|
1
|
Galant N, Grenda A, Krawczyk P, Pięt M, Milanowski J. Liquid biopsy in diagnosis and monitoring of treatment efficacy in patients with small cell lung cancer. Mol Biol Rep 2025; 52:455. [PMID: 40358752 PMCID: PMC12075280 DOI: 10.1007/s11033-025-10569-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025]
Abstract
Small-cell lung cancer (SCLC) remains one of the deadliest cancers worldwide. Patients' survival remains poor due to its rapid growth, high metastatic rate and limited possibilities of treatment. For many years, SCLC management has been based mostly on chemo and radiotherapy. However, new therapeutic approaches have been proposed in the past few years, including immunotherapy, which is currently implemented in clinical practice. Unfortunately, in many cases, response to therapy, especially chemotherapy, remains poor, or the patient becomes resistant to initially effective treatment. One of the crucial problems during SCLC patient care is a lack of appropriate predictive biomarkers for various therapeutic approaches. Another critical issue is the scarcity of collected tissue during biopsy, which may be insufficient or of too poor quality for analysis. A liquid biopsy might be the key to solving both of those problems as it is collected in a non-invasive way and enables the measurement of various biomarkers, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). In this review, we discuss various approaches to potentially incorporating liquid biopsy into clinical application - as a companion to imaging during SCLC diagnostics, a new approach to molecular subtyping, and a material enabling predictive or prognostic biomarkers assessment. We also summarize ongoing clinical trials encompassing SCLC patients in which liquid biopsy is collected and examined.
Collapse
Affiliation(s)
- Natalia Galant
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
| | - Anna Grenda
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Mateusz Pięt
- Department of Virology and Immunology, Maria Curie-Skłodowska University, Lublin, Poland
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| |
Collapse
|
|
2
|
Celik Demirbas B, Kilic Erciyas S, Sukruoglu Erdogan O, Pasin O, Yalniz Kayim Z, Özgel MÇ, Tuncer SB. Genetic insights into BRCA1/2 associated breast cancer in Türkiye: focus on early-onset and aggressive subtypes. Discov Oncol 2025; 16:746. [PMID: 40355587 PMCID: PMC12069179 DOI: 10.1007/s12672-025-02192-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025] Open
Abstract
AIM The prevalence of BRCA1/2 pathogenic variants among Turkish breast cancer (BC) patients is not well-characterized. We specifically examine the age at onset and cancer sub-types concerning BRCA1/2 mutation status, focusing on patients with no family history of breast or ovarian cancer. METHODS Peripheral blood samples were collected from 3184 BC patients applied to the Istanbul University Oncology Institute. Genetic testing for BRCA1/2 mutations was conducted using the Illumina MiSeq® platform, with variant classification performed according to ACMG criteria. RESULTS Among the 3184 patients, 2764 (86.8%) were BRCA1/2-, while 247 (7.8%) were BRCA1 + and 173 (5.4%) were BRCA2 + . The mean age at BC onset was significantly lower in BRCA1 + (39.73 years) and BRCA2 + (41.07 years) patients compared to BRCA1/2- patients (43.17 years, p < 0.001). Among patients with no family history, HER2 positive cases had a significantly higher mean age at onset than Triple-Negative Breast Cancer(TNBC) cases (41.78 years vs. 40.44 years, p = 0.017). CONCLUSIONS This study highlights the strong association between BRCA1/2 + mutations and earlier BC onset, particularly in patients with no family history of breast or ovarian cancer in Türkiye.
Collapse
Affiliation(s)
- Betul Celik Demirbas
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Seda Kilic Erciyas
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Ozge Sukruoglu Erdogan
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Ozge Pasin
- Department of Biostatistics and Medical Informatics, Hamidiye Medical Faculty, University of Health Sciences, Istanbul, Türkiye
| | - Zubeyde Yalniz Kayim
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Merve Çiğdem Özgel
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Seref Bugra Tuncer
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye.
| |
Collapse
|
|
3
|
Pastò B, Vida R, Dri A, Foffano L, Della Rossa S, Gerratana L, Puglisi F. Beyond Hormone Receptors: liquid biopsy tools to unveil new clinical meanings and empower therapeutic decision-making in Luminal-like metastatic breast cancer. Breast 2025; 79:103859. [PMID: 39708442 PMCID: PMC11872398 DOI: 10.1016/j.breast.2024.103859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 10/29/2024] [Accepted: 12/11/2024] [Indexed: 12/23/2024] Open
Abstract
Immunohistochemical (IHC) tissue profiling is a standard practice in the management of metastatic breast cancer (mBC), that enables the identification of distinct biological phenotypes based on hormone receptors' expression. Luminal-like tumors primarily benefit from a first line treatment strategy combining endocrine therapy and cyclin-dependent kinase 4/6 inhibitors. However, IHC analyses necessitate invasive procedures and may encounter technical and interpretational challenges. In the current era of precision medicine, liquid biopsy holds potential to provide clinicians with additional insights into disease biology, including mechanisms underlying endocrine resistance and disease progression. Several liquid-based biomarkers are entering clinical practice and hold prognostic and predictive values in Luminal-like mBC, while many others are currently being investigated. The present work aims to summarize the current evidence regarding the clinical meanings of hormone receptors and their downstream molecular pathways, alongside their implications for therapeutic decision-making in Luminal-like mBC.
Collapse
Affiliation(s)
- Brenno Pastò
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy
| | - Riccardo Vida
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy
| | - Arianna Dri
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy
| | - Lorenzo Foffano
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy
| | - Serena Della Rossa
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy
| | - Lorenzo Gerratana
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy.
| | - Fabio Puglisi
- Department of Medicine (DMED), University of Udine, 33100, Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy
| |
Collapse
|
|
4
|
Zhang W, Ye B, Song Y, Yang P, Si W, Jing H, Yang F, Yuan D, Wu Z, Lyu J, Peng K, Zhang X, Wang L, Li Y, Liu Y, Wu C, Hao X, Zhang Y, Qi W, Wang J, Dong F, Zhao Z, Jing H, Li Y. Integrating multi-omics features enables non-invasive early diagnosis and treatment response prediction of diffuse large B-cell lymphoma. Clin Transl Med 2025; 15:e70174. [PMID: 39776291 PMCID: PMC11705727 DOI: 10.1002/ctm2.70174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/13/2024] [Accepted: 12/28/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Multi-omics features of cell-free DNA (cfDNA) can effectively improve the performance of non-invasive early diagnosis and prognosis of cancer. However, multimodal characterization of cfDNA remains technically challenging. METHODS We developed a comprehensive multi-omics solution (COMOS) to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. The COMOS was tested on 214 plasma samples of diffuse large B-cell lymphoma (DLBCL) and matched healthy controls. RESULTS For early diagnosis, COMOS improved the area under the curve (AUC) value to .993 compared with the individual omics model, with a sensitivity of 95% at 98% specificity. Detection sensitivity achieved 91% at 99% specificity in early-stage patients, while the AUC values of the individual omics model were 0.942, 0.968, 0.989, 0.935, 0.921, 0.781 and 0.917, respectively, with lower sensitivity and specificity. In the treatment response cohort, COMOS yielded a superior sensitivity of 88% at 86% specificity (AUC, 0.903). COMOS has achieved excellent performance in early diagnosis and treatment response prediction. CONCLUSIONS Our study provides an effectively improved approach with high accuracy for the diagnosis and prognosis of DLBCL, showing great potential for future clinical application. KEY POINTS A comprehensive multi-omics solution to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. Integrated model of cfDNA multi-omics could be used for non-invasive early diagnosis of DLBCL. Integrated model of cfDNA multi-omics could effectively evaluate the efficacy of R-CHOP before DLBCL treatment.
Collapse
MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/blood
- Female
- Male
- Middle Aged
- Aged
- Adult
- Early Detection of Cancer/methods
- Prognosis
- Cell-Free Nucleic Acids/blood
- Cell-Free Nucleic Acids/analysis
- Rituximab/therapeutic use
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Doxorubicin/therapeutic use
- Early Diagnosis
- Cyclophosphamide/therapeutic use
- Multiomics
Collapse
Affiliation(s)
- Weilong Zhang
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | | | - Yang Song
- BOE Technology Group Co., LtdBeijingChina
| | - Ping Yang
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Wenzhe Si
- Department of Laboratory MedicinePeking University Third HospitalBeijingChina
| | | | - Fan Yang
- BOE Technology Group Co., LtdBeijingChina
| | - Dan Yuan
- BOE Technology Group Co., LtdBeijingChina
| | - Zhihong Wu
- BOE Technology Group Co., LtdBeijingChina
| | - Jiahao Lyu
- BOE Technology Group Co., LtdBeijingChina
| | - Kang Peng
- BOE Technology Group Co., LtdBeijingChina
| | - Xu Zhang
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Lingli Wang
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Yan Li
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Yan Liu
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Chaoling Wu
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Xiaoyu Hao
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Yuqi Zhang
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Wenxin Qi
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Jing Wang
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Fei Dong
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | | | - Hongmei Jing
- Department of HematologyLymphoma Research CenterPeking University Third HospitalBeijingChina
| | - Yanzhao Li
- BOE Technology Group Co., LtdBeijingChina
| |
Collapse
|
|
5
|
Harary PM, Rajaram S, Chen MS, Hori YS, Park DJ, Chang SD. Genomic predictors of radiation response: recent progress towards personalized radiotherapy for brain metastases. Cell Death Discov 2024; 10:501. [PMID: 39695143 DOI: 10.1038/s41420-024-02270-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
Radiotherapy remains a key treatment modality for both primary and metastatic brain tumors. Significant technological advances in precision radiotherapy, such as stereotactic radiosurgery and intensity-modulated radiotherapy, have contributed to improved clinical outcomes. Notably, however, molecular genetics is not yet widely used to inform brain radiotherapy treatment. By comparison, genetic testing now plays a significant role in guiding targeted therapies and immunotherapies, particularly for brain metastases (BM) of lung cancer, breast cancer, and melanoma. Given increasing evidence of the importance of tumor genetics to radiation response, this may represent a currently under-utilized means of enhancing treatment outcomes. In addition, recent studies have shown potentially actionable mutations in BM which are not present in the primary tumor. Overall, this suggests that further investigation into the pathways mediating radiation response variability is warranted. Here, we provide an overview of key mechanisms implicated in BM radiation resistance, including intrinsic and acquired resistance and intratumoral heterogeneity. We then discuss advances in tumor sampling methods, such as a collection of cell-free DNA and RNA, as well as progress in genomic analysis. We further consider how these tools may be applied to provide personalized radiotherapy for BM, including patient stratification, detection of radiotoxicity, and use of radiosensitization agents. In addition, we describe recent developments in preclinical models of BM and consider their relevance to investigating radiation response. Given the increase in clinical trials evaluating the combination of radiotherapy and targeted therapies, as well as the rising incidence of BM, it is essential to develop genomically informed approaches to enhance radiation response.
Collapse
Affiliation(s)
- Paul M Harary
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Sanjeeth Rajaram
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Maggie S Chen
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
- Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Yusuke S Hori
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - David J Park
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
| | - Steven D Chang
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
6
|
Zameer MZ, Jou E, Middleton M. The role of circulating tumor DNA in melanomas of the uveal tract. Front Immunol 2024; 15:1509968. [PMID: 39697328 PMCID: PMC11652350 DOI: 10.3389/fimmu.2024.1509968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024] Open
Abstract
Melanoma of the uveal tract or uveal melanoma (UM) originates from melanocytes of the eye and is the most common intraocular malignancy in adults. Despite considerable advances in diagnostic procedures and treatments, prognosis remains poor in those with advanced disease. Accordingly, although current treatments have an excellent local disease control rate, approximately 50% of patients develop metastatic relapse within 10 years. The high risk for metastatic disease with a variable and often long latency period is thought to be due to early spread of cancer cells disseminating into organs such as the liver, followed by a period of dormancy, before the eventual emergence of radiologically measurable disease. Early detection of disease relapse or metastasis is therefore crucial to allow timely treatment and ultimately improve patient outcome. Recently, advances in minimally-invasive liquid biopsy techniques and biomarkers such as circulating tumor DNA (ctDNA) have demonstrated potential to transform the field of cancer care by aiding diagnosis, prognosis and monitoring of various cancer types. UM is particularly suitable for ctDNA-based approaches due to the relatively well-characterized spectrum of genetic mutations, along with the inherent difficulties and risks associated with getting sufficient tumor samples via traditional biopsy methods. Key potential advantage of ctDNA are the detection of molecular residual disease (MRD) in patients post definitive treatment, and in the early identification of metastasis. This is particularly relevant contemporarily with the recent demonstration of tebentafusp improving survival in metastatic UM patients, and opens avenues for further research to investigate the potential utilization of tebentafusp combined with ctDNA-based strategies in adjuvant settings and early intervention for MRD. The present review illustrates the current understanding of ctDNA-based strategies in UM, discusses the potential clinical applications, explores the potential of utilizing ctDNA in UM MRD in the context of an ongoing clinical trial, and highlights the challenges that need to be overcome prior to routine clinical implementation.
Collapse
Affiliation(s)
- Mohammed Zeeshan Zameer
- Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Eric Jou
- Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
- Kellogg College, University of Oxford, Oxford, United Kingdom
| | - Mark Middleton
- Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
7
|
Chen J, Liu X, Zhang Z, Su R, Geng Y, Guo Y, Zhang Y, Su M. Early Diagnostic Markers for Esophageal Squamous Cell Carcinoma: Copy Number Alteration Gene Identification and cfDNA Detection. J Transl Med 2024; 104:102127. [PMID: 39182610 DOI: 10.1016/j.labinv.2024.102127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/17/2024] [Accepted: 08/19/2024] [Indexed: 08/27/2024] Open
Abstract
The high mortality rate of esophageal squamous cell carcinoma (ESCC) is exacerbated by the absence of early diagnostic markers. The pronounced heterogeneity of mutations in ESCC renders copy number alterations (CNAs) more prevalent among patients. The identification of CNA genes within esophageal squamous dysplasia (ESD), a precancerous stage of ESCC, is crucial for advancing early detection efforts. Utilization of liquid biopsies via droplet-based digital PCR (ddPCR) offers a novel strategy for detecting incipient tumor traces. This study undertook a thorough investigation of CNA profiles across ESCC development stages, integrating data from existing databases and prior investigations to pinpoint and confirm CNA markers conducive to early detection of ESCC. Targeted sequencing was employed to select potential early detection genes, followed by the establishment of prediction models for ESCC early detection using ddPCR. Our analysis revealed widespread CNAs during the ESD stage, mirroring the CNA landscape observed in ESCC. A total of 40 CNA genes were identified as highly frequent in both ESCC and ESD lesions, through a comprehensive gene-level CNA analysis encompassing ESD and ESCC tissues, ESCC cell lines, and pan-cancer data sets. Subsequent validation of 5 candidate markers via ddPCR underscored the efficacy of combined predictive models encompassing PIK3CA, SOX2, EGFR, MYC, and CCND1 in early ESCC screening, as evidenced by the area-under-the-curve values exceeding 0.92 (P < .0001) across various detection contexts. The findings highlighted the significant utility of CNA genes in the early screening of ESCC, presenting robust models that could facilitate early detection, broad-scale population screening, and adjunctive diagnosis.
Collapse
Affiliation(s)
- Jiamin Chen
- Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China
| | - Xi Liu
- Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China
| | - Zhihua Zhang
- Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China
| | - Ruibing Su
- Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China; Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Yiqun Geng
- Department of Molecular Pathology, Shantou University Medical College, Shantou, China
| | - Yi Guo
- Department of Endoscopy, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Yimin Zhang
- Clinical Research Center, Shantou Central Hospital, Shantou, China
| | - Min Su
- Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China.
| |
Collapse
|
|
8
|
Wang W, Huang Y, Kong J, Lu L, Liao Q, Zhu J, Wang T, Yan L, Dai M, Chen Z, You J. Plasma ctDNA enhances the tissue-based detection of oncodriver mutations in colorectal cancer. Clin Transl Oncol 2024; 26:1976-1987. [PMID: 38777950 PMCID: PMC11249419 DOI: 10.1007/s12094-024-03422-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/24/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE The advent of circulating tumor DNA (ctDNA) technology has provided a convenient and noninvasive means to continuously monitor cancer genomic data, facilitating personalized cancer treatment. This study aimed to evaluate the supplementary benefits of plasma ctDNA alongside traditional tissue-based next-generation sequencing (NGS) in identifying targetable mutations and tumor mutational burden (TMB) in colorectal cancers (CRC). METHODS Our study involved 76 CRC patients, collecting both tissue and plasma samples for NGS. We assessed the concordance of gene mutational status between ctDNA and tissue, focusing on actionable genes such as KRAS, NRAS, PIK3CA, BRAF, and ERBB2. Logistic regression analysis was used to explore variables associated with discordance and positive mutation rates. RESULTS In total, 26 cancer-related genes were identified. The most common variants in tumor tissues and plasma samples were in APC (57.9% vs 19.7%), TP53 (55.3% vs 22.4%) and KRAS (47.4% vs 43.4%). Tissue and ctDNA showed an overall concordance of 73.53% in detecting actionable gene mutations. Notably, plasma ctDNA improved detection for certain genes and gene pools. Variables significantly associated with discordance included gender and peritoneal metastases. TMB analysis revealed a higher detection rate in tissues compared to plasma, but combining both increased detection. CONCLUSIONS Our study highlights the importance of analyzing both tissue and plasma for detecting actionable mutations in CRC, with plasma ctDNA offering added value. Discordance is associated with gender and peritoneal metastases, and TMB analysis can benefit from a combination of tissue and plasma data. This approach provides valuable insights for personalized CRC treatment.
Collapse
Affiliation(s)
- Wei Wang
- The First People's Hospital of Foshan, Foshan, 528000, Guangdong, China
| | - Yisen Huang
- Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362002, Fujian, China
| | - Jianqiao Kong
- Department of General Surgery, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, 441000, Hubei, China
| | - Lin Lu
- Colorectal Surgery Department, General Hospital of Ningxia Medical University, Yinchuan, 750001, Ningxia, China
| | - Qianxiu Liao
- Department of Laboratory Medicine, Chengdu First People's Hospital, Chengdu, 610041, Sichuan, China
| | - Jingtao Zhu
- The Third Clinical Medical College, Fujian Medical University, Xiamen, 361001, Fujian, China
| | - Tinghao Wang
- The Third Clinical Medical College, Fujian Medical University, Xiamen, 361001, Fujian, China
| | - Linghua Yan
- Shanghai Tongshu Biotechnology Co., Ltd, Shanghai, 201900, China
| | - Min Dai
- Department of Pathology, Wuhu Hospital, East China Normal University (The Second People's Hospital, Wuhu), Wuhu, 241000, Anhui, China.
| | - Zhan Chen
- Department of General Surgery, Chenggong Hospital of Xiamen University School of Medicine, Xiamen, 361001, Fujian, China.
| | - Jun You
- Department of Gastrointestinal Oncology Surgery, Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361001, Fujian, China.
| |
Collapse
|
|
9
|
Seyhan AA. Circulating Liquid Biopsy Biomarkers in Glioblastoma: Advances and Challenges. Int J Mol Sci 2024; 25:7974. [PMID: 39063215 PMCID: PMC11277426 DOI: 10.3390/ijms25147974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Gliomas, particularly glioblastoma (GBM), represent the most prevalent and aggressive tumors of the central nervous system (CNS). Despite recent treatment advancements, patient survival rates remain low. The diagnosis of GBM traditionally relies on neuroimaging methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scans and postoperative confirmation via histopathological and molecular analysis. Imaging techniques struggle to differentiate between tumor progression and treatment-related changes, leading to potential misinterpretation and treatment delays. Similarly, tissue biopsies, while informative, are invasive and not suitable for monitoring ongoing treatments. These challenges have led to the emergence of liquid biopsy, particularly through blood samples, as a promising alternative for GBM diagnosis and monitoring. Presently, blood and cerebrospinal fluid (CSF) sampling offers a minimally invasive means of obtaining tumor-related information to guide therapy. The idea that blood or any biofluid tests can be used to screen many cancer types has huge potential. Tumors release various components into the bloodstream or other biofluids, including cell-free nucleic acids such as microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs) or exosomes, metabolites, and other factors. These factors have been shown to cross the blood-brain barrier (BBB), presenting an opportunity for the minimally invasive monitoring of GBM as well as for the real-time assessment of distinct genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes associated with brain tumors. Despite their potential, the clinical utility of liquid biopsy-based circulating biomarkers is somewhat constrained by limitations such as the absence of standardized methodologies for blood or CSF collection, analyte extraction, analysis methods, and small cohort sizes. Additionally, tissue biopsies offer more precise insights into tumor morphology and the microenvironment. Therefore, the objective of a liquid biopsy should be to complement and enhance the diagnostic accuracy and monitoring of GBM patients by providing additional information alongside traditional tissue biopsies. Moreover, utilizing a combination of diverse biomarker types may enhance clinical effectiveness compared to solely relying on one biomarker category, potentially improving diagnostic sensitivity and specificity and addressing some of the existing limitations associated with liquid biomarkers for GBM. This review presents an overview of the latest research on circulating biomarkers found in GBM blood or CSF samples, discusses their potential as diagnostic, predictive, and prognostic indicators, and discusses associated challenges and future perspectives.
Collapse
Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
| |
Collapse
|
|
10
|
Boukovala M, Westphalen CB, Probst V. Liquid biopsy into the clinics: Current evidence and future perspectives. THE JOURNAL OF LIQUID BIOPSY 2024; 4:100146. [PMID: 40027149 PMCID: PMC11863819 DOI: 10.1016/j.jlb.2024.100146] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 03/05/2025]
Abstract
As precision oncology has become a major part of the treatment landscape in oncology, liquid biopsies have developed as a particularly powerful tool as it surmounts several limitations of traditional tissue biopsies. These biopsies involve most commonly the isolation of circulating extracellular nucleic acids, including cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA), as well as circulating tumor cells (CTCs), typically from blood. The clinical applications of liquid biopsies are diverse, encompassing the initial diagnosis and cancer detection, the application as a tool for prognostication in early and advanced tumor settings, the identification of potentially actionable alterations, the monitoring of response and resistance under systemic therapy and the detection of resistance mechanisms, the differentiation of distinct immune checkpoint blockade response patterns through serial samples, the prediction of immune checkpoint blockade responses based on initial liquid biopsy characteristics and the assessment of tumor heterogeneity. Moreover, molecular relapse monitoring in early-stage cancers and the personalization of adjuvant or additive therapy via MRD have become a major field of research in recent years. Compared to tissue biopsies, liquid biopsies are less invasive and can be collected serially, offering real-time molecular insights. Furthermore, liquid biopsies may allow for a more holistic evaluation of a patient's disease, as they assess material from all tumor sites and can theoretically reflect tumor heterogeneity. Furthermore, quicker turnaround-time also constitutes an advantage of liquid biopsies. Disadvantages or hurdles include the challenge of detecting low amounts of tumor deposits in peripheral blood or other fluids and the potential of different amounts tumor-shedding from different metastatic sites, as well as potentially false-positive from clonal hematopoietic mutations of indeterminate potential (CHIP) mutations. The clinical utility of liquid biopsies still must be validated in most settings and further research has to be done. Clinal trials including alternate bodily fluids and leveraging AI-technology are expected to revolutionize the field of liquid biopsies.
Collapse
|
|
11
|
O'Sullivan NJ, Temperley HC, Kyle ET, Sweeney KJ, O'Neill M, Gilham C, O'Sullivan J, O'Kane G, Mehigan B, O'Toole S, Larkin J, Gallagher D, McCormick P, Kelly ME. Assessing circulating tumour DNA (ctDNA) as a prognostic biomarker in locally advanced rectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis 2024; 39:82. [PMID: 38809315 PMCID: PMC11136793 DOI: 10.1007/s00384-024-04656-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 05/30/2024]
Abstract
INTRODUCTION Circulating tumour DNA (ctDNA) has emerged as a promising biomarker in various cancer types, including locally advanced rectal cancer (LARC), offering potential insights into disease progression, treatment response and recurrence. This review aims to comprehensively evaluate the utility of ctDNA as a prognostic biomarker in LARC. METHODS PubMed, EMBASE and Web of Science were searched as part of our review. Studies investigating the utility of ctDNA in locally advanced rectal cancer (LARC) were assessed for eligibility. Quality assessment of included studies was performed using the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, ctDNA details and survival data. A meta-analysis was performed on eligible studies to determine pooled recurrence-free survival (RFS). RESULTS Twenty-two studies involving 1676 participants were included in our analysis. Methodological quality categorised by the Newcastle Ottawa Scale was generally satisfactory across included studies. ctDNA detected at various time intervals was generally associated with poor outcomes across included studies. Meta-analysis demonstrated a pooled hazard ratio of 8.87 (95% CI 4.91-16.03) and 15.15 (95% CI 8.21-27.95), indicating an increased risk of recurrence with ctDNA positivity in the post-neoadjuvant and post-operative periods respectively. CONCLUSION Our systematic review provides evidence supporting the prognostic utility of ctDNA in patients with LARC, particularly in identifying patients at higher risk of disease recurrence in the post-neoadjuvant and post-operative periods.
Collapse
Affiliation(s)
- Niall J O'Sullivan
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland.
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
| | - Hugo C Temperley
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
| | - Eimear T Kyle
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Kevin J Sweeney
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Maeve O'Neill
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Charles Gilham
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Department of Radiation Oncology, St. James's Hospital, Dublin 8, Ireland
| | - Jacintha O'Sullivan
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, Trinity College, St. James's Hospital, Dublin, Ireland
| | - Grainne O'Kane
- Department of Medical Oncology, St. James's Hospital, Dublin 8, Ireland
| | - Brian Mehigan
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Sharon O'Toole
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, Trinity College, St. James's Hospital, Dublin, Ireland
| | - John Larkin
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - David Gallagher
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Department of Medical Oncology, St. James's Hospital, Dublin 8, Ireland
- Department of Genetics, St. James's Hospital, Dublin 8, Ireland
| | - Paul McCormick
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Michael E Kelly
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Trinity St. James's Cancer Institute, St. James's Hospital, Dublin 8, Ireland
| |
Collapse
|
|
12
|
Galant N, Nicoś M, Kuźnar-Kamińska B, Krawczyk P. Variant Allele Frequency Analysis of Circulating Tumor DNA as a Promising Tool in Assessing the Effectiveness of Treatment in Non-Small Cell Lung Carcinoma Patients. Cancers (Basel) 2024; 16:782. [PMID: 38398173 PMCID: PMC10887123 DOI: 10.3390/cancers16040782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients with NSCLC is variant allele frequency (VAF) analysis. VAF is a metric characterized as the measurement of the specific variant allele proportion within a genomic locus, and it can be determined using methods based on NGS or PCR. It can be assessed using not only tissue samples but also ctDNA (circulating tumor DNA) isolated from liquid biopsy. The non-invasive characteristic of liquid biopsy enables a more frequent collection of material and increases the potential of VAF analysis in monitoring therapy. Several studies have been performed on patients with NSCLC to evaluate the possibility of VAF usage. The research carried out so far demonstrates that the evaluation of VAF dynamics may be useful in monitoring tumor progression, remission, and recurrence during or after treatment. Moreover, the use of VAF analysis appears to be beneficial in making treatment decisions. However, several issues require better understanding and standardization before VAF testing can be implemented in clinical practice. In this review, we discuss the difficulties in the application of ctDNA VAF analysis in clinical routine, discussing the diagnostic and methodological challenges in VAF measurement in liquid biopsy. We highlight the possible applications of VAF-based measurements that are under consideration in clinical trials in the monitoring of personalized treatments for patients with NSCLC.
Collapse
Affiliation(s)
- Natalia Galant
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland
| | - Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland
| | - Barbara Kuźnar-Kamińska
- Department of Pulmonology, Allergology and Respiratory Oncology, Poznan University of Medical Sciences, 61-710 Poznan, Poland;
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland
| |
Collapse
|
|
13
|
Ma W, Wu H, Chen Y, Xu H, Jiang J, Du B, Wan M, Ma X, Chen X, Lin L, Su X, Bao X, Shen Y, Xu N, Ruan J, Jiang H, Ding Y. New techniques to identify the tissue of origin for cancer of unknown primary in the era of precision medicine: progress and challenges. Brief Bioinform 2024; 25:bbae028. [PMID: 38343328 PMCID: PMC10859692 DOI: 10.1093/bib/bbae028] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 12/10/2023] [Accepted: 01/11/2024] [Indexed: 02/15/2024] Open
Abstract
Despite a standardized diagnostic examination, cancer of unknown primary (CUP) is a rare metastatic malignancy with an unidentified tissue of origin (TOO). Patients diagnosed with CUP are typically treated with empiric chemotherapy, although their prognosis is worse than those with metastatic cancer of a known origin. TOO identification of CUP has been employed in precision medicine, and subsequent site-specific therapy is clinically helpful. For example, molecular profiling, including genomic profiling, gene expression profiling, epigenetics and proteins, has facilitated TOO identification. Moreover, machine learning has improved identification accuracy, and non-invasive methods, such as liquid biopsy and image omics, are gaining momentum. However, the heterogeneity in prediction accuracy, sample requirements and technical fundamentals among the various techniques is noteworthy. Accordingly, we systematically reviewed the development and limitations of novel TOO identification methods, compared their pros and cons and assessed their potential clinical usefulness. Our study may help patients shift from empirical to customized care and improve their prognoses.
Collapse
Affiliation(s)
- Wenyuan Ma
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Wu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiran Chen
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongxia Xu
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China
| | - Junjie Jiang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bang Du
- Real Doctor AI Research Centre, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Mingyu Wan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaolu Ma
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyu Chen
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lili Lin
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinhui Su
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuanwen Bao
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifei Shen
- Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
14
|
Huang X, Leo P, Jones L, Duijf PHG, Hartel G, Kenny L, Vasani S, Punyadeera C. A comparison between mutational profiles in tumour tissue DNA and circulating tumour DNA in head and neck squamous cell carcinoma - A systematic review. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2024; 793:108477. [PMID: 37977279 DOI: 10.1016/j.mrrev.2023.108477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 11/10/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Head and neck cancer is the seventh most common malignancy globally. Head and neck squamous cell carcinoma (HNSCC) originates from squamous cells and 90% of HNC are HNSCC. The gold standard for diagnosing HNSCC is tissue biopsy. However, given tumour heterogeneity, biopsies may miss important cancer-associated molecular signatures, and more importantly, after the tumour is excised, there is no means of tracking response to treatment in patients. Captured under liquid biopsy, circulating tumour DNA (ctDNA), may identify in vivo molecular genotypes and complements tumour tissue analysis in cancer management. A systematic search was conducted in PubMed, Embase, Scopus and the Cochran Library between 2012 to early 2023 on ctDNA in HNSCC using publications written in English. We summarise 20 studies that compared mutational profiles between tumour tissue DNA (tDNA) and ctDNA, using a cohort of 631 HNSCC patients and 139 controls. Among these studies, the concordance rates varied greatly and the most mutated and the most concordant gene was TP53, followed by PIK3CA, CDKN2A, NOTCH1 and FAT1. Concordant variants were mainly found in Stage IV tumours, and the mutation type is mostly single nucleotide variants (SNV). We conclude that, as a biomarker for HNSCC, ctDNA demonstrates great promise as it recapitulates tumour genotypes, however additional multi-central trials are needed.
Collapse
Affiliation(s)
- Xiaomin Huang
- Saliva and Liquid Biopsy Translational Laboratory, Griffith Institute for Drug Discovery, The School of Environment and Science, Griffith University, Brisbane, QLD, Australia
| | - Paul Leo
- School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia; Center for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, Australia; Australian Translational Genomics Center, Brisbane, QLD, Australia
| | - Lee Jones
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Research Methods Group, School of Public Health and Social Work, Queensland University of Technology, Kelvin Grove, Brisbane, QLD, Australia
| | - Pascal H G Duijf
- School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia; Center for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, Australia; Centre for Cancer Biology, Clinical and Health Sciences, University of South Australia & SA Pathology, Adelaide, SA, Australia; Department of Medical Genetics, Oslo University Hospital, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Gunter Hartel
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Lizbeth Kenny
- School of Medicine, University of Queensland, Brisbane, QLD, Australia; Cancer Care Service, Royal Brisbane Women's Hospital, Brisbane, QLD, Australia
| | - Sarju Vasani
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Department of Otolaryngology, Royal Brisbane Women's Hospital, Brisbane, QLD, Australia
| | - Chamindie Punyadeera
- Saliva and Liquid Biopsy Translational Laboratory, Griffith Institute for Drug Discovery, The School of Environment and Science, Griffith University, Brisbane, QLD, Australia; Menzies Health Institute Queensland, Griffith University, QLD, Australia.
| |
Collapse
|
|
15
|
Gavryushin AV, Veselkov AA, Khukhlaeva EA, Konovalov AN, Druy AE. [Liquid biopsy in diagnosis of central nervous system tumors]. ZHURNAL VOPROSY NEIROKHIRURGII IMENI N. N. BURDENKO 2024; 88:110-117. [PMID: 39670787 DOI: 10.17116/neiro202488061110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
Tumor tissue samples are necessary for histological diagnosis. Biopsy is associated with certain difficulties, especially in neuro-oncology. An alternative approach (liquid biopsy) is currently being developed. The last one is based on analysis of biological fluids regarding DNA of tumors and other biomarkers. This less invasive diagnostic method may be valuable to overcome the disadvantages of traditional biopsy. OBJECTIVE To analyze available literature data on potential benefits and disadvantages of liquid biopsy. MATERIAL AND METHODS We reviewed the PubMed database throughout the last 18 years. RESULTS The main targets for liquid biopsy are circulating tumor cells, extracellular vesicles, free circulating DNA and tumor microRNA. Analysis of these biomarkers is perspective for diagnostics and assessment of diseases in neuro-oncology. However, this technique is still poorly understood and has limitations. Therefore, further research is required to explore its capabilities for wider use in clinical practice. CONCLUSION Tissue and liquid biopsy can improve the accuracy of diagnosis, assessment of prognosis and effectiveness of treatment of CNS tumors.
Collapse
Affiliation(s)
- A V Gavryushin
- Burdenko Neurosurgical Center, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | | | | | | | - A E Druy
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| |
Collapse
|
|
16
|
Boscolo Bielo L, Trapani D, Repetto M, Crimini E, Valenza C, Belli C, Criscitiello C, Marra A, Subbiah V, Curigliano G. Variant allele frequency: a decision-making tool in precision oncology? Trends Cancer 2023; 9:1058-1068. [PMID: 37704501 DOI: 10.1016/j.trecan.2023.08.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/15/2023]
Abstract
Precision oncology requires additional predictive biomarkers for targeted therapy selection. Variant allele frequency (VAF), measuring the proportion of variant alleles within a genomic locus, provides insights into tumor clonality in somatic genomic testing, yielding a strong rationale for targeting dominant cancer cell populations. The prognostic and predictive roles of VAF have been evaluated across different studies. Yet, the absence of validated VAF thresholds and a lack of standardization between sequencing assays currently hampers its clinical utility. Therefore, analytical and clinical validation must be further examined. This Review summarizes the evidence regarding the use of VAF as a predictive biomarker and discusses challenges and opportunities for its clinical implementation as a decision-making tool for targeted therapy selection.
Collapse
Affiliation(s)
- Luca Boscolo Bielo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Matteo Repetto
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Early Drug Development service, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - Edoardo Crimini
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmen Belli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Antonio Marra
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
| | - Vivek Subbiah
- Drug Development Unit, Sarah Cannon Research Institute, Nashville, TN, USA
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
| |
Collapse
|
|
17
|
Bronkhorst AJ, Holdenrieder S. The changing face of circulating tumor DNA (ctDNA) profiling: Factors that shape the landscape of methodologies, technologies, and commercialization. MED GENET-BERLIN 2023; 35:201-235. [PMID: 38835739 PMCID: PMC11006350 DOI: 10.1515/medgen-2023-2065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
Liquid biopsies, in particular the profiling of circulating tumor DNA (ctDNA), have long held promise as transformative tools in cancer precision medicine. Despite a prolonged incubation phase, ctDNA profiling has recently experienced a strong wave of development and innovation, indicating its imminent integration into the cancer management toolbox. Various advancements in mutation-based ctDNA analysis methodologies and technologies have greatly improved sensitivity and specificity of ctDNA assays, such as optimized preanalytics, size-based pre-enrichment strategies, targeted sequencing, enhanced library preparation methods, sequencing error suppression, integrated bioinformatics and machine learning. Moreover, research breakthroughs have expanded the scope of ctDNA analysis beyond hotspot mutational profiling of plasma-derived apoptotic, mono-nucleosomal ctDNA fragments. This broader perspective considers alternative genetic features of cancer, genome-wide characterization, classical and newly discovered epigenetic modifications, structural variations, diverse cellular and mechanistic ctDNA origins, and alternative biospecimen types. These developments have maximized the utility of ctDNA, facilitating landmark research, clinical trials, and the commercialization of ctDNA assays, technologies, and products. Consequently, ctDNA tests are increasingly recognized as an important part of patient guidance and are being implemented in clinical practice. Although reimbursement for ctDNA tests by healthcare providers still lags behind, it is gaining greater acceptance. In this work, we provide a comprehensive exploration of the extensive landscape of ctDNA profiling methodologies, considering the multitude of factors that influence its development and evolution. By illuminating the broader aspects of ctDNA profiling, the aim is to provide multiple entry points for understanding and navigating the vast and rapidly evolving landscape of ctDNA methodologies, applications, and technologies.
Collapse
Affiliation(s)
- Abel J Bronkhorst
- Technical University Munich Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center Lazarettstr. 36 80636 Munich Germany
| | - Stefan Holdenrieder
- Technical University Munich Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center Lazarettstr. 36 80636 Munich Germany
| |
Collapse
|
|
18
|
Tsimberidou AM, Kahle M, Vo HH, Baysal MA, Johnson A, Meric-Bernstam F. Molecular tumour boards - current and future considerations for precision oncology. Nat Rev Clin Oncol 2023; 20:843-863. [PMID: 37845306 DOI: 10.1038/s41571-023-00824-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 10/18/2023]
Abstract
Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments. The criteria for determining the actionability of molecular alterations and selecting matched treatments are constantly evolving. Therefore, MTBs have an increasingly necessary role in optimizing the allocation of biomarker-directed therapies and the implementation of precision oncology. Ultimately, increased MTB availability, accessibility and performance are likely to improve patient care. The challenges faced by MTBs are increasing, owing to the plethora of identifiable molecular alterations and immune markers in tumours of individual patients and their evolving clinical significance as more and more data on patient outcomes and results from clinical trials become available. Beyond next-generation sequencing, broader biomarker analyses can provide useful information. However, greater funding, resources and expertise are needed to ensure the sustainability of MTBs and expand their outreach to underserved populations. Harmonization between practice and policy will be required to optimally implement precision oncology. Herein, we discuss the evolving role of MTBs and current and future considerations for their use in precision oncology.
Collapse
Affiliation(s)
- Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Michael Kahle
- Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Henry Hiep Vo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mehmet A Baysal
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amber Johnson
- Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
19
|
Rose KM, Huelster HL, Meeks JJ, Faltas BM, Sonpavde GP, Lerner SP, Ross JS, Spiess PE, Grass GD, Jain RK, Kamat AM, Vosoughi A, Wang L, Wang X, Li R. Circulating and urinary tumour DNA in urothelial carcinoma - upper tract, lower tract and metastatic disease. Nat Rev Urol 2023; 20:406-419. [PMID: 36977797 DOI: 10.1038/s41585-023-00725-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2023] [Indexed: 03/30/2023]
Abstract
Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays.
Collapse
Affiliation(s)
- Kyle M Rose
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Heather L Huelster
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Joshua J Meeks
- Department of Urology, Northwestern University, Chicago, IL, USA
| | - Bishoy M Faltas
- Department of Hematology/Oncology, Weill-Cornell Medicine, New York, NY, USA
| | - Guru P Sonpavde
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Seth P Lerner
- Department of Urology, Baylor College of Medicine, Houston, TX, USA
| | - Jeffrey S Ross
- Foundation Medicine, Inc, Cambridge, MA, USA
- Departments of Urology and Pathology, Upstate Medical University, Syracuse, NY, USA
| | - Philippe E Spiess
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - G Daniel Grass
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Rohit K Jain
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Ashish M Kamat
- Department of Urology, MD Anderson Cancer Center, Houston, TX, USA
| | - Aram Vosoughi
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Liang Wang
- Department of Tumour Biology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Xuefeng Wang
- Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Roger Li
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
| |
Collapse
|
|
20
|
Xie J, Yao W, Chen L, Zhu W, Liu Q, Geng G, Fang J, Zhao Y, Xiao L, Huang Z, Zhao J. Plasma ctDNA increases tissue NGS-based detection of therapeutically targetable mutations in lung cancers. BMC Cancer 2023; 23:294. [PMID: 37004022 PMCID: PMC10063947 DOI: 10.1186/s12885-023-10674-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 02/23/2023] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) has been becoming a novel convenient and noninvasive method for dynamically monitoring landscape of genomic information to guild personalized cancer treatment. In this study we comprehensively evaluated the additional value of plasma ctDNA to routine tissue next generation sequencing (NGS) of therapeutically targetable mutations in lung cancers. METHODS The tumor tissues and peripheral blood samples from 423 cases of patients with lung cancer were subjected to NGS of mutations in oncodrivers (EGFR, ERBB2, ALK, ROS1, C-MET, KRAS, BRAF, RET, BRCA1 and BRCA2). RESULTS One hundred and ninety-seven cases showed both plasma and tissue positive and 96 showed both negative. The concordance for tissue and blood detection was 69.27% (293/423). 83 (19.62%) cases showed positive by tissue NGS alone and 47 (11.11%) positive by plasma ctDNA alone. The sensitivity of tissue and plasma detection was 85.63%, and 74.62%, respectively. Plasma had lower detection and sensitivity than tissue, but plasma additionally detected some important mutations which were omitted by tissue NGS. Plasma plus tissue increased the detection rate of 66.19% by tissue alone to 77.30% as well as the sensitivity of 85.63-100%. Similar results were also observed when the cases were classified into subpopulations according to different stages (IV vs. III vs. I-II), grades (low vs. middle grade) and metastatic status (metastasis vs. no metastasis). CONCLUSION Plasma ctDNA shares a high concordance with tissue NGS, and plasma plus tissue enhances the detection rate and sensitivity by tissue alone, implying that the tissue and plasma detection should be mutually complementary in the clinical application.
Collapse
Affiliation(s)
- Jianjiang Xie
- Department of Thoracic surgery, School of Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Weishen Yao
- Department of Cardiothoracic Surgery, Nanhai District People's Hospital of Foshan, Foshan, 528200, China
| | - Lingxiu Chen
- Department of Pulmonary and Critical Care Medicine, Three Gorges Hospital of Chongqing University, Chongqing, 404000, China
| | - Wenjun Zhu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China
| | - Qiang Liu
- Shenyang Chest Hospital & Tenth People's Hospital, Shenyang, Liaoning, 110044, China
| | - Geng Geng
- Department of Thoracic and Cardiac Surgery, WuHu Hospital, East China Normal University, Wuhu, Anhui, 241000, China
| | - Jing Fang
- Department of Oncology, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Yang Zhao
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Li Xiao
- Department of Oncology, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China.
| | - Zhenhua Huang
- Department of Oncology, Nanfang Hospital of Southern Medical University, Guangzhou, 510515, China.
| | - Jing Zhao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China.
| |
Collapse
|
|
21
|
David P, Mittelstädt A, Kouhestani D, Anthuber A, Kahlert C, Sohn K, Weber GF. Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease-From Early Cancer Detection to Individualized Cancer Treatment. Cancers (Basel) 2023; 15:cancers15071924. [PMID: 37046585 PMCID: PMC10093361 DOI: 10.3390/cancers15071924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.
Collapse
Affiliation(s)
- Paul David
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anke Mittelstädt
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Dina Kouhestani
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anna Anthuber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christoph Kahlert
- Department of Surgery, Carl Gustav Carus University Hospital, 01307 Dresden, Germany
| | - Kai Sohn
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, 70569 Stuttgart, Germany
| | - Georg F Weber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| |
Collapse
|
|
22
|
Patterns of Somatic Variants in Colorectal Adenoma and Carcinoma Tissue and Matched Plasma Samples from the Hungarian Oncogenome Program. Cancers (Basel) 2023; 15:cancers15030907. [PMID: 36765865 PMCID: PMC9913259 DOI: 10.3390/cancers15030907] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 02/04/2023] Open
Abstract
Analysis of circulating cell-free DNA (cfDNA) of colorectal adenoma (AD) and cancer (CRC) patients provides a minimally invasive approach that is able to explore genetic alterations. It is unknown whether there are specific genetic variants that could explain the high prevalence of CRC in Hungary. Whole-exome sequencing (WES) was performed on colon tissues (27 AD, 51 CRC) and matched cfDNAs (17 AD, 33 CRC); furthermore, targeted panel sequencing was performed on a subset of cfDNA samples. The most frequently mutated genes were APC, KRAS, and FBN3 in AD, while APC, TP53, TTN, and KRAS were the most frequently mutated in CRC tissue. Variants in KRAS codons 12 (AD: 8/27, CRC: 11/51 (0.216)) and 13 (CRC: 3/51 (0.06)) were the most frequent in our sample set, with G12V (5/27) dominance in ADs and G12D (5/51 (0.098)) in CRCs. In terms of the cfDNA WES results, tumor somatic variants were found in 6/33 of CRC cases. Panel sequencing revealed somatic variants in 8 out of the 12 enrolled patients, identifying 12/20 tumor somatic variants falling on its targeted regions, while WES recovered only 20% in the respective regions in cfDNA of the same patients. In liquid biopsy analyses, WES is less efficient compared to the targeted panel sequencing with a higher coverage depth that can hold a relevant clinical potential to be applied in everyday practice in the future.
Collapse
|
|
23
|
Balkrishna A, Umar Zango U, Kauser Nasir S, Arya V. A Clinical Cognizance of Molecular and Pathological Diagnostic Approach of TNBC. THERAPEUTIC DRUG TARGETS AND PHYTOMEDICINE FOR TRIPLE NEGATIVE BREAST CANCER 2023:26-46. [DOI: 10.2174/9789815079784123010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Genetic, transcriptional, and clinical heterogeneity of disease has remained
to be a prominent obstacle to the development of a targeted therapeutic approach
against TNBC. So far, based on tumor size, lymph node status, and histologic features
TNBC subtypes were stratified. Insights into inter and intratumoral heterogeneity of
TNBC were gained by next-generation sequencing, genomic, transcriptomic,
proteomic, and clinicopathological characterization. To depict tumor response to
neoadjuvant chemotherapy, radiological characterization may also a play significant
role. Biomarkers for subtyping TNBC were highly needed to depict the survival
outcome. This chapter discussed the available and possible molecular and pathological
diagnostic approaches to TNBC. Furthermore, the integration of morphological and
genomic data may emerge as a promising approach for the identification of new
therapeutic and prognostic markers to predict the likely outcome of the disease. This
chapter aims to highlight the molecular and pathological diagnostic approaches to
depict both metastatic and non-metastatic TNBC. <br>
Collapse
Affiliation(s)
- Acharya Balkrishna
- Patanjali Research Institute,Patanjali Herbal Research Department,Haridwar,India,
| | - Usman Umar Zango
- Sa'adatu Rimi College of Education,Department of Biology,Kumbotso,Nigeria,
| | - Saima Kauser Nasir
- Indian Institute of Science Bangalore,Department of Microbiology and Cell Biology (MCB),Bangalore,India,
| | - Vedpriya Arya
- Patanjali Research Institute,Patanjali Herbal Research Department,Haridwar,India,
| |
Collapse
|
|
24
|
Chen H, Xu C, Fang Z, Mao S. Cell-Free DNA, MicroRNAs, Proteins, and Peptides as Liquid Biopsy Biomarkers in Prostate Cancer and Bladder Cancer. Methods Mol Biol 2023; 2695:165-179. [PMID: 37450118 DOI: 10.1007/978-1-0716-3346-5_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Liquid biopsy, as a novel noninvasive tool for biomarker discovery, has gained a lot of attention and represents a significant innovation in precision medicine. Due to its minimally invasive nature, liquid biopsy has fewer complications and can be scheduled more frequently to provide individualized snapshots of the disease at successive time points. This is particularly valuable in providing simultaneous measurements of tumor burden during treatment and early detection of tumor recurrence or drug resistance. Blood-based liquid biopsy is an attractive, minimally invasive alternative, which has shown promise in diagnosis, risk stratification, disease monitoring, and more. Urine has gained popularity due to its less invasive sampling, the ability to easily repeat samples, and the ability to track tumor evolution in real time, making it a powerful tool for diagnosis and treatment monitoring, especially in urologic cancers. In this review, we provide a detailed discussion on the potential clinical applications of prostate cancer (PCa) and bladder cancer (BCa), with cell-free DNA (cfDNA), microRNAs (miRNAs), proteins, and peptides as liquid biopsy biomarkers.
Collapse
Affiliation(s)
- Haoran Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenyang Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zujun Fang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shanhua Mao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
25
|
Han X, Tang X, Zhu H, Zhu D, Zhang X, Meng X, Hua Y, Wang Z, Zhang Y, Huang W, Wang L, Yuan S, Zhang P, Gong H, Sun Y, Zhang Y, Liu Z, Dong X, Gai F, Huang Z, Zhu C, Guo J, Wang Z. Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial. J Immunother Cancer 2022; 10:jitc-2022-004952. [PMID: 36600554 PMCID: PMC9730395 DOI: 10.1136/jitc-2022-004952] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/10/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Robust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients. METHODS A total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m2, day 3, every 3 weeks) for 4-6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated. RESULTS Patients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005). CONCLUSION ctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.
Collapse
Affiliation(s)
- Xiao Han
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Xiaoyong Tang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Hui Zhu
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Dongyuan Zhu
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Xiqin Zhang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Xiangjiao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ying Hua
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Zhongtang Wang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Yan Zhang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Wei Huang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Linlin Wang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Shuanghu Yuan
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Pinliang Zhang
- Internal Medicine Department, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Heyi Gong
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Yulan Sun
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Yingjie Zhang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Zengjun Liu
- Internal Medicine Department, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Xiaomeng Dong
- Medical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, China
| | - Fei Gai
- Medical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, China
| | - Zhan Huang
- Medical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, China
| | - Changbin Zhu
- Medical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, China
| | - Jun Guo
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Zhehai Wang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| |
Collapse
|
|
26
|
Husain A, Mishra S, Hadi R, Sahu A, Kumari S, Rastogi M, Khurana R, Shukla S, Siddiqui MH, Husain N. Dynamics of cell-free DNA in predicting response in adult diffuse glioma on chemoradiotherapy. Cancer Genet 2022; 268-269:55-63. [PMID: 36166960 DOI: 10.1016/j.cancergen.2022.09.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 06/25/2022] [Accepted: 09/17/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Adult diffuse glioma (ADG) is a heterogeneous primary brain tumor with a variable prognosis and treatment response. Tissue biomarkers and molecular genetic profiling form an integral part of diagnosis and prognostication. However, obtaining tissue in inoperable locations and diagnosis of recurrence can be an issue. Cell-free DNA (cfDNA) may help to meet these challenges in the management of ADG. OBJECTIVES The study aimed to serially quantify cfDNA in ADG on chemoradiation and to correlate mutational profiling of the cfDNA with biopsy. MATERIAL AND METHODS The study group comprised of histopathological confirmed ADG (n = 50), including grade II, III and IV glioma, and controls (n = 25). Serum cfDNA was extracted using ChargeSwitch gDNA 1 mL Serum Kit (Invitrogen, USA) and quantified using SYBR based quantitative polymerase chain reaction (qPCR). Next-generation sequencing (NGS) was performed in 07 pre-operative and 05 post-operative cfDNA and tumor biopsy DNA on an Ion personal genome machine (IonPGM) with an in-house designed NGS panel (including TP53, ATRX, and IDH1 and IDH2). RESULTS In patients with ADG, the pre-radiotherapy cfDNA level was significantly higher (Median; 113.46 ng/mL) than normal controls (Median; 74.37 ng/mL), (p = 0.048). Non-responders had significantly higher cfDNA levels (Median; 184.4 ng/mL), than responders (Median; 68.12 ng/mL), (p = 0.023). TP53 gene mutation was most common in both pre-operative and post-operative cfDNA samples. CONCLUSION Pre-radiotherapy cfDNA levels are associated with clinical outcomes independent of other prognostic factors. Targeted NGS in pre-operative cfDNA matches the results of IHC analysis with high concordance, and it may be helpful in inoperable cases or ADG recurrence.
Collapse
Affiliation(s)
- Adil Husain
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India; Department of Biosciences, Integral University, Lucknow, India
| | - Sridhar Mishra
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | - Rahat Hadi
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | - Avnish Sahu
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | - Swati Kumari
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | - Madhup Rastogi
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | - Rohini Khurana
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | - Saumya Shukla
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
| | | | - Nuzhat Husain
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India.
| |
Collapse
|
|
27
|
Shah UJ, Alsulimani A, Ahmad F, Mathkor DM, Alsaieedi A, Harakeh S, Nasiruddin M, Haque S. Bioplatforms in liquid biopsy: advances in the techniques for isolation, characterization and clinical applications. Biotechnol Genet Eng Rev 2022; 38:339-383. [PMID: 35968863 DOI: 10.1080/02648725.2022.2108994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tissue biopsy analysis has conventionally been the gold standard for cancer prognosis, diagnosis and prediction of responses/resistances to treatments. The existing biopsy procedures used in clinical practice are, however, invasive, painful and often associated with pitfalls like poor recovery of tumor cells and infeasibility for repetition in single patients. To circumvent these limitations, alternative non-invasive, rapid and economical, yet sturdy, consistent and dependable, biopsy techniques are required. Liquid biopsy is an emerging technology that fulfills these criteria and potentially much more in terms of subject-specific real-time monitoring of cancer progression, determination of tumor heterogeneity and treatment responses, and specific identification of the type and stages of cancers. The present review first briefly revisits the state-of-the-art technique of liquid biopsy and then proceeds to address in detail, the advances in the potential clinical applications of four major biological agencies present in liquid biopsy samples (circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes and tumor-educated platelets (TEPs)). Finally, the authors conclude with the limitations that need to be addressed in order for liquid biopsy to effectively replace the conventional invasive biopsy methods in the clinical settings.
Collapse
Affiliation(s)
- Ushma Jaykamal Shah
- MedGenome Labs Ltd, Kailash Cancer Hospital and Research Center, Vadodara, India
| | - Ahmad Alsulimani
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, India
| | - Darin Mansor Mathkor
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ahdab Alsaieedi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Steve Harakeh
- King Fahd Medical Research Center, and Yousef Abdullatif Jameel Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Nasiruddin
- MedGenome Labs Ltd, Narayana Health City, Bangalore, India.,Genomics Lab, Orbito Asia Diagnostics, Coimbatore, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| |
Collapse
|
|
28
|
Wei J, Wang Y, Gao J, Li Z, Pang R, Zhai T, Ma Y, Wang Z, Meng X. Detection of BRAFV600E mutation of thyroid cancer in circulating tumor DNA by an electrochemical-enrichment assisted ARMS-qPCR assay. Microchem J 2022. [DOI: 10.1016/j.microc.2022.107452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
29
|
Geng N, Chen S, Liu J, Cao W, Zhang D, Feng C. Circulating tumor cells in blood as a prognostic biomarker in tongue squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 134:213-219. [PMID: 35725964 DOI: 10.1016/j.oooo.2021.12.129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/02/2021] [Accepted: 12/19/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE The study aimed to evaluate the role of circulating tumor cells (CTCs) as a prognostic biomarker of tongue squamous cell carcinoma (TSCC). STUDY DESIGN CTC levels in the peripheral blood of 50 patients with TSCC at baseline (i.e., before treatment) and of 8 healthy donors were determined using the NanoVelcro system. The relationship between CTC levels and clinicopathologic parameters and clinical outcomes such as recurrence, metastasis, and death during follow-up (mean 17 months) was analyzed. RESULTS CTCs levels were closely correlated with TSCC clinical staging (P = .002), N staging (P = .007), and progression status (P = .002) in TSCC patients. Receiver operating characteristic (ROC) analysis revealed that the count of CTC ≥4 (area under curve: 0.832 [95% confidence interval 0.695-0.950]; sensitivity: 0.83; specificity: 0.75; P < .001) was a better prognostic marker than TNM stage (area under curve: 0.692 [0.536-0.848]; sensitivity: 0.83; specificity: 0.55; P = .023). In addition, univariate and multivariate analysis showed that the CTC was an important and independent predictive factor for overall survival and disease-free survival (P < .001). CONCLUSIONS CTC was an independent prognostic indicator in patients with TSCC. CTC may be used as an auxiliary parameter to predict the prognosis of TSCC.
Collapse
Affiliation(s)
- Ningbo Geng
- Department of Stomatology, The Frist Affiliated Hosptial of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Shan Chen
- Department of Stomatology, The Frist Affiliated Hosptial of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Jiameng Liu
- Department of Stomatology, The Frist Affiliated Hosptial of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China; Department of Stomatology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, People's Republic of China
| | - Wei Cao
- Department of Stomatology, The Frist Affiliated Hosptial of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Dandan Zhang
- Department of Stomatology, The Frist Affiliated Hosptial of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Chongjin Feng
- Department of Stomatology, The Frist Affiliated Hosptial of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
| |
Collapse
|
|
30
|
Liquid Biopsy in Glioblastoma. Cancers (Basel) 2022; 14:cancers14143394. [PMID: 35884454 PMCID: PMC9323318 DOI: 10.3390/cancers14143394] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Glioblastoma is the most common and malignant primary brain tumor. Despite intensive research for new treatments, the survival of patients has not significantly improved in recent decades. Currently, glioblastoma is mainly diagnosed by neuroimaging techniques followed by histopathological and molecular analysis of the resected or biopsied tissue. Both imaging and tissue-based methods have, despite their advantages, some important limitations highlighting the necessity for alternative techniques such as liquid biopsy. It appears as an attractive and non-invasive alternative to support the diagnosis and the follow-up of patients with glioblastoma and to identify early recurrence. Liquid biopsy, primarily through blood tests, involves the detection and quantification of tumoral content released by tumors into the biofluids. The aim of the present review is to discuss the biological bases, the advantages, and the disadvantages of the most important circulating biomarkers so far proposed for glioblastoma. Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Despite recent advances in therapy modalities, the overall survival of GBM patients remains poor. GBM diagnosis relies on neuroimaging techniques. However, confirmation via histopathological and molecular analysis is necessary. Given the intrinsic limitations of such techniques, liquid biopsy (mainly via blood samples) emerged as a non-invasive and easy-to-implement alternative that could aid in both the diagnosis and the follow-up of GBM patients. Cancer cells release tumoral content into the bloodstream, such as circulating tumor DNA, circulating microRNAs, circulating tumor cells, extracellular vesicles, or circulating nucleosomes: all these could serve as a marker of GBM. In this narrative review, we discuss the current knowledge, the advantages, and the disadvantages of each circulating biomarker so far proposed.
Collapse
|
|
31
|
Rink BD, Stevens BK, Norton ME. Incidental Detection of Maternal Malignancy by Fetal Cell-Free DNA Screening. Obstet Gynecol 2022. [DOI: 10.109710.1097/aog.0000000000004833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
|
|
32
|
Incidental Detection of Maternal Malignancy by Fetal Cell-Free DNA Screening. Obstet Gynecol 2022; 140:121-131. [DOI: 10.1097/aog.0000000000004833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/03/2022] [Indexed: 10/18/2022]
|
|
33
|
Cancer: A pathologist's journey from morphology to molecular. Med J Armed Forces India 2022; 78:255-263. [DOI: 10.1016/j.mjafi.2022.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
|
|
34
|
Pascual J, Attard G, Bidard FC, Curigliano G, De Mattos-Arruda L, Diehn M, Italiano A, Lindberg J, Merker JD, Montagut C, Normanno N, Pantel K, Pentheroudakis G, Popat S, Reis-Filho JS, Tie J, Seoane J, Tarazona N, Yoshino T, Turner NC. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2022; 33:750-768. [PMID: 35809752 DOI: 10.1016/j.annonc.2022.05.520] [Citation(s) in RCA: 318] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 12/16/2022] Open
Abstract
Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease (MRD) or molecular relapse (MR), has high evidence of clinical validity in anticipating future relapse in many cancers. MRD/MR detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations prior to clinical progression, and in screening asymptomatic people for cancer. Recommendation for reporting of results, future development of ctDNA assays, and future clinical research are made.
Collapse
Affiliation(s)
- Javier Pascual
- Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Malaga, Spain
| | - Gerhardt Attard
- Urological Cancer Research, University College London, London, UK
| | - François-Clément Bidard
- Department of Medical Oncology, Institut Curie, Paris, France; University of Versailles Saint-Quentin-en-Yvelines (UVSQ)/Paris-Saclay University, Saint Cloud, France
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy; Division of Early Drug Development, European Institute of Oncology, IRCCS, Milano, Italy
| | - Leticia De Mattos-Arruda
- IrsiCaixa, Hospital Universitari Trias i Pujol, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Maximilian Diehn
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, US
| | - Antoine Italiano
- Early Phase Trials and Sarcoma Units, Institut Bergonie, Bordeaux, France; DITEP, Gustave Roussy, Villejuif, France; Faculty of Medicine, University of Bordeaux, Bordeaux, France
| | - Johan Lindberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden
| | - Jason D Merker
- Departments of Pathology and Laboratory Medicine & Genetics, UNC School of Medicine, Chapel Hill, NC, US
| | - Clara Montagut
- Medical Oncology Department, Hospital del Mar-IMIM, CIBERONC, Universitat Pompeu Fabra, Barcelona, Spain
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori, 'Fondazione G. Pascale' - IRCCS, Naples, Italy
| | - Klaus Pantel
- Institute for Tumour Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - George Pentheroudakis
- Scientific and Medical Division, European Society for Medical Oncology, Lugano, Switzerland
| | - Sanjay Popat
- Royal Marsden Hospital, London, UK; Institute of Cancer Research, London, UK
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, US
| | - Jeanne Tie
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Joan Seoane
- Preclinical and Translational Research Programme, Vall d'Hebron Institute of Oncology (VHIO), ICREA, CIBERONC, Barcelona, Spain,; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Noelia Tarazona
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Nicholas C Turner
- Royal Marsden Hospital, London, UK; Institute of Cancer Research, London, UK
| |
Collapse
|
|
35
|
The diagnostic importance of pathogenic variants and variant coexistence determined by NGS-based liquid biopsy approach in patients with lung adenocarcinoma. Mol Cell Probes 2022; 64:101819. [DOI: 10.1016/j.mcp.2022.101819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 11/23/2022]
|
|
36
|
Berger F, Marce M, Delaloge S, Hardy-Bessard AC, Bachelot T, Bièche I, Pradines A, De La Motte Rouge T, Canon JL, André F, Arnould L, Clatot F, Lemonnier J, Marques S, Bidard FC. Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1. BMJ Open 2022; 12:e055821. [PMID: 35241469 PMCID: PMC8896060 DOI: 10.1136/bmjopen-2021-055821] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety. METHODS PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients. ETHICS AND DISSEMINATION The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals. TRIAL REGISTRATION NUMBERS EudraCT: 2016-004360-18; NCT03079011.
Collapse
Affiliation(s)
- Frédérique Berger
- Biometry Unit, Institut Curie, PSL Research University, Paris and Saint-Cloud, France
| | - Margaux Marce
- Biometry Unit, Data Center, Institut Régional du Cancer de Montpellier, Montpellier, France
| | | | | | - Thomas Bachelot
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Ivan Bièche
- Pharmacogenomic Unit, Genetics laboratory, Department of Diagnostic and Theranostic Medicine, Institut Curie and PSL University, Paris, France
| | - Anne Pradines
- INSERM U1037 CNRS ERL5294 UPS, Cancer Research Center of Toulouse, Toulouse, France
- Prospective Biology Unit, Medical Laboratory, Claudius Regaud Institute, Toulouse University Cancer Institute (IUCT-O), Toulouse, France
| | | | - Jean-Luc Canon
- Department of Medical Oncology, Grand Hôpital de Charleroi, Charleroi, Belgique
| | - Fabrice André
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Laurent Arnould
- Department of Pathology, Centre Georges François Leclerc, Dijon, France
| | - Florian Clatot
- Department of Medical Oncology, Centre Henri Becquerel, Rouen, France
| | | | | | - François-Clement Bidard
- Department of Medical Oncology, Institut Curie, UVSQ/Paris Saclay University, Saint Cloud, France
- Circulating Tumor Biomarkers laboratory, Inserm CIC-BT 1428, Institut Curie, Paris, France
| |
Collapse
|
|
37
|
Song P, Wu LR, Yan YH, Zhang JX, Chu T, Kwong LN, Patel AA, Zhang DY. Limitations and opportunities of technologies for the analysis of cell-free DNA in cancer diagnostics. Nat Biomed Eng 2022; 6:232-245. [PMID: 35102279 PMCID: PMC9336539 DOI: 10.1038/s41551-021-00837-3] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Cell-free DNA (cfDNA) in the circulating blood plasma of patients with cancer contains tumour-derived DNA sequences that can serve as biomarkers for guiding therapy, for the monitoring of drug resistance, and for the early detection of cancers. However, the analysis of cfDNA for clinical diagnostic applications remains challenging because of the low concentrations of cfDNA, and because cfDNA is fragmented into short lengths and is susceptible to chemical damage. Barcodes of unique molecular identifiers have been implemented to overcome the intrinsic errors of next-generation sequencing, which is the prevailing method for highly multiplexed cfDNA analysis. However, a number of methodological and pre-analytical factors limit the clinical sensitivity of the cfDNA-based detection of cancers from liquid biopsies. In this Review, we describe the state-of-the-art technologies for cfDNA analysis, with emphasis on multiplexing strategies, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve cancer diagnostics and patient care.
Collapse
Affiliation(s)
- Ping Song
- Department of Bioengineering, Rice University, Houston, TX, USA
| | - Lucia Ruojia Wu
- Department of Bioengineering, Rice University, Houston, TX, USA
| | | | | | - Tianqing Chu
- Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lawrence N Kwong
- Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA
| | - Abhijit A Patel
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
| | | |
Collapse
|
|
38
|
ctDNA as a biomarker of progression in oesophageal adenocarcinoma. ESMO Open 2022; 7:100452. [PMID: 35798469 PMCID: PMC9271467 DOI: 10.1016/j.esmoop.2022.100452] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/09/2022] [Accepted: 02/20/2022] [Indexed: 12/24/2022] Open
Abstract
Background The incidence of oesophageal adenocarcinoma (OAC) is rapidly increasing and despite improvements in treatment, the 5-year survival rate remains poor. Prognostic biomarkers that address the genomic heterogeneity in this highly complex disease will aid the development of precision therapeutics and improve patient survival. The aim of this study was to determine whether circulating tumour DNA (ctDNA) has prognostic significance as a biomarker in OAC patients. Patients and methods We profiled 209 blood and tumour samples from 57 OAC patients. Using a panel of 77 cancer genes, we sequenced ctDNA in plasma samples (n = 127) which were taken at multiple time points before and after therapy. In parallel, we sequenced matched tumour samples from 39 patients using the same gene panel. To assess whether the ctDNA profile reflected the tumour heterogeneity, we sequenced additional multi-region primary tumour samples in 17 patients. In addition, we analysed whole-genome and whole-exome sequencing data from primary tumours for a subset of 18 patients. Results Using a tumour-agnostic approach, we found that detectable ctDNA variants in post-treatment plasma samples were associated with worse disease-specific survival. To evaluate whether the ctDNA originated from the primary tumour, we carried out a tumour-informed analysis which confirmed post-treatment ctDNA variants were associated with worse survival. To determine whether ctDNA could be used as a clinical follow-up test, we assessed blood samples from multiple time points before and after treatment, in a subset of patients. Results showed that the variant allele frequency of ctDNA variants increased with disease recurrence. Conclusion This study demonstrates that ctDNA variants can be detected in patients with OAC and this has potential clinical utility as a prognostic biomarker for survival.
Detection of ctDNA variants was associated with worse disease-specific survival in OAC. In a tumour-informed approach, ctDNA variants were confirmed using multiple biopsies from the primary tumour. ctDNA variants reflected the intratumour heterogeneity associated with OAC. ctDNA can be used as a personalised prognostic biomarker for patients with OAC.
Collapse
|
|
39
|
Marcozzi A, Jager M, Elferink M, Straver R, van Ginkel JH, Peltenburg B, Chen LT, Renkens I, van Kuik J, Terhaard C, de Bree R, Devriese LA, Willems SM, Kloosterman WP, de Ridder J. Accurate detection of circulating tumor DNA using nanopore consensus sequencing. NPJ Genom Med 2021; 6:106. [PMID: 34887408 PMCID: PMC8660781 DOI: 10.1038/s41525-021-00272-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 11/09/2021] [Indexed: 12/26/2022] Open
Abstract
Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ~60×, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in clinical workflows.
Collapse
Affiliation(s)
- Alessio Marcozzi
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands.,Cyclomics, Utrecht, CG, The Netherlands
| | - Myrthe Jager
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Martin Elferink
- Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Roy Straver
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Joost H van Ginkel
- Department of pathology, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands.,Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Boris Peltenburg
- Department of Radiotherapy, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Li-Ting Chen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Ivo Renkens
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Joyce van Kuik
- Department of pathology, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands
| | - Chris Terhaard
- Department of Radiotherapy, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Remco de Bree
- Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lot A Devriese
- Department of Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Stefan M Willems
- Department of pathology, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands.,Department of Pathology and Medical Biology, University Medical Center Groningen, Rijksuniversiteit Groningen, Groningen, GZ, The Netherlands
| | - Wigard P Kloosterman
- Cyclomics, Utrecht, CG, The Netherlands. .,Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands.
| | - Jeroen de Ridder
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, CX, The Netherlands. .,Cyclomics, Utrecht, CG, The Netherlands.
| |
Collapse
|
|
40
|
Guven DC, Sahin TK, Yildirim HC, Aktepe OH, Dizdar O, Yalcin S. A systematic review and meta-analysis of the association between circulating tumor DNA (ctDNA) and prognosis in pancreatic cancer. Crit Rev Oncol Hematol 2021; 168:103528. [PMID: 34800650 DOI: 10.1016/j.critrevonc.2021.103528] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 10/26/2021] [Accepted: 11/15/2021] [Indexed: 02/08/2023] Open
Abstract
Pancreatic cancer is a deadly disease with limited therapeutic options. Several strategies are being investigated to improve disease management, including the early diagnosis of recurrences and treatment tailoring by better prognosis estimation. Circulating tumor DNA (ctDNA) could be a promising tool in this regard, although the data is limited. Therefore, we conducted a systemical review and meta-analysis of the published studies on the association of ctDNA and survival outcomes in pancreatic cancer. In the pooled analysis, positive preoperative or postoperative ctDNA was associated with lower RFS/PFS (HR: 2.27, 95 % CI: 1.59-3.24, p < 0.001) and OS (HR: 2.04, 95 % CI: 1.29-3.21, p = 0.002) in localized pancreatic cancer. Similarly, positive baseline ctDNA was associated with lower RFS/PFS (HR: 2.61, 95 % CI: 1.94-3.51, p < 0.001) and OS (HR: 2.41, 95 % CI: 1.74-3.34, p < 0.001) in advanced pancreatic cancer. In conclusion, ctDNA could be a promising tool to individualize treatment planning and to improve outcomes in pancreatic cancer.
Collapse
Affiliation(s)
| | | | | | | | - Omer Dizdar
- Hacettepe University Cancer Institute, Ankara, Turkey
| | - Suayib Yalcin
- Hacettepe University Cancer Institute, Ankara, Turkey
| |
Collapse
|
|
41
|
Pérez-Ruiz E, Gutiérrez V, Muñoz M, Oliver J, Sánchez M, Gálvez-Carvajal L, Rueda-Domínguez A, Barragán I. Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma. Biomedicines 2021; 9:biomedicines9101478. [PMID: 34680596 PMCID: PMC8533108 DOI: 10.3390/biomedicines9101478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 11/16/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours.
Collapse
Affiliation(s)
- Elisabeth Pérez-Ruiz
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Oncology Department, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (V.G.); (M.M.); (L.G.-C.)
- Correspondence: (E.P.-R.); (A.R.-D.)
| | - Vanesa Gutiérrez
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Oncology Department, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (V.G.); (M.M.); (L.G.-C.)
| | - Marta Muñoz
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Oncology Department, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (V.G.); (M.M.); (L.G.-C.)
| | - Javier Oliver
- Researcher Unit, Unidad de Gestión Clínica Intercentros de Oncología Médica, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (J.O.); or (I.B.)
| | - Marta Sánchez
- Maxillofacial Surgery Department, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain;
| | - Laura Gálvez-Carvajal
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Oncology Department, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (V.G.); (M.M.); (L.G.-C.)
| | - Antonio Rueda-Domínguez
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Oncology Department, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (V.G.); (M.M.); (L.G.-C.)
- Correspondence: (E.P.-R.); (A.R.-D.)
| | - Isabel Barragán
- Researcher Unit, Unidad de Gestión Clínica Intercentros de Oncología Médica, Institute of Biomedical Investigation of Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, 29010 Malaga, Spain; (J.O.); or (I.B.)
- Group of Pharmacoepigenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
| |
Collapse
|
|
42
|
Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes. EPMA J 2021; 12:545-558. [PMID: 34642594 PMCID: PMC8495186 DOI: 10.1007/s13167-021-00254-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022]
Abstract
The agenda of pharmacology discovery in the field of personalized oncology was dictated by the search of molecular targets assumed to deterministically drive tumor development. In this perspective, genes play a fundamental "causal" role while cells simply act as causal proxies, i.e., an intermediate between the molecular input and the organismal output. However, the ceaseless genomic change occurring across time within the same primary and metastatic tumor has broken the hope of a personalized treatment based only upon genomic fingerprint. Indeed, current models are unable in capturing the unfathomable complexity behind the outbreak of a disease, as they discard the contribution of non-genetic factors, environment constraints, and the interplay among different tiers of organization. Herein, we posit that a comprehensive personalized model should view at the disease as a "historical" process, in which different spatially and timely distributed factors interact with each other across multiple levels of organization, which collectively interact with a dynamic gene-expression pattern. Given that a disease is a dynamic, non-linear process - and not a static-stable condition - treatments should be tailored according to the "timing-frame" of each condition. This approach can help in detecting those critical transitions through which the system can access different attractors leading ultimately to diverse outcomes - from a pre-disease state to an overt illness or, alternatively, to recovery. Identification of such tipping points can substantiate the predictive and the preventive ambition of the Predictive, Preventive and Personalized Medicine (PPPM/3PM). However, an unusual effort is required to conjugate multi-omics approaches, data collection, and network analysis reconstruction (eventually involving innovative Artificial Intelligent tools) to recognize the critical phases and the relevant targets, which could help in patient stratification and therapy personalization.
Collapse
|
|
43
|
The scope of liquid biopsy in the clinical management of oral cancer. Int J Oral Maxillofac Surg 2021; 51:591-601. [PMID: 34462176 DOI: 10.1016/j.ijom.2021.08.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/18/2021] [Accepted: 08/11/2021] [Indexed: 12/24/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most prevalent forms of head and neck cancer, and it remains a leading cause of death in developing countries. Failure to detect the disease at an early stage is the main reason for the lack of improvement in the overall survival rate over the decades. Even though tissue biopsy is considered as the gold standard for diagnosis and molecular workup, it is an invasive, expensive and time-consuming procedure. Besides, it may not indicate the genetic status of the entire tumour owing to the heterogeneity of the cancer. In this context, liquid biopsy could be quite useful as it provides a more representative picture of the circulating tumour cells, circulating tumour DNA, circulating RNA, and tumour-derived exosomes obtained from all types of body fluids. This technique provides real-time assessment of variations in the molecular profile of the whole tumour and enables the serial monitoring of the disease status. The method has many advantages, such as easy accessibility, reliability, reproducibility and the possibility for early detection of the disease. However, the concept is still in its infancy, and the research on its application in various tumours including OSCC is rapidly progressing.
Collapse
|
|
44
|
Liquid Biopsy for Biomarker Testing in Non-Small Cell Lung Cancer: A European Perspective. JOURNAL OF MOLECULAR PATHOLOGY 2021. [DOI: 10.3390/jmp2030022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
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.
Collapse
|
|
45
|
Liebs S, Eder T, Klauschen F, Schütte M, Yaspo ML, Keilholz U, Tinhofer I, Kidess-Sigal E, Braunholz D. Applicability of liquid biopsies to represent the mutational profile of tumor tissue from different cancer entities. Oncogene 2021; 40:5204-5212. [PMID: 34230613 PMCID: PMC8376638 DOI: 10.1038/s41388-021-01928-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 06/18/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023]
Abstract
Genetic investigation of tumor heterogeneity and clonal evolution in solid cancers could be assisted by the analysis of liquid biopsies. However, tumors of various entities might release different quantities of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) into the bloodstream, potentially limiting the diagnostic potential of liquid biopsy in distinct tumor histologies. Patients with advanced colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), and melanoma (MEL) were enrolled in the study, representing tumors with different metastatic patterns. Mutation profiles of cfDNA, CTCs, and tumor tissue were assessed by panel sequencing, targeting 327 cancer-related genes. In total, 30 tissue, 18 cfDNA, and 7 CTC samples from 18 patients were sequenced. Best concordance between the mutation profile of tissue and cfDNA was achieved in CRC and MEL, possibly due to the remarkable heterogeneity of HNSCC (63%, 55% and 11%, respectively). Concordance especially depended on the amount of cfDNA used for library preparation. While 21 of 27 (78%) tissue mutations were retrieved in high-input cfDNA samples (30-100 ng, N = 8), only 4 of 65 (6%) could be detected in low-input samples (<30 ng, N = 10). CTCs were detected in 13 of 18 patients (72%). However, downstream analysis was limited by poor DNA quality, allowing targeted sequencing of only seven CTC samples isolated from four patients. Only one CTC sample reflected the mutation profile of the respective tumor. Private mutations, which were detected in CTCs but not in tissue, suggested the presence of rare subclones. Our pilot study demonstrated superiority of cfDNA- compared to CTC-based mutation profiling. It was further shown that CTCs may serve as additional means to detect rare subclones possibly involved in treatment resistance. Both findings require validation in a larger patient cohort.
Collapse
Affiliation(s)
- Sandra Liebs
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
| | - Theresa Eder
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Frederick Klauschen
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | | | - Marie-Laure Yaspo
- Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of Cancer, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ingeborg Tinhofer
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Evelyn Kidess-Sigal
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Department of Medicine, Division of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Diana Braunholz
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
46
|
Gutiérrez E, Sánchez I, Díaz O, Valles A, Balderrama R, Fuentes J, Lara B, Olimón C, Ruiz V, Rodríguez J, Bayardo LH, Chan M, Villafuerte CJ, Padayachee J, Sun A. Current Evidence for Stereotactic Body Radiotherapy in Lung Metastases. ACTA ACUST UNITED AC 2021; 28:2560-2578. [PMID: 34287274 PMCID: PMC8293144 DOI: 10.3390/curroncol28040233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/25/2022]
Abstract
Lung metastases are the second most common malignant neoplasms of the lung. It is estimated that 20–54% of cancer patients have lung metastases at some point during their disease course, and at least 50% of cancer-related deaths occur at this stage. Lung metastases are widely accepted to be oligometastatic when five lesions or less occur separately in up to three organs. Stereotactic body radiation therapy (SBRT) is a noninvasive, safe, and effective treatment for metastatic lung disease in carefully selected patients. There is no current consensus on the ideal dose and fractionation for SBRT in lung metastases, and it is the subject of study in ongoing clinical trials, which examines different locations in the lung (central and peripheral). This review discusses current indications, fractionations, challenges, and technical requirements for lung SBRT.
Collapse
Affiliation(s)
- Enrique Gutiérrez
- Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON M5G2M9, Canada; (E.G.); (M.C.); (C.J.V.); (J.P.)
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5G2M9, Canada
| | - Irving Sánchez
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Omar Díaz
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Adrián Valles
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Ricardo Balderrama
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Jesús Fuentes
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Brenda Lara
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Cipatli Olimón
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Víctor Ruiz
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - José Rodríguez
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Luis H. Bayardo
- Western National Medical Center, Department of Radiation Oncology, Mexican Institute of Social Security (IMSS), Belisario Domínguez 1000, Guadalajara 44340, Jalisco, Mexico; (I.S.); (O.D.); (A.V.); (R.B.); (J.F.); (B.L.); (C.O.); (V.R.); (J.R.); (L.H.B.)
| | - Matthew Chan
- Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON M5G2M9, Canada; (E.G.); (M.C.); (C.J.V.); (J.P.)
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5G2M9, Canada
| | - Conrad J. Villafuerte
- Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON M5G2M9, Canada; (E.G.); (M.C.); (C.J.V.); (J.P.)
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5G2M9, Canada
| | - Jerusha Padayachee
- Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON M5G2M9, Canada; (E.G.); (M.C.); (C.J.V.); (J.P.)
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5G2M9, Canada
| | - Alexander Sun
- Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON M5G2M9, Canada; (E.G.); (M.C.); (C.J.V.); (J.P.)
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5G2M9, Canada
- Correspondence: ; Tel.: +1-41-6946-2853
| |
Collapse
|
|
47
|
Bohers E, Viailly PJ, Jardin F. cfDNA Sequencing: Technological Approaches and Bioinformatic Issues. Pharmaceuticals (Basel) 2021; 14:ph14060596. [PMID: 34205827 PMCID: PMC8234829 DOI: 10.3390/ph14060596] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/18/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022] Open
Abstract
In the era of precision medicine, it is crucial to identify molecular alterations that will guide the therapeutic management of patients. In this context, circulating tumoral DNA (ctDNA) released by the tumor in body fluids, like blood, and carrying its molecular characteristics is becoming a powerful biomarker for non-invasive detection and monitoring of cancer. Major recent technological advances, especially in terms of sequencing, have made possible its analysis, the challenge still being its reliable early detection. Different parameters, from the pre-analytical phase to the choice of sequencing technology and bioinformatic tools can influence the sensitivity of ctDNA detection.
Collapse
|
|
48
|
Russo A, Incorvaia L, Del Re M, Malapelle U, Capoluongo E, Gristina V, Castiglia M, Danesi R, Fassan M, Giuffrè G, Gori S, Marchetti A, Normanno N, Pinto C, Rossi G, Santini D, Sartore-Bianchi A, Silvestris N, Tagliaferri P, Troncone G, Cinieri S, Beretta GD. The molecular profiling of solid tumors by liquid biopsy: a position paper of the AIOM-SIAPEC-IAP-SIBioC-SIC-SIF Italian Scientific Societies. ESMO Open 2021; 6:100164. [PMID: 34091263 PMCID: PMC8182269 DOI: 10.1016/j.esmoop.2021.100164] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/02/2021] [Accepted: 05/05/2021] [Indexed: 02/08/2023] Open
Abstract
The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts' opinions, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.
Collapse
Affiliation(s)
- A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
| | - L Incorvaia
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - M Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - U Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - E Capoluongo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE, Biotecnologie Avanzate, Naples, Italy
| | - V Gristina
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - M Castiglia
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - R Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - M Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy; Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
| | - G Giuffrè
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Section of Pathology, University of Messina, Messina, Italy
| | - S Gori
- Department of Oncology, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella, Italy
| | - A Marchetti
- Center of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, Chieti, Italy
| | - N Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - C Pinto
- Medical Oncology Unit, Clinical Cancer Centre, IRCCS-AUSL di Reggio Emilia, Reggio Emilia, Italy
| | - G Rossi
- Pathology Unit, Ospedale Santa Maria Delle Croci, Ravenna, Italy
| | - D Santini
- Department of Medical Oncology, University Campus Biomedico, Rome, Italy
| | - A Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - N Silvestris
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori 'Giovanni Paolo II' of Bari, Bari, Italy; Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - P Tagliaferri
- Medical and Translational Oncology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - G Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - S Cinieri
- Medical Oncology Division and Breast Unit, Senatore Antonio Perrino Hospital, ASL Brindisi, Brindisi, Italy
| | - G D Beretta
- Department of Oncology, Humanitas Gavazzeni, Bergamo, Italy
| |
Collapse
|
|
49
|
Jones J, Nguyen H, Drummond K, Morokoff A. Circulating Biomarkers for Glioma: A Review. Neurosurgery 2021; 88:E221-E230. [PMID: 33442748 DOI: 10.1093/neuros/nyaa540] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/10/2020] [Indexed: 12/18/2022] Open
Abstract
Accurate circulating biomarkers have potential clinical applications in population screening, tumor subclassification, monitoring tumor status, and the delivery of individualized treatments resulting from tumor genotyping. Recently, significant progress has been made within this field in several cancer types, but despite the many potential benefits, currently there is no validated circulating biomarker test for patients with glioma. A number of circulating factors have been examined, including circulating tumor cells, cell-free DNA, microRNA, exosomes, and proteins from both peripheral blood and cerebrospinal fluid with variable results. In the following article, we provide a narrative review of the current evidence pertaining to circulating biomarkers in patients with glioma, including discussion of the advantages and challenges encountered with the current methods used for discovery. Additionally, the potential clinical applications are described with reference to the literature.
Collapse
Affiliation(s)
- Jordan Jones
- Department of Surgery, University of Melbourne, Melbourne, Australia.,Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Australia
| | - Hong Nguyen
- Department of Surgery, University of Melbourne, Melbourne, Australia
| | - Katharine Drummond
- Department of Surgery, University of Melbourne, Melbourne, Australia.,Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Australia
| | - Andrew Morokoff
- Department of Surgery, University of Melbourne, Melbourne, Australia.,Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Australia
| |
Collapse
|
|
50
|
Laprovitera N, Riefolo M, Ambrosini E, Klec C, Pichler M, Ferracin M. Cancer of Unknown Primary: Challenges and Progress in Clinical Management. Cancers (Basel) 2021; 13:451. [PMID: 33504059 PMCID: PMC7866161 DOI: 10.3390/cancers13030451] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3-5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies.
Collapse
Affiliation(s)
- Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
- Department of Life Sciences and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Elisa Ambrosini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Christiane Klec
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Martin Pichler
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| |
Collapse
|