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Liquid Biopsies in Lung Cancer
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Liquid Biopsies in Lung Cancer

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 25233

Special Issue Editors

Prof. Dr. Natália Cruz-Martins

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Guest Editor
1. Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal
2. Institute for Research and Inovation in Health (i3S), University of Porto, 4099-002 Porto, Portugal
Interests: evidence-based medicine; phytochemistry; phytopharmacology; drug discovery; natural products biochemistry; bioactive molecules; functional foods; nutraceuticals; fungal and bacterial infections; resistance to antimicrobials
Special Issues, Collections and Topics in MDPI journals
Dr. Gabriela Fernandes

E-Mail Website
Guest Editor
1. Pulmonology Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
2. Faculty of Medicine, University of Porto, Porto, Portugal
Interests: thoracic tumors; oncology; tumors biology; interventional pulmonology; cancer diagnostics; cancer immunology
Dr. Vanessa Santos

E-Mail Website
Guest Editor
Pulmonology Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
Interests: oncology; interventional pulmonology; lung diseases; pulmonary rehabilitation; malignant pleural effusion; pleural tuberculosis; lung cancer

Special Issue Information

Dear Colleagues,

Tumor biopsies are considered the standard for anatomopathological and molecular diagnosis. Besides being obtained by invasive methods, they only represent a point in time and a point in space of all tumor biology and evolution. For several years, clinicians and researchers dedicated to cancer have pursued the idea of non-invasive diagnosis, through the study of peripheral blood and other bodily fluids. Indeed, tumors release parts of themselves into the circulation (e.g. free nucleic acids, tumor cells, exosomes, among others), and these elements can be extracted and analyzed. Considering that lung cancer is one of the leading causes of cancer mortality, it is of utmost interest to ensure constant progress in cancer biology comprehension. In fact, the substantial knowledge reached in lung cancer biology has led to several advances in targeted therapies and immunotherapy, while the recent achievements in sequencing technologies have made this ambition a reality. Therefore, the development of the non-invasive evaluation of tumor-releasing or tumor-associated elements, called liquid biopsy, may offer a unique opportunity to help with lung cancer screening, to detect minimal residual disease and early relapses, to detect specific mutations, to monitor the development of treatment response and resistance mechanisms, as well as to assess immunotherapy-related parameters. Currently, liquid biopsy is conceived as an inescapable reality, with special emphasis on lung cancer management. However, their inclusion in both diagnostic and therapeutic decision-making processes raises many questions. Thus, and in a broad sense, all of the questions and advances that intersect both the present and future of liquid biopsies in lung cancer management are welcome in this Special Issue. Original articles, comprehensive and critical reviews, case reports and even letters are of utmost interest, given the expansive interest of this area.

Prof. Dr. Natália Martins
Dr. Gabriela Fernandes
Dr. Vanessa Santos
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Liquid biopsies
  • Lung cancer
  • Cell-free DNA
  • Circulating tumor DNA
  • Next-generation sequencing
  • Resistance mechanisms
  • Predictive and prognostic biomarkers
  • Genetic mutations
  • Targeted therapy
  • Biological monitoring

Published Papers (7 papers)

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Research

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12 pages, 1649 KiB  
Article
Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab
by Guillaume Herbreteau, Alexandra Langlais, Laurent Greillier, Clarisse Audigier-Valette, Lionel Uwer, José Hureaux, Denis Moro-Sibilot, Florian Guisier, Delphine Carmier, Jeannick Madelaine, Josiane Otto, Pierre-Jean Souquet, Valérie Gounant, Patrick Merle, Olivier Molinier, Aldo Renault, Audrey Rabeau, Franck Morin, Marc G Denis and Jean-Louis Pujol
J. Clin. Med. 2020, 9(12), 3861; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9123861 - 27 Nov 2020
Cited by 25 | Viewed by 2805
Abstract
Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients [...] Read more.
Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. Methods: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. Results: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. Conclusion: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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18 pages, 2612 KiB  
Article
TMPRSS4: A Novel Tumor Prognostic Indicator for the Stratification of Stage IA Tumors and a Liquid Biopsy Biomarker for NSCLC Patients
by Maria Villalba, Francisco Exposito, Maria Jose Pajares, Cristina Sainz, Miriam Redrado, Ana Remirez, Ignacio Wistuba, Carmen Behrens, Eloisa Jantus-Lewintre, Carlos Camps, Luis M. Montuenga, Ruben Pio, Maria Dolores Lozano, Carlos de Andrea and Alfonso Calvo
J. Clin. Med. 2019, 8(12), 2134; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8122134 - 03 Dec 2019
Cited by 14 | Viewed by 3361
Abstract
Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification [...] Read more.
Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47–3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25–3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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17 pages, 3333 KiB  
Article
The Factors Predicting Concordant Epidermal Growth Factor Receptor (EGFR) Mutation Detected in Liquid/Tissue Biopsy and the Related Clinical Outcomes in Patients of Advanced Lung Adenocarcinoma with EGFR Mutations
by Chia-Yu Kuo, Mei-Hsuan Lee, Ming-Ju Tsai, Chih-Jen Yang, Jen-Yu Hung and Inn-Wen Chong
J. Clin. Med. 2019, 8(11), 1758; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111758 - 23 Oct 2019
Cited by 10 | Viewed by 2457
Abstract
Liquid biopsy to identify epidermal growth factor receptor (EGFR) gene mutations from circulating tumor DNA (ctDNA) for lung adenocarcinoma is less invasive than traditional tissue biopsy. Most patients have concordant results in liquid/tissue biopsy, while the clinical significance of concordant results [...] Read more.
Liquid biopsy to identify epidermal growth factor receptor (EGFR) gene mutations from circulating tumor DNA (ctDNA) for lung adenocarcinoma is less invasive than traditional tissue biopsy. Most patients have concordant results in liquid/tissue biopsy, while the clinical significance of concordant results remains unclear. Our study aimed to evaluate the predicting factors and clinical outcomes associated with concordant results in liquid/tissue biopsy in newly diagnosed lung adenocarcinoma patients with EGFR mutations. In the 80 patients of stage III or IV lung adenocarcinoma, 51 patients had EGFR mutations detected in tissue samples, while 33 (65%) of them had concordant results shown in liquid biopsy. Multivariable regression analysis showed that lymph node involvement (adjusted odds ratio (95% CI): 8.71 (1.88–40.35), p = 0.0057) and bone metastasis (adjusted odds ratio (95% CI): 9.65 (1.72–54.05), p = 0.0099) were the independent predicting factors for concordant results. Forty of these 51 patients were stage IV and were treated with EGFR tyrosine kinase inhibitors (TKIs). The concordant results in liquid/tissue samples were associated with significantly poorer progression-free survival (PFS) in univariate analysis. However, multivariable analysis showed that lymph node involvement was the only independent predicting factor for poorer PFS, while concordant results in liquid/tissue samples were excluded during variable selection. The concordant results in liquid/tissue samples might indicate a larger tumor burden, which actually contributes to poorer PFS. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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14 pages, 1269 KiB  
Article
Subtyping Lung Cancer Using DNA Methylation in Liquid Biopsies
by Sandra P. Nunes, Francisca Diniz, Catarina Moreira-Barbosa, Vera Constâncio, Ana Victor Silva, Júlio Oliveira, Marta Soares, Sofia Paulino, Ana Luísa Cunha, Jéssica Rodrigues, Luís Antunes, Rui Henrique and Carmen Jerónimo
J. Clin. Med. 2019, 8(9), 1500; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091500 - 19 Sep 2019
Cited by 35 | Viewed by 4632
Abstract
Background: Lung cancer (LCa) is the most frequently diagnosed and lethal cancer worldwide. Histopathological subtyping, which has important therapeutic and prognostic implications, requires material collection through invasive procedures, which might be insufficient to enable definitive diagnosis. Aberrant DNA methylation is an early event [...] Read more.
Background: Lung cancer (LCa) is the most frequently diagnosed and lethal cancer worldwide. Histopathological subtyping, which has important therapeutic and prognostic implications, requires material collection through invasive procedures, which might be insufficient to enable definitive diagnosis. Aberrant DNA methylation is an early event in carcinogenesis, detectable in circulating cell-free DNA (ccfDNA). Herein, we aimed to assess methylation of selected genes in ccfDNA from LCa patients and determine its accuracy for tumor subtyping. Methods: Methylation levels of APC, HOXA9, RARβ2, and RASSF1A were assessed in three independent study groups (study group #1: 152 tissue samples; study group #2: 129 plasma samples; study group #3: 28 benign lesions of lung) using quantitative methylation-specific PCR. Associations between gene promoter methylation levels and LCa subtypes were evaluated using non-parametric tests. Receiver operating characteristic (ROC) curve analysis was performed. Results: In study group #2, HOXA9 and RASSF1A displayed higher methylation levels in small-cell lung cancer (SCLC) than in non-small-cell lung cancer (NSCLC). HOXA9 displayed high sensitivity (63.8%), whereas RASSF1A disclosed high specificity (96.2%) for SCLC detection in ccfDNA. Furthermore, HOXA9 methylation levels showed to be higher in squamous cell carcinoma in comparison with adenocarcinoma in study group #1. Conclusions: Methylation level assessments in ccfDNA may provide a minimally invasive procedure for LCa subtyping, complementing standard diagnostic procedures. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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12 pages, 671 KiB  
Article
Prognostic Relevance of Circulating Tumor Cells and Circulating Cell-Free DNA Association in Metastatic Non-Small Cell Lung Cancer Treated with Nivolumab
by Angela Alama, Simona Coco, Carlo Genova, Giovanni Rossi, Vincenzo Fontana, Marco Tagliamento, Maria Giovanna Dal Bello, Alessandra Rosa, Simona Boccardo, Erika Rijavec, Federica Biello, Luca Longo, Zita Cavalieri, Cristina Bruzzo and Francesco Grossi
J. Clin. Med. 2019, 8(7), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8071011 - 10 Jul 2019
Cited by 39 | Viewed by 3035
Abstract
The treatment of advanced non-small cell lung cancer (NSCLC) has been revolutionized by immune checkpoint inhibitors (ICIs). The identification of prognostic and predictive factors in ICIs-treated patients is presently challenging. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) were evaluated in 89 previously [...] Read more.
The treatment of advanced non-small cell lung cancer (NSCLC) has been revolutionized by immune checkpoint inhibitors (ICIs). The identification of prognostic and predictive factors in ICIs-treated patients is presently challenging. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) were evaluated in 89 previously treated NSCLC patients receiving nivolumab. Blood samples were collected before therapy and at the first and second radiological response assessments. CTCs were isolated by a filtration-based method. cfDNA was extracted from plasma and estimated by quantitative PCR. Patients with baseline CTC number and cfDNA below their median values (2 and 836.5 ng from 3 mL of blood and plasma, respectively) survived significantly longer than those with higher values (p = 0.05 and p = 0.04, respectively). The two biomarkers were then used separately and jointly as time-dependent covariates in a regression model confirming their prognostic role. Additionally, a four-fold risk of death for the subgroup presenting both circulating biomarkers above the median values was observed (p < 0.001). No significant differences were found between circulating biomarkers and best response. However, progressing patients with concomitant lower CTCs and cfDNA performed clinically well (p = 0.007), suggesting that jointed CTCs and cfDNA might help discriminate a low-risk population which might benefit from continuing ICIs beyond progression. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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Review

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19 pages, 1588 KiB  
Review
The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer
by D. Akhoundova, J. Mosquera Martinez, L. E. Musmann, C. Britschgi, C. Rütsche, M. Rechsteiner, E. Nadal, M. R. Garcia Campelo and A. Curioni-Fontecedro
J. Clin. Med. 2020, 9(11), 3674; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9113674 - 16 Nov 2020
Cited by 9 | Viewed by 2977
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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24 pages, 1159 KiB  
Review
Liquid Biopsy for the Detection of Resistance Mechanisms in NSCLC: Comparison of Different Blood Biomarkers
by Luigi Pasini and Paola Ulivi
J. Clin. Med. 2019, 8(7), 998; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8070998 - 09 Jul 2019
Cited by 27 | Viewed by 5135
Abstract
The use of targeted agents and immunotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) has made it mandatory to characterize tumor tissue for patient selection. Moreover, the development of agents that are active against specific resistance mechanisms arising during treatment make [...] Read more.
The use of targeted agents and immunotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) has made it mandatory to characterize tumor tissue for patient selection. Moreover, the development of agents that are active against specific resistance mechanisms arising during treatment make it equally important to characterize the tumor tissue at progression by performing tissue re-biopsy. Given that tumor tissue is not always available for molecular characterization due to the paucity of diagnostic specimens or problems relating to the carrying out of invasive procedures, the use of liquid biopsy represents a valid approach to overcoming these difficulties. The most common material used for liquid biopsy in this setting is plasma-derived cell free DNA (cfDNA), which originates from cells undergoing apoptosis or necrosis. However, other sources of tumor material can be considered, such as extracellular vesicle (EV)-derived nucleic acids, which are actively secreted from living cells and closely correspond to tumor dynamics. In this review, we discuss the role of liquid biopsy in the therapeutic management of NSCLC with particular regard to targeted therapy and immunotherapy, and analyze the pros and cons of the different types of samples used in this context. Full article
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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