|
1
|
Kotsifa E, Saffioti F, Mavroeidis VK. Cholangiocarcinoma: The era of liquid biopsy. World J Gastroenterol 2025; 31:104170. [PMID: 40124277 PMCID: PMC11924015 DOI: 10.3748/wjg.v31.i11.104170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/14/2025] [Indexed: 03/13/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous malignancy arising from the epithelial cells of the biliary tract. The limitations of the current methods in the diagnosis of CCA highlight the urgent need for new, accurate tools for early cancer detection, better prognostication and patient monitoring. Liquid biopsy (LB) is a modern and non-invasive technique comprising a diverse group of methodologies aiming to detect tumour biomarkers from body fluids. These biomarkers include circulating tumour cells, cell-free DNA, circulating tumour DNA, RNA and extracellular vesicles. The aim of this review is to explore the current and potential future applications of LB in CCA management, with a focus on diagnosis, prognostication and monitoring. We examine both its significant potential and the inevitable limitations associated with this technology. We conclude that LB holds considerable promise, but further research is necessary to fully integrate it into precision oncology for CCA.
Collapse
Affiliation(s)
- Evgenia Kotsifa
- The Second Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
| | - Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
- University College London Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and University College London, London NW3 2QG, United Kingdom
- Division of Clinical and Molecular Hepatology, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina 98124, Italy
| | - Vasileios K Mavroeidis
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of Gastrointestinal Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of HPB Surgery, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8HW, United Kingdom
| |
Collapse
|
|
2
|
Vargas-Accarino E, Higuera M, Bermúdez-Ramos M, Soriano-Varela A, Torrens M, Pons M, Aransay AM, Martín JE, Rodríguez-Frías F, Merino X, Mínguez B. Harnessing Plasma Biomarkers to Predict Immunotherapy Outcomes in Hepatocellular Carcinoma: The Role of cfDNA, ctDNA, and Cytokines. Int J Mol Sci 2025; 26:2794. [PMID: 40141436 PMCID: PMC11942713 DOI: 10.3390/ijms26062794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/07/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Immunotherapy has improved survival in patients with advanced hepatocellular carcinoma (HCC); yet, objective radiological responses occur in only about 20% of cases, suggesting variable benefits. This study aimed to identify serologic markers predictive of response to immune checkpoint inhibitors (ICIs). A cohort of 38 advanced HCC patients receiving immunotherapy was prospectively analyzed. Levels of cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and cytokines were measured pre-treatment and three months post-treatment initiation. Genomic profiling of ctDNA was also conducted. Baseline levels of cfDNA and ctDNA effectively discriminated HCC patients based on their radiological response to ICIs. Additionally, individuals with pathologic mutations in the CDKN2A gene exhibited significantly reduced survival. Patients with progressive disease (PD) as their best radiological response had significantly fewer copy number variations (CNVs) than those with a radiological response. Furthermore, levels of IL10, PD1, and TGFβ assessed after three months of treatment showed significant variations correlating with survival status. In conclusion, the analysis of cfDNA, ctDNA, and cytokines may improve treatment selection for HCC patients by predicting their expected response to immunotherapies.
Collapse
Affiliation(s)
- Elena Vargas-Accarino
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
| | - Mónica Higuera
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
| | - María Bermúdez-Ramos
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
| | - Agnès Soriano-Varela
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - María Torrens
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Mònica Pons
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Ana María Aransay
- Genome Analysis Platform, CIC bioGUNE, 48160 Derio, Spain; (A.M.A.); (J.E.M.)
| | | | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Microbiology and Biochemistry Department, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Xavier Merino
- Radiology Department, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain;
| | - Beatriz Mínguez
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| |
Collapse
|
|
3
|
Bousou TE, Sarantis P, Anastasiou IA, Trifylli EM, Liapopoulos D, Korakaki D, Koustas E, Katsimpoulas M, Karamouzis MV. Biomarkers for the Evaluation of Immunotherapy in Patients with Cholangiocarcinoma. Cancers (Basel) 2025; 17:555. [PMID: 39941920 PMCID: PMC11817672 DOI: 10.3390/cancers17030555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Cholangiocarcinoma is a rare primary liver cancer with poor prognosis, due to the advanced stage at the time of diagnosis and limited therapeutic options, with poor response. Chemotherapy remains the standard first-line treatment, but the advent of immunotherapy has recently induced promising results. Given the fact that diagnosis frequency is increasing nowadays and the survival rate remains very low, it is crucial to recognize patients who are suitable for immunotherapy and will have the best response. Different types of biomarkers, such as interleukins, exosomes, mi-RNA, ctDNA, and gene mutations, have been studied for their feasibility, not only for the early diagnosis of biliary tract cancer but also for the determination of responsiveness in treatment. Less frequently, these studies focus on finding and observing biomarkers in patients who receive immunotherapy. This review aims to summarize current knowledge of existing/promising biomarkers in patients with unresectable or metastatic cholangiocarcinoma, treated with immunotherapy as monotherapy, or combined with chemotherapy.
Collapse
Affiliation(s)
- Thaleia-Eleftheria Bousou
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| | - Panagiotis Sarantis
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Ioanna A. Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Agiou Thoma 17, 115 27 Athens, Greece;
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Agiou Thoma 17, 115 27 Athens, Greece
| | - Eleni-Myrto Trifylli
- GI-Liver Unit, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 115 27 Athens, Greece;
| | - Dimitris Liapopoulos
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| | - Dimitra Korakaki
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Evangelos Koustas
- Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece;
| | - Michalis Katsimpoulas
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Michalis V. Karamouzis
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| |
Collapse
|
|
4
|
Ascari S, Chen R, Vivaldi C, Stefanini B, De Sinno A, Dalbeni A, Federico P, Tovoli F. Advancements in immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 2025; 25:151-165. [PMID: 39913170 DOI: 10.1080/14737140.2025.2461631] [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: 11/11/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION The advent of immune-based combinations, primarily leveraging immune checkpoint inhibitors, has revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). The current scenario features multiple therapies that have shown superiority over tyrosine kinase inhibitors; however, the absence of direct comparisons and validated prognostic biomarkers complicates therapeutic decision-making. Additionally, a significant proportion of patients still exhibit primary or secondary resistance to existing immunotherapies, underscoring the ongoing need for novel therapeutic strategies. AREAS COVERED This narrative review discusses current strategies aimed at improving the efficacy of immunotherapy for HCC, focusing on the following aspects: available therapeutic options, identification of prognostic biomarkers, approaches to overcoming resistance (including the development of neoantigen vaccines), and the exploration of adjuvant and neoadjuvant strategies. EXPERT OPINION The future of systemic therapies for HCC is likely to be driven by advancements in immunotherapy. Key areas of exploration for the coming years include the discovery of novel checkpoint inhibitors or complementary agents to enhance tumor response when combined with existing treatments, a shift toward neoadjuvant/perioperative trials instead of traditional adjuvant approaches, and the development of personalized neoantigen vaccines.
Collapse
Affiliation(s)
- Sara Ascari
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rusi Chen
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea De Sinno
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Dalbeni
- Liver Unit, Medicine Department, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
- Unit of General Medicine C, Medicine Department, University of Verona and Hospital Trust (AOUI) of Verona, Verona, Italy
| | | | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| |
Collapse
|
|
5
|
Battaglin F, Lenz HJ. Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers. JCO Oncol Pract 2024; 20:1481-1490. [PMID: 39531845 PMCID: PMC11567053 DOI: 10.1200/op.24.00167] [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: 02/29/2024] [Revised: 04/11/2024] [Accepted: 05/01/2024] [Indexed: 11/16/2024] Open
Abstract
Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms. Here, we review the clinical applications, advantages, and limitations of ctDNA profiling for precision oncology in GI cancers.
Collapse
Affiliation(s)
- Francesca Battaglin
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| |
Collapse
|
|
6
|
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
|
|
7
|
Lee SH, Song SY. Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications. Cancers (Basel) 2024; 16:1761. [PMID: 38730713 PMCID: PMC11083053 DOI: 10.3390/cancers16091761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings.
Collapse
Affiliation(s)
- Sang-Hoon Lee
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Republic of Korea;
| | - Si Young Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03772, Republic of Korea
| |
Collapse
|
|
8
|
Chen X, Kou L, Xie X, Su S, Li J, Li Y. Prognostic biomarkers associated with immune checkpoint inhibitors in hepatocellular carcinoma. Immunology 2024; 172:21-45. [PMID: 38214111 DOI: 10.1111/imm.13751] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 12/31/2023] [Indexed: 01/13/2024] Open
Abstract
The treatment of hepatocellular carcinoma (HCC), particularly advanced HCC, has been a serious challenge. Immune checkpoint inhibitors (ICIs) are landmark drugs in the field of cancer therapy in recent years, which have changed the landscape of cancer treatment. In the field of HCC treatment, this class of drugs has shown good therapeutic prospects. For example, atezolizumab in combination with bevacizumab has been approved as first-line treatment for advanced HCC due to significant efficacy. However, sensitivity to ICI therapy varies widely among HCC patients. Therefore, there is an urgent need to search for determinants of resistance/sensitivity to ICIs and to screen biomarkers that can predict the efficacy of ICIs. This manuscript reviews the research progress of prognostic biomarkers associated with ICIs in HCC in order to provide a scientific basis for the development of clinically individualised precision medication regimens.
Collapse
Affiliation(s)
- Xiu Chen
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Liqiu Kou
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiaolu Xie
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Song Su
- Department of Hepatology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Jun Li
- Department of Traditional Chinese Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Yaling Li
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| |
Collapse
|
|
9
|
Liu Y, Bi X, Leng Y, Chen D, Wang J, Ma Y, Zhang MZ, Han BW, Li Y. A deep-learning-based genomic status estimating framework for homologous recombination deficiency detection from low-pass whole genome sequencing. Heliyon 2024; 10:e26121. [PMID: 38404843 PMCID: PMC10884843 DOI: 10.1016/j.heliyon.2024.e26121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/07/2024] [Indexed: 02/27/2024] Open
Abstract
Genome-wide sequencing allows for prediction of clinical treatment responses and outcomes by estimating genomic status. Here, we developed Genomic Status scan (GSscan), a long short-term memory (LSTM)-based deep-learning framework, which utilizes low-pass whole genome sequencing (WGS) data to capture genomic instability-related features. In this study, GSscan directly surveys homologous recombination deficiency (HRD) status independent of other existing biomarkers. In breast cancer, GSscan achieved an AUC of 0.980 in simulated low-pass WGS data, and obtained a higher HRD risk score in clinical BRCA-deficient breast cancer samples (p = 1.3 × 10-4, compared with BRCA-intact samples). In ovarian cancer, GSscan obtained higher HRD risk scores in BRCA-deficient samples in both simulated data and clinical samples (p = 2.3 × 10-5 and p = 0.039, respectively, compared with BRCA-intact samples). Moreover, HRD-positive patients predicted by GSscan showed longer progression-free intervals in TCGA datasets (p = 0.0011) treated with platinum-based adjuvant chemotherapy, outperforming existing low-pass WGS-based methods. Furthermore, GSscan can accurately predict HRD status using only 1 ng of input DNA and a minimum sequencing coverage of 0.02 × , providing a reliable, accessible, and cost-effective approach. In summary, GSscan effectively and accurately detected HRD status, and provide a broadly applicable framework for disease diagnosis and selecting appropriate disease treatment.
Collapse
Affiliation(s)
- Yang Liu
- Department of BC Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiang Bi
- Department of Breast Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Yang Leng
- Guangdong Jiyin Biotech Co. Ltd, Shenzhen, Guangdong, China
| | - Dan Chen
- Guangdong Jiyin Biotech Co. Ltd, Shenzhen, Guangdong, China
| | - Juan Wang
- Guangdong Jiyin Biotech Co. Ltd, Shenzhen, Guangdong, China
| | - Youjia Ma
- Guangdong Jiyin Biotech Co. Ltd, Shenzhen, Guangdong, China
| | - Min-Zhe Zhang
- GeneGenieDx Corp, 160 E Tasman Dr, San Jose, CA, USA
| | - Bo-Wei Han
- Guangdong Jiyin Biotech Co. Ltd, Shenzhen, Guangdong, China
| | - Yalun Li
- Department of Breast Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| |
Collapse
|
|
10
|
Zhang N, Yang X, Piao M, Xun Z, Wang Y, Ning C, Zhang X, Zhang L, Wang Y, Wang S, Chao J, Lu Z, Yang X, Wang H, Zhao H. Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma. Biomark Res 2024; 12:26. [PMID: 38355603 PMCID: PMC10865587 DOI: 10.1186/s40364-023-00535-z] [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: 09/20/2023] [Accepted: 10/23/2023] [Indexed: 02/16/2024] Open
Abstract
Systemic therapies using programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have demonstrated commendable efficacy in some patients with advanced hepatocellular carcinoma (HCC); however, other individuals do not respond favorably. Hence, identifying the biomarkers, the prognostic factors, and their underlying mechanisms is crucial. In this review, we summarized the latest advancements in this field. Within the tumor microenvironment, PD-L1 expression is commonly utilized to predict response. Moreover, the characteristics of tumor-infiltrating lymphocytes are associated with the effectiveness of immunotherapy. Preclinical studies have identified stimulatory dendritic cells, conventional dendritic cells, and macrophages as potential biomarkers. The emergence of single-cell sequencing and spatial transcriptomics has provided invaluable insights into tumor heterogeneity through the lens of single-cell profiling and spatial distribution. With the widespread adoption of next-generation sequencing, certain genomic characteristics, including tumor mutational burden, copy number alterations, specific genes (TP53, CTNNB1, and GZMB), and signaling pathways (WNT/β-catenin) have been found to correlate with prognosis. Furthermore, clinical features such as tumor size, number, and metastasis status have demonstrated prognostic value. Notably, common indicators such as the Child-Pugh score and Eastern Cooperative Oncology Group score, which are used in patients with liver diseases, have shown potential. Similarly, commonly employed laboratory parameters such as baseline transforming growth factor beta, lactate dehydrogenase, dynamic changes in alpha-fetoprotein (AFP) and abnormal prothrombin, CRAFITY score (composed of C-reactive protein and AFP), and immune adverse events have been identified as predictive biomarkers. Novel imaging techniques such as EOB-MRI and PET/CT employing innovative tracers also have potential. Moreover, liquid biopsy has gained widespread use in biomarker studies owing to its non-invasive, convenient, and highly reproducible nature, as well as its dynamic monitoring capabilities. Research on the gut microbiome, including its composition, dynamic changes, and metabolomic analysis, has gained considerable attention. Efficient biomarker discovery relies on continuous updating of treatment strategies. Next, we summarized recent advancements in clinical research on HCC immunotherapy and provided an overview of ongoing clinical trials for contributing to the understanding and improvement of HCC immunotherapy.
Collapse
Affiliation(s)
- Nan Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Beijing, 100730, China
| | - Mingjian Piao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Ziyu Xun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Yunchao Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Cong Ning
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Xinmu Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Longhao Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Yanyu Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Shanshan Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Jiashuo Chao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Zhenhui Lu
- Hepatobiliary and Pancreatic Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, No.36 Industrial 8 Road, Nanshan District, Shenzhen City, Guangdong province, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China.
| | - Hanping Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Beijing, 100730, China.
| |
Collapse
|
|
11
|
Yang X, Lian B, Zhang N, Long J, Li Y, Xue J, Chen X, Wang Y, Wang Y, Xun Z, Piao M, Zhu C, Wang S, Sun H, Song Z, Lu L, Dong X, Wang A, Liu W, Pan J, Hou X, Guan M, Huo L, Shi J, Zhang H, Zhou J, Lu Z, Mao Y, Sang X, Wu L, Yang X, Wang K, Zhao H. Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma. BMC Med 2024; 22:42. [PMID: 38281914 PMCID: PMC10823746 DOI: 10.1186/s12916-024-03257-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/15/2024] [Indexed: 01/30/2024] Open
Abstract
BACKGROUND Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).
Collapse
Affiliation(s)
- Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Breast Surgery, Peking, Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | | | - Nan Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junyu Long
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiran Li
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingnan Xue
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangqi Chen
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunchao Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanyu Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ziyu Xun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingjian Piao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenpei Zhu
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shanshan Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huishan Sun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | | | | | | | | | - Jie Pan
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaorong Hou
- Department of Radiotherapy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mei Guan
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Li Huo
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jie Shi
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Zhenhui Lu
- Hepatobiliary and Pancreatic Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China
| | - Yilei Mao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liqun Wu
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kai Wang
- OrigiMed Co., Ltd, Shanghai, China.
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
12
|
Kim K, Kim H, Shin I, Noh SJ, Kim JY, Suh KJ, Kim YN, Lee JY, Cho DY, Kim SH, Kim JH, Lee SH, Choi JK. Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer. Sci Rep 2023; 13:22482. [PMID: 38110532 PMCID: PMC10728099 DOI: 10.1038/s41598-023-49639-4] [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: 08/08/2023] [Accepted: 12/10/2023] [Indexed: 12/20/2023] Open
Abstract
Genomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, it remains unclear whether this approach can be applied to cell-free DNA (cfDNA) and whether it can address the issue of low tumor purity encountered in tissue-based methylation profiling. In this study, we developed an assay named iMethyl, designed to estimate the genomic hypomethylation status from cfDNA. This was achieved through deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n = 167; tissue n = 137; cfDNA early during treatment n = 40), breast cancer (cfDNA n = 91; tissue n = 50; PBMC n = 50; cfDNA at progression n = 44), and ovarian cancer (tissue n = 74). iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. In conclusion, our iMethyl-liquid method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy.
Collapse
Affiliation(s)
- Kyeonghui Kim
- Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea
| | - Hyemin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Inkyung Shin
- Penta Medix Co., Ltd, Seongnam-si, Gyeongi-do, Republic of Korea
| | - Seung-Jae Noh
- Penta Medix Co., Ltd, Seongnam-si, Gyeongi-do, Republic of Korea
| | - Jeong Yeon Kim
- Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea
| | - Koung Jin Suh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeongi-do, Republic of Korea
| | - Yoo-Na Kim
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung-Yun Lee
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dae-Yeon Cho
- Penta Medix Co., Ltd, Seongnam-si, Gyeongi-do, Republic of Korea
| | - Se Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeongi-do, Republic of Korea.
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeongi-do, Republic of Korea.
| | - Se-Hoon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
| | - Jung Kyoon Choi
- Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
- Penta Medix Co., Ltd, Seongnam-si, Gyeongi-do, Republic of Korea.
| |
Collapse
|
|
13
|
Dong W, Ji Y, Pi S, Chen QF. Noninvasive imaging-based machine learning algorithm to identify progressive disease in advanced hepatocellular carcinoma receiving second-line systemic therapy. Sci Rep 2023; 13:10690. [PMID: 37393336 PMCID: PMC10314898 DOI: 10.1038/s41598-023-37862-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/28/2023] [Indexed: 07/03/2023] Open
Abstract
The aim of this study was to predict tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies (TKI-PD-1) efficacy as second-line treatment in advanced hepatocellular carcinoma (HCC) using radiomics analysis. From November 2018 to November 2019, a total of 55 patients were included. Radiomic features were obtained from the CT images before treatment and filtered using intraclass correlation coefficients (ICCs) and least absolute shrinkage and selection operator (LASSO) methods. Subsequently, ten prediction algorithms were developed and validated based on radiomic characteristics. The accuracy of the constructed model was measured through area under the receiver operating characteristic curve (AUC) analysis; survival analysis was performed via Kaplan-Meier and Cox regression analyses. Overall, 18 (32.7%) out of 55 patients had progressive disease. Through ICCs and LASSO, ten radiomic features were entered into the algorithm construction and validation. Ten machine learning algorithms showed different accuracies, with the support vector machine (SVM) model having the highest AUC value of 0.933 in the training cohort and 0.792 in the testing cohort. The radiomic features were associated with overall survival. In conclsion, the SVM algorithm is a useful method to predict TKI-PD-1 efficacy in patients with advanced HCC using images taken prior to treatment.
Collapse
Affiliation(s)
- Wei Dong
- Department of Medical Oncology, Nanyang Second People's Hospital, Nanyang, China
| | - Ye Ji
- Department of Medical Oncology, Nanyang Central Hospital, Nanyang, China
| | - Shan Pi
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
| | - Qi-Feng Chen
- Department of Medical Imaging and Interventional Radiology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China.
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
| |
Collapse
|
|
14
|
Ren XD, Su N, Sun XG, Li WM, Li J, Li BW, Li RX, Lv J, Xu QY, Kong WL, Huang Q. Advances in liquid biopsy-based markers in NSCLC. Adv Clin Chem 2023; 114:109-150. [PMID: 37268331 DOI: 10.1016/bs.acc.2023.02.004] [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: 06/04/2023]
Abstract
Lung cancer is the second most-frequently occurring cancer and the leading cause of cancer-associated deaths worldwide. Non-small cell lung cancer (NSCLC), the most common type of lung cancer is often diagnosed in middle or advanced stages and have poor prognosis. Diagnosis of disease at an early stage is a key factor for improving prognosis and reducing mortality, whereas, the currently used diagnostic tools are not sufficiently sensitive for early-stage NSCLC. The emergence of liquid biopsy has ushered in a new era of diagnosis and management of cancers, including NSCLC, since analysis of circulating tumor-derived components, such as cell-free DNA (cfDNA), circulating tumor cells (CTCs), cell-free RNAs (cfRNAs), exosomes, tumor-educated platelets (TEPs), proteins, and metabolites in blood or other biofluids can enable early cancer detection, treatment selection, therapy monitoring and prognosis assessment. There have been great advances in liquid biopsy of NSCLC in the past few years. Hence, this chapter introduces the latest advances on the clinical application of cfDNA, CTCs, cfRNAs and exosomes, with a particular focus on their application as early markers in the diagnosis, treatment and prognosis of NSCLC.
Collapse
Affiliation(s)
- Xiao-Dong Ren
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Ning Su
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Xian-Ge Sun
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Wen-Man Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Jin Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Bo-Wen Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Ruo-Xu Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Jing Lv
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Qian-Ying Xu
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Wei-Long Kong
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Qing Huang
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China.
| |
Collapse
|
|
15
|
Yang M, Zhao Y, Li Y, Cui X, Liu F, Wu W, Wang XA, Li M, Liu Y, Liu Y. Afatinib in combination with GEMOX chemotherapy as the adjuvant treatment in patients with ErbB pathway mutated, resectable gallbladder cancer: study protocol for a ctDNA-based, multicentre, open-label, randomised, controlled, phase II trial. BMJ Open 2023; 13:e061892. [PMID: 36854604 PMCID: PMC9980349 DOI: 10.1136/bmjopen-2022-061892] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 03/02/2023] Open
Abstract
INTRODUCTION Gallbladder cancer (GBC) is an aggressive type of digestive system cancer with a dismal outcome. Given the lack of effective treatment options, the disease rapidly reoccurs and 5-year survival rate is <5%. Our team previously found that a significant percentage of GBC tissues harboured mutations of the ErbB-related pathway. Afatinib is a chemically synthesised drug specifically targeting the ErbB pathway mutations. However, its efficacy in the treatment of patients with GBC remains unknown. Circulating tumour DNA (ctDNA) refers to a proportion of cell-free DNA in the blood which is released by apoptotic and necrotic cells from tumours in situ, metastatic foci or circulating tumour cells. ctDNA-based liquid biopsy is a non-invasive pathological detection method that offers additional value to evaluate the therapeutic efficacy of antitumour drugs. METHODS AND ANALYSIS We conduct a multicentre and randomised study on afatinib combined with gemcitabine and oxaliplatin (GEMOX) in patients with ErbB pathway mutated GBC. Clinical and biological evaluation involving ErbB pathway ctDNA detection will be made during the 3-year follow-up after participation. The primary objective of this clinical trial is to evaluate the clinical efficacy of afatinib. Disease-free survival is the primary end point and will be correlated with plasma ctDNA of patients in the treatment with afatinib. In addition, we will evaluate the sensitivity and specificity of plasma ctDNA for monitoring tumour recurrence and progression. Finally, we will assess the safety of afatinib by keeping an eye on the safety indicators. ETHICS AND DISSEMINATION The study was approved by the medical-ethical review committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The clinical trials results, even inconclusive, will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT04183712.
Collapse
Affiliation(s)
- Mao Yang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yuhao Zhao
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yongsheng Li
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Xuya Cui
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Fatao Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Wenguang Wu
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Xu-An Wang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yun Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| |
Collapse
|
|
16
|
Labiano I, Huerta AE, Arrazubi V, Hernandez-Garcia I, Mata E, Gomez D, Arasanz H, Vera R, Alsina M. State of the Art: ctDNA in Upper Gastrointestinal Malignancies. Cancers (Basel) 2023; 15:1379. [PMID: 36900172 PMCID: PMC10000247 DOI: 10.3390/cancers15051379] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive source to characterize genetic alterations related to the tumor. Upper gastrointestinal cancers, including gastroesophageal adenocarcinoma (GEC), biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PADC) are poor prognostic malignancies, usually diagnosed at advanced stages when no longer amenable to surgical resection and show a poor prognosis even for resected patients. In this sense, ctDNA has emerged as a promising non-invasive tool with different applications, from early diagnosis to molecular characterization and follow-up of tumor genomic evolution. In this manuscript, novel advances in the field of ctDNA analysis in upper gastrointestinal tumors are presented and discussed. Overall, ctDNA analyses can help in early diagnosis, outperforming current diagnostic approaches. Detection of ctDNA prior to surgery or active treatment is also a prognostic marker that associates with worse survival, while ctDNA detection after surgery is indicative of minimal residual disease, anticipating in some cases the imaging-based detection of progression. In the advanced setting, ctDNA analyses characterize the genetic landscape of the tumor and identify patients for targeted-therapy approaches, and studies show variable concordance levels with tissue-based genetic testing. In this line, several studies also show that ctDNA serves to follow responses to active therapy, especially in targeted approaches, where it can detect multiple resistance mechanisms. Unfortunately, current studies are still limited and observational. Future prospective multi-center and interventional studies, carefully designed to assess the value of ctDNA to help clinical decision-making, will shed light on the real applicability of ctDNA in upper gastrointestinal tumor management. This manuscript presents a review of the evidence available in this field up to date.
Collapse
Affiliation(s)
- Ibone Labiano
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Ana Elsa Huerta
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Virginia Arrazubi
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Irene Hernandez-Garcia
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Elena Mata
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - David Gomez
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Hugo Arasanz
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Ruth Vera
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Maria Alsina
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| |
Collapse
|
|
17
|
Peng X, Gong C, Zhang W, Zhou A. Advanced development of biomarkers for immunotherapy in hepatocellular carcinoma. Front Oncol 2023; 12:1091088. [PMID: 36727075 PMCID: PMC9885011 DOI: 10.3389/fonc.2022.1091088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/20/2022] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Mono-immunotherapy and combination therapy with immune checkpoint inhibitors (ICIs) and multitargeted tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) inhibitors have become new standard therapies in advanced HCC (aHCC). However, the clinical benefit of these treatments is still limited. Thus, proper biomarkers which can predict treatment response to immunotherapy to maximize clinical benefit while sparing unnecessary toxicity are urgently needed. Contrary to other malignancies, up until now, no acknowledged biomarkers are available to predict resistance or response to immunotherapy for HCC patients. Furthermore, biomarkers, which are established in other cancer types, such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), have no stable predictive effect in HCC. Thus, plenty of research focusing on biomarkers for HCC is under exploration. In this review, we summarize the predictive and prognostic biomarkers as well as the potential predictive mechanism in order to guide future research direction for biomarker exploration and clinical treatment options in HCC.
Collapse
|
|
18
|
Wang X, Yang X, Wang J, Dong C, Ding J, Wu M, Wang Y, Ding H, Zhang H, Sang X, Zhao H, Huo L. Metabolic Tumor Volume Measured by 18F-FDG PET/CT is Associated with the Survival of Unresectable Hepatocellular Carcinoma Treated with PD-1/PD-L1 Inhibitors Plus Molecular Targeted Agents. J Hepatocell Carcinoma 2023; 10:587-598. [PMID: 37063093 PMCID: PMC10094465 DOI: 10.2147/jhc.s401647] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/21/2023] [Indexed: 04/18/2023] Open
Abstract
Purpose The combination of PD-1/PD-L1 inhibitors and molecular targeted agents showed promising efficacy for unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the prognostic value of metabolic parameters from 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in patients with uHCC underwent the combined therapies. Patients and Methods Patients with uHCC treated with a combination of immunotherapy and targeted therapy who underwent baseline 18F-FDG PET/CT between July 2018 and December 2021 were recruited retrospectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake values (SUVmax), and clinical and biological parameters were recorded. A multivariate prediction model was developed for overall survival (OS) using these parameters together with clinical prognostic factors. Results Seventy-seven patients were finally included. The median OS was 16.8 months. We found that a high MTV (≥39.65 cm3 as the median value) was significantly associated with OS (P<0.05). In multivariate analyses for OS, a high MTV, high Eastern Cooperative Oncology Group performance status (ECOG-PS, ≥1), Child-Pugh (B-C) grade, and the presence of bone metastasis were significantly associated with poor OS (HR 1.371, HR 3.73, HR 15.384, and HR 2.994, all P<0.05, respectively). A multivariate prognostic model including MTV and prognostic factors, such as ECOG-PS, Child-Pugh grade, and bone metastasis, further improved the identification of different OS subgroups. Conclusion High MTV is an adverse prognostic factor in patients with uHCC treated with a combination of immunotherapy and molecular targeted agents. Integrating PET/CT parameters with clinical prognostic factors could help to personalize immunotherapy.
Collapse
Affiliation(s)
- Xuezhu Wang
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Jingnan Wang
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Chengyan Dong
- GE Healthcare China, Beijing, People’s Republic of China
| | - Jie Ding
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Meiqi Wu
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yanyu Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Haiyan Ding
- Department of Biomedical Engineering, Tsinghua University, Beijing, People’s Republic of China
| | - Hui Zhang
- Department of Biomedical Engineering, Tsinghua University, Beijing, People’s Republic of China
| | - Xinting Sang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Correspondence: Li Huo; Haitao Zhao, #1 Shuaifuyuan, Dongcheng District, Beijing, People’s Republic of China, Tel +86 13910801986; +86 13901246374, Email ;
| | - Li Huo
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Correspondence: Li Huo; Haitao Zhao, #1 Shuaifuyuan, Dongcheng District, Beijing, People’s Republic of China, Tel +86 13910801986; +86 13901246374, Email ;
| |
Collapse
|
|
19
|
Yang X, Zhang N, Song Y, Yang X, Sang X, Zhao H. Immunotherapy prototype Mark 3.0 model in primary liver cancer: adding locoregional stereotactic therapy and prognostic factors classification management. MEDICAL REVIEW (2021) 2022; 2:547-552. [PMID: 37724259 PMCID: PMC10471086 DOI: 10.1515/mr-2022-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 12/22/2022] [Indexed: 09/20/2023]
Abstract
Immune checkpoint inhibitors (ICIs) like programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor have shown considerable efficacy in several important cancers including primary liver cancer (PLC) like hepatocellular carcinoma and cholangiocarcinoma. However, only some patients with PLC will benefit, so combination therapy and biomarker classification detected by next-generation sequencing or immunohistochemistry are very important. Herein, we briefly summarize ICI-based therapies and stratify these evolving therapies for advanced PLC into three stages of immunotherapies Mark (Mk.) 1.0, 2.0, and 3.0. We illustrated the significance of ICI monotherapy (Mk. 1.0), offering combinational approaches with traditional strategies (Mk. 2.0) and additional locoregional therapy (Mk. 3.0) to achieve longer survival and even meet the "No Evidence of Disease" status. We also highlight the importance of biomarkers and prognostic factors for patients with advanced PLC treated with ICI-based therapies. Multidisciplinary team management should be investigated and collaborated closely to manage adverse events and sequential therapy suggestions for patients.
Collapse
Affiliation(s)
- Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Nan Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Song
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
20
|
Dong Y, Zhao Z, Simayi M, Chen C, Xu Z, Lv D, Tang B. Transcriptome profiles of fatty acid metabolism-related genes and immune infiltrates identify hot tumors for immunotherapy in cutaneous melanoma. Front Genet 2022; 13:860067. [PMID: 36199579 PMCID: PMC9527329 DOI: 10.3389/fgene.2022.860067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 08/30/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Immunotherapy with checkpoint inhibitors usually has a low response rate in some cutaneous melanoma (CM) cases due to its cold nature. Hence, identification of hot tumors is important to improve the immunotherapeutic efficacy and prognoses of CMs. Methods: Fatty acid (FA) metabolism-related genes were extracted from the Gene Set Enrichment Analysis and used in the non-negative matrix factorization (NMF), copy number variation frequency, tumor mutation burden (TMB), and immune-related analyses, such as immunophenoscore (IPS). We generate a risk model and a nomogram for predicting patient prognoses and predicted the potential drugs for therapies using the Connectivity Map. Moreover, the NMF and the risk model were validated in a cohort of cases in the GSE65904 and GSE54467. At last, immunohistochemistry (IHC) was used for further validation. Results: Based on the NMF of 11 FA metabolism-related DEGs, CM cases were stratified into two clusters. Cluster 2 cases had the characteristics of a hot tumor with higher immune infiltration levels, higher immune checkpoint (IC) molecules expression levels, higher TMB, and more sensitivity to immunotherapy and more potential immunotherapeutic drugs and were identified as hot tumors for immunotherapy. The risk model and nomogram displayed excellent predictor values. In addition, there were more small potential molecule drugs for therapies of CM patients, such as ambroxol. In immunohistochemistry (IHC), we could find that expression of PLA2G2D, ACOXL, and KMO was upregulated in CM tissues, while the expression of IL4I1, BBOX1, and CIDEA was reversed or not detected. Conclusion: The transcriptome profiles of FA metabolism-related genes were effective for distinguishing CM into hot–cold tumors. Our findings may be valuable for development of effective immunotherapy for CM patients and for proposing new therapy strategies.
Collapse
Affiliation(s)
- Yunxian Dong
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zirui Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Maijimi Simayi
- Department of General Surgery, The First People’s Hospital of Kashgar, Kashgar, China
| | - Chufen Chen
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhongye Xu
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dongming Lv
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bing Tang
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- *Correspondence: Bing Tang,
| |
Collapse
|
|
21
|
Zuo B, Yang X, Yang X, Bian J, Long J, Wang D, Ning C, Wang Y, Xun Z, Wang Y, Lu X, Mao Y, Sang X, Zhao H. A real-world study of the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer. Cancer Immunol Immunother 2022; 71:1889-1896. [DOI: 10.1007/s00262-021-03121-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
|
|
22
|
Liu M, Xia S, Zhang X, Zhang B, Yan L, Yang M, Ren Y, Guo H, Zhao J. Development and validation of a blood-based genomic mutation signature to predict the clinical outcomes of atezolizumab therapy in NSCLC. Lung Cancer 2022; 170:148-155. [DOI: 10.1016/j.lungcan.2022.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/09/2022] [Accepted: 06/25/2022] [Indexed: 11/29/2022]
|
|
23
|
Arrichiello G, Nacca V, Paragliola F, Giunta EF. Liquid biopsy in biliary tract cancer from blood and bile samples: current knowledge and future perspectives. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:362-374. [PMID: 36045913 PMCID: PMC9400719 DOI: 10.37349/etat.2022.00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/18/2022] [Indexed: 12/05/2022] Open
Abstract
Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease.
Collapse
Affiliation(s)
- Gianluca Arrichiello
- Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Valeria Nacca
- Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Fernando Paragliola
- Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Emilio Francesco Giunta
- Department of Experimental Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80138 Naples, Italy
| |
Collapse
|
|
24
|
Luo C, Wang S, Shan W, Liao W, Zhang S, Wang Y, Xin Q, Yang T, Hu S, Xie W, Xu N, Zhang Y. A Whole Exon Screening-Based Score Model Predicts Prognosis and Immune Checkpoint Inhibitor Therapy Effects in Low-Grade Glioma. Front Immunol 2022; 13:909189. [PMID: 35769464 PMCID: PMC9234137 DOI: 10.3389/fimmu.2022.909189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 11/23/2022] Open
Abstract
Objective This study aims to identify prognostic factors for low-grade glioma (LGG) via different machine learning methods in the whole genome and to predict patient prognoses based on these factors. We verified the results through in vitro experiments to further screen new potential therapeutic targets. Method A total of 940 glioma patients from The Cancer Genome Atlas (TCGA) and The Chinese Glioma Genome Atlas (CGGA) were included in this study. Two different feature extraction algorithms – LASSO and Random Forest (RF) – were used to jointly screen genes significantly related to the prognosis of patients. The risk signature was constructed based on these screening genes, and the K-M curve and ROC curve evaluated it. Furthermore, we discussed the differences between the high- and low-risk groups distinguished by the signature in detail, including differential gene expression (DEG), single-nucleotide polymorphism (SNP), copy number variation (CNV), immune infiltration, and immune checkpoint. Finally, we identified the function of a novel molecule, METTL7B, which was highly correlated with PD-L1 expression on tumor cell, as verified by in vitro experiments. Results We constructed an accurate prediction model based on seven genes (AUC at 1, 3, 5 years= 0.91, 0.85, 0.74). Further analysis showed that extracellular matrix remodeling and cytokine and chemokine release were activated in the high-risk group. The proportion of multiple immune cell infiltration was upregulated, especially macrophages, accompanied by the high expression of most immune checkpoints. According to the in vitro experiment, we preliminarily speculate that METTL7B affects the stability of PD-L1 mRNA by participating in the modification of m6A. Conclusion The seven gene signatures we constructed can predict the prognosis of patients and identify the potential benefits of immune checkpoint inhibitors (ICI) therapy for LGG. More importantly, METTL7B, one of the risk genes, is a crucial molecule that regulates PD-L1 and could be used as a new potential therapeutic target.
Collapse
Affiliation(s)
- Cheng Luo
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Department of Biomedical Engineering, Tsinghua University, Beijing, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
| | - Songmao Wang
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Wenjie Shan
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Open Faculty for Innovation, Education, Science, Technology and Art, Tsinghua Shenzhen International Graduate School, Shenzhen, China
| | - Weijie Liao
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
| | - Shikuan Zhang
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Yanzhi Wang
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Qilei Xin
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Department of Chemical Engineering, Tsinghua University, Beijing, China
| | - Tingpeng Yang
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Department of Chemical Engineering, Tsinghua University, Beijing, China
| | - Shaoliang Hu
- Research and Development Department, Shenzhen Combined Biotech Co., Ltd, Shenzhen, China
| | - Weidong Xie
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Open Faculty for Innovation, Education, Science, Technology and Art, Tsinghua Shenzhen International Graduate School, Shenzhen, China
| | - Naihan Xu
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Open Faculty for Innovation, Education, Science, Technology and Art, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- *Correspondence: Naihan Xu, ; Yaou Zhang,
| | - Yaou Zhang
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Open Faculty for Innovation, Education, Science, Technology and Art, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- *Correspondence: Naihan Xu, ; Yaou Zhang,
| |
Collapse
|
|
25
|
Wang J, Ma X, Ma Z, Ma Y, Wang J, Cao B. Research Progress of Biomarkers for Immune Checkpoint Inhibitors on Digestive System Cancers. Front Immunol 2022; 13:810539. [PMID: 35493526 PMCID: PMC9043345 DOI: 10.3389/fimmu.2022.810539] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 03/21/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy represented by immune checkpoint inhibitors has gradually entered a new era of precision medicine. In view of the limited clinical benefits of immunotherapy in patients with digestive system cancers, as well as the side-effects and high treatment costs, development of biomarkers to predict the efficacy of immune therapy is a key imperative. In this article, we review the available evidence of the value of microsatellite mismatch repair, tumor mutation burden, specific mutated genes or pathways, PD-L1 expression, immune-related adverse reactions, blood biomarkers, and patient-related biomarkers in predicting the efficacy of immunotherapy against digestive system cancers. Establishment of dynamic personalized prediction models based on multiple biomarkers is a promising area for future research.
Collapse
Affiliation(s)
- Jingting Wang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiao Ma
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhongjun Ma
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yan Ma
- Department of Comprehensive Medicine, Beijing Shijingshan Hospital, Beijing, China
| | - Jing Wang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
26
|
Wadden J, Ravi K, John V, Babila CM, Koschmann C. Cell-Free Tumor DNA (cf-tDNA) Liquid Biopsy: Current Methods and Use in Brain Tumor Immunotherapy. Front Immunol 2022; 13:882452. [PMID: 35464472 PMCID: PMC9018987 DOI: 10.3389/fimmu.2022.882452] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/14/2022] [Indexed: 11/27/2022] Open
Abstract
Gliomas are tumors derived from mutations in glial brain cells. Gliomas cause significant morbidity and mortality and development of precision diagnostics and novel targeted immunotherapies are critically important. Radiographic imaging is the most common technique to diagnose and track response to treatment, but is an imperfect tool. Imaging does not provide molecular information, which is becoming critically important for identifying targeted immunotherapies and monitoring tumor evolution. Furthermore, immunotherapy induced inflammation can masquerade as tumor progression in images (pseudoprogression) and confound clinical decision making. More recently, circulating cell free tumor DNA (cf-tDNA) has been investigated as a promising biomarker for minimally invasive glioma diagnosis and disease monitoring. cf-tDNA is shed by gliomas into surrounding biofluids (e.g. cerebrospinal fluid and plasma) and, if precisely quantified, might provide a quantitative measure of tumor burden to help resolve pseudoprogression. cf-tDNA can also identify tumor genetic mutations to help guide targeted therapies. However, due to low concentrations of cf-tDNA, recovery and analysis remains challenging. Plasma cf-tDNA typically represents <1% of total cf-DNA due to the blood-brain barrier, limiting their usefulness in practice and motivating the development and use of highly sensitive and specific detection methods. This mini review summarizes the current and future trends of various approaches for cf-tDNA detection and analysis, including new methods that promise more rapid, lower-cost, and accessible diagnostics. We also review the most recent clinical case studies for longitudinal disease monitoring and highlight focus areas, such as novel accurate detection methodologies, as critical research priorities to enable translation to clinic.
Collapse
Affiliation(s)
- Jack Wadden
- Department of Pediatric Hematology and Oncology, Michigan Medicine, Ann Arbor, MI, United States
| | | | | | | | - Carl Koschmann
- Department of Pediatric Hematology and Oncology, Michigan Medicine, Ann Arbor, MI, United States
| |
Collapse
|
|
27
|
Lyu X, Tsui YM, Ho DWH, Ng IOL. Liquid Biopsy Using Cell-Free or Circulating Tumor DNA in the Management of Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol 2022; 13:1611-1624. [PMID: 35183803 PMCID: PMC9048068 DOI: 10.1016/j.jcmgh.2022.02.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/18/2022]
Abstract
Liver cancer (hepatocellular carcinoma [HCC]) is a fatal cancer worldwide and often is detected at an advanced stage when treatment options are very limited. This drives the development of techniques and platforms for early detection of HCC. In recent years, liquid biopsy has provided a means of noninvasive detection of cancers. By detecting plasma circulating tumor DNA (ctDNA) released from dying cancer cells, the presence of HCC can be detected in a noninvasive manner. In this review, we discuss the molecular characteristics of ctDNA and its various molecular landscapes in HCC. These include the mutational landscape, single-nucleotide variations, copy number variations, methylation landscape, end motif/coordinate preference, hepatitis B virus integration, and mitochondrial DNA mutations. The consistency between the plasma ctDNA and the tumor tissue genomic DNA mutational profile is pivotal for the clinical utility of ctDNA in the clinical management of HCC. With strategic use of genetic information provided from plasma ctDNA profiling and procedure standardization to facilitate implementation in clinical practice, better clinical management would become permissible through more efficient detection and diagnosis of HCC, better prognostication, precision-matched treatment guidance, and more reliable disease monitoring.
Collapse
Affiliation(s)
| | | | - Daniel Wai-Hung Ho
- Correspondence Address correspondence to: Daniel Wai-Hung Ho, PhD, Department of Pathology, L704, Laboratory Block, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong. fax: (852) 2819-5375.
| | - Irene Oi-Lin Ng
- Irene Oi-Lin Ng, MD, PhD, Department of Pathology, Room 7-13, Block T, Queen Mary Hospital, Pokfulam, Hong Kong. fax: 852-28872-5197.
| |
Collapse
|
|
28
|
Xu Y, Jiang Y, Yu M, Lou J, Song M, Xu H, Cui Y, Zeng X, Wang Q, Ma H, Wang Z, Zhu S, Li G, Zhao A. Meta-Analysis of the Diagnostic Value of Cell-free DNA for Renal Cancer. Front Mol Biosci 2021; 8:683844. [PMID: 34458320 PMCID: PMC8385273 DOI: 10.3389/fmolb.2021.683844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/27/2021] [Indexed: 11/18/2022] Open
Abstract
Cell-free DNA (cf-DNA) has been reported to represent a suitable material for liquid biopsy in the diagnosis and prognosis of various cancers. We performed a meta-analysis of published data to investigate the diagnostic value of cf-DNA for renal cancer (RCa). Systematic searches were conducted using Pubmed, Embase databases, Web of Science, Medline and Cochrane Library to identify relevant publications until the 31st March 2021. For all patients, we evaluated the true diagnostic value of cf-DNA by calculating the number of true positive, false positive, true negative, and false negative, diagnoses by extracting specificity and sensitivity data from the selected literature. In total, 8 studies, featuring 754 RCa patients, and 355 healthy controls, met our inclusion criteria. The overall diagnostic sensitivity and specificity for cf-DNA was 0.71 (95% confidence interval (CI), 0.55–0.83) and 0.79 (95% CI, 0.66–0.88), respectively. The pooled positive likelihood ratio and pooled negative likelihood ratio were 3.42 (95% CI, 2.04–5.72) and 0.36 (95% CI, 0.23–0.58), respectively. The area under the summary receiver operating characteristic curve was 0.82 (95% CI, 0.79–0.85), and the diagnostic odds ratio was 7.80 (95% CI, 4.40–13.85). Collectively, our data demonstrate that cf-DNA has high specificity and sensitivity for diagnosing RCa. Therefore, cf-DNA is a useful biomarker for the diagnosis of RCa.
Collapse
Affiliation(s)
- Yipeng Xu
- Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzho, China
| | - Yingjun Jiang
- Hangzhou Traditional Chinese Medicine Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mingke Yu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jianmin Lou
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mei Song
- Department of Ultrasound, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
| | - Han Xu
- Central Research Laboratory, Children's Hospital of Nanchang University, Hangzhou, China
| | - Yingying Cui
- Translational Radiation Oncology Research Laboratory, Department of Radiooncology and Radiotherapy, Charite University Hospital, Berlin, Germany
| | - Xiaowei Zeng
- Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzho, China.,Hangzhou Traditional Chinese Medicine Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qibo Wang
- Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzho, China
| | - Hanyun Ma
- Comprehensive Cancer Center, Charité Universitätsmedizin, Berlin, Germany
| | - Zongping Wang
- Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzho, China
| | - Shaoxing Zhu
- Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzho, China
| | - Guorong Li
- Department of Urology, North Hospital, University of Jean-Monnet, Saint-Etienne, France
| | - An Zhao
- Experimental Research Center, Zhejiang Cancer Hospital, Institute of Cancer Research and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
| |
Collapse
|