. Conclusion Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

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 Plasma circulating tumor DNA-based genetic profiling of lung cancer patients in Vietnam using ultra-deep massive parallel sequencing with unique identifier tagging.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 58-58
Author(s):  
Huy Phuoc Do ◽  
Thao Thanh Tran Nguyen ◽  
Uyen Vu Tran ◽  
Thanh-Truong Tran ◽  
Anh-Thu Huynh Dang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsy ◽  
Circulating Tumor Dna ◽  
Massive Parallel Sequencing ◽  
Driver Mutations ◽  
Unique Identifier ◽  
Parallel Sequencing ◽  
Cancer Driver ◽  
Lung Cancer Patients ◽  
Tumor Dna

58 Background: Lung cancer is by far the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Genotype-directed therapy becomes a promising method for cancer treatment beside surgery and chemo-radiotherapy. Liquid biopsy using massive parallel sequencing has emerged as a non-invasive alternative procedure in profiling cancer driver mutations. In this study, we report the spectrum of clinically actionable mutations in plasma circulating tumor DNA of 299 non-small cell lung cancer patients using ultra-deep massive parallel sequencing with unique identifier tagging. Methods: Plasma circulating tumor DNA was extracted, ligated with unique identifier (Swift Bioscience), enriched of the target coding regions of EGFR, KRAS, NRAS, BRAF and the breakpoints of ALK, ROS1 (IDT) and sequenced using NextSeq 550 (Illumina) at mean coverage depth of 20,000X. Results: Out of 299 patients tested, 128 (42,8%) carried driver mutations. Genetic alterations were identified in EGFR (79 samples, 26,4%), KRAS (30 samples, 10%), ALK (7 samples, 2,34%), ROS1 (6 samples, 2%), BRAF (3 samples, 1%). There was no sample with NRAS mutation. In 79 EGFR-cases, there were 23 carry two pathogenic variants. 28 mutation types of EGFR were found including 19 indels and 9 missense variants L858R and T790M were the major ones. One case was found with concomitant EGFR and BRAF. Our study showed the spectrum and frequency of the cancer driver mutations detected in liquid biopsy was correlated to those detected in tissue biopsy samples. Conclusions: For the first time the spectrum of mutation types in liquid biopsy of Vietnamese NSCLC patients were investigated and showed the correlation with those detected in tissue biopsy samples.

Detection of low abundant mutants from circulating tumor DNA of plasma, pleural effusion, and cerebrospinal fluid of lung cancer patients using a novel mutant-capture enrichment approach.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14520-e14520
Author(s):  
Rui Lin ◽  
Yue Pu ◽  
Li Mao
Keyword(s):  
Lung Cancer ◽  
Cerebrospinal Fluid ◽  
Pleural Effusion ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Lung Cancer Patients ◽  
Egfr Tki ◽  
Tumor Dna

e14520 Background: In the era of precision medicine, liquid biopsy analysis is well accepted based on advantages including availability, non-invasiveness, and non-heterogeneity. However, the circulating tumor DNA (ctDNA) in liquid biopsy is diluted by a large excess of wild-type alleles, which necessitates high sensitivity approach for ctDNA detection. In addition, ctDNA analysis from different liquid biopsy samples need to be evaluated. Methods: We have developed a novel mutant-capture based method, termed PErsonalized Analysis of Cancer (PEAC), for high sensitivity detection of cancer driver mutants at abundance as low as 0.01-0.1% for circulating free DNA (cfDNA) standards. ctDNA samples were extracted from body fluids of lung cancer patients including plasma, pleural effusion and cerebrospinal fluid. EGFR mutants predictive of EGFR tyrosine kinase activity were enriched using PEAC technology, and analyzed using Sanger sequencing. Results: Plasma ctDNA samples B7110003, B7110010, and B7112012 had no or barely detectable L858R mutation, which was enriched to 50-90% after PEAC and readily detected by Sanger. T790M was undetectable before PEAC in plasma sample B7112052 and became 50% after PEAC enrichment. Pleural effusion samples E8106029 and E8111305 had dominated L858R and T790M peaks, respectively, in Sanger chromatograms after PEAC, which was almost to the background levels prior to PEAC. Interestingly, both EGFR L858R and T790M mutants were detected in pleural effusion sample E8106029 after PEAC; the sample was from a patient who had previously treated with an EGFR tyrosine kinase inhibitor (TKI), suggestive of resistance developed after target therapy and the utility of PEAC in monitoring patient’s response to EGFR TKI. In addition to enriching point mutations, we also established enrichment of the most frequently occurred EGFR 19 deletion, E746_A750del (c. 2235_2249 del15), which were dominant after PEAC enrichment of ctDNA from plasma samples (B8101186 and B8101241), pleural effusion (E8108088) and cerebrospinal fluid (C8108095); the mutants were undetectable without PEAC enrichment. Conclusions: PEAC technology can enrich ctDNA from body fluids in lung cancer patients and allow detection of low abundant mutants predictive for EGFR TKI therapy. With further validation, the technology may improve current detection methods used in clinical practice.

scholarly journals Role of Circulating Tumor DNA in Hematological Malignancy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2078
Author(s):  
Miho Ogawa ◽  
Kazuaki Yokoyama ◽  
Seiya Imoto ◽  
Arinobu Tojo
Keyword(s):  
Liquid Biopsy ◽  
Hematological Malignancies ◽  
Residual Disease ◽  
Current Knowledge ◽  
Circulating Tumor Dna ◽  
Liquid Biopsies ◽  
Recent Advances ◽  
Minimal Residual Disease Monitoring ◽  
Tumor Dna

With the recent advances in noninvasive approaches for cancer diagnosis and surveillance, the term “liquid biopsy” has become more familiar to clinicians, including hematologists. Liquid biopsy provides a variety of clinically useful genetic data. In this era of personalized medicine, genetic information is critical to early diagnosis, aiding risk stratification, directing therapeutic options, and monitoring disease relapse. The validity of circulating tumor DNA (ctDNA)-mediated liquid biopsies has received increasing attention. This review summarizes the current knowledge of liquid biopsy ctDNA in hematological malignancies, focusing on the feasibility, limitations, and key areas of clinical application. We also highlight recent advances in the minimal residual disease monitoring of leukemia using ctDNA. This article will be useful to those involved in the clinical practice of hematopoietic oncology.

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