|
1
|
Zhang Y, Du H, Wang N, Wang L, Huang Y. An update of clinical value of circulating tumor DNA in esophageal cancer: a systematic review and meta-analysis. BMC Cancer 2024; 24:129. [PMID: 38267901 PMCID: PMC10809487 DOI: 10.1186/s12885-024-11879-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 01/13/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Esophageal cancer (EC) is a deadly disease with limited therapeutic options. Although circulating tumor DNA (ctDNA) could be a promising tool in this regard, the availiable evidence is limited. We performed a systematic review and meta-analysis to summarize the clinical applicability of the next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR) technology on the ctDNA detection of the EC and listed the current challenges. METHODS We systematically searched MEDLINE (via PubMed), Embase (via OVID), ISI Web of Science database and Cochrane Library from January, 2000 to April, 2023. Progression-free survival (PFS) and overall survival (OS) were set as primary outcome endpoints. Pathologic response was evaluated by tumor regression grade (TRG), according to the eighth edition of the American Joint Committee on Cancer (AJCC). Major pathologic regression (MPR) was defined as TRG 1 and 2. The MPR was set as secondary endpoint. Hazard rate (HR) and associated 95% CI were used as the effect indicators the association between ctDNA and prognosis of EC. MPR rates were also calculated. Fixed-effect model (Inverse Variance) or random-effect model (Mantel-Haenszel method) was performed depending on the statistically heterogeneity. RESULTS Twenty-two studies, containing 1144 patients with EC, were included in this meta-analysis. The results showed that OS (HR = 3.87; 95% CI, 2.86-5.23) and PFS (HR = 4.28; 95% CI, 3.34-5.48) were shorter in ctDNA-positive patients. In the neoadjuvant therapy, the sensitivity analysis showed the clarified HR of ctDNA-positive was 1.13(95% CI, 1.01-1.28). We also found that TP53, NOTCH1, CCND1 and CNKN2A are the most frequent mutation genes. CONCLUSIONS Positive ctDNA is associated with poor prognosis, which demonstrated clinical value of ctDNA. Longitudinal ctDNA monitoring showed potential prognostic value in the neoadjuvant therapy. In an era of precision medicine, ctDNA could be a promising tool to individualize treatment planning and to improve outcomes in EC. PROSPERO REGISTRATION NUMBER CRD42023412465.
Collapse
Affiliation(s)
- Yaozhong Zhang
- Department of Infectious diseases, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Huazhen Du
- Department of Emergency, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Na Wang
- Department of Molecular Biology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lei Wang
- Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yajie Huang
- Department of Medical oncology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
| |
Collapse
|
|
2
|
Wang H, Zhang X, Zhao X, Song C, Deng W, Shen W. Minimal residual disease guided radical chemoradiotherapy combined with immunotherapy after neoadjuvant immunochemotherapy followed by adjuvant immunotherapy for esophageal squamous cell cancer (ECMRD-001): a study protocol for a prospective cohort study. Front Immunol 2024; 14:1330928. [PMID: 38274807 PMCID: PMC10808458 DOI: 10.3389/fimmu.2023.1330928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 12/26/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction For locally advanced, inoperable esophageal cancer, concurrent chemoradiotherapy (CCRT) becomes the norm. Combining immunotherapy with radiotherapy has been shown to improve efficacy. Circulating tumor DNA (ctDNA) is a strong predictor of effectiveness and tumor recurrence and is indicative of minimal residual disease (MRD). Patients with inoperable stage II-III esophageal squamous cell carcinoma (ESCC) are enrolled in the ECMRD-001 trial to evaluate changes in MRD status before and after CCRT combined with immunotherapy and adjuvant immunotherapy following neoadjuvant immunochemotherapy. Methods and analysis The ECMRD-001 trial is a prospective cohort study. Eligible patients will receive radical concurrent chemoradiotherapy combined with immunotherapy after neoadjuvant immunochemotherapy, followed by adjuvant immunotherapy for at least one year. Follow-up will be up to three years. MRD-related blood and tissue samples and T-cell immunohistobank related blood and tissue samples collected before, during and after treatment and follow-up will be grouped into sample collection time points. The relationship between MRD status at different time points and treatment efficacy is the primary outcome. Correlation between MRD status and immune microenvironment, radiotherapy dose, and tumor recurrence are the secondary outcomes. Examination of ctDNA mutations is the exploratory outcome. Discussion ctDNA-based MRD may be a potential predictive marker for the efficacy and tumor recurrence of inoperable ESCC patients. Elevated ctDNA-MRD may predict tumor recurrence earlier than imaging. ctDNA-based MRD analysis and ctDNA-based MRD guided diagnosis and treatment should be implemented into clinical practice to improve efficacy and reduce tumor recurrence of inoperable stage II-III ESCC. Trial registration The ECMRD-001 study has been registered at ClinicalTrials.gov as NCT05952661 (July 19, 2023), https://classic.clinicaltrials.gov/ct2/show/NCT05952661.
Collapse
Affiliation(s)
| | | | | | | | | | - Wenbin Shen
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| |
Collapse
|
|
3
|
Ng HY, Ko JMY, Lam KO, Kwong DLW, Lo AWI, Wong IYH, Wong CLY, Chan SY, Chan KK, Law TT, Dai W, Fong HCH, Choy FSF, Lo CK, Chen C, Law SYK, Lung ML. Circulating Tumor DNA Dynamics as Prognostic Markers in Locally Advanced and Metastatic Esophageal Squamous Cell Carcinoma. JAMA Surg 2023; 158:1141-1150. [PMID: 37728901 PMCID: PMC10512170 DOI: 10.1001/jamasurg.2023.4395] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/10/2023] [Indexed: 09/22/2023]
Abstract
Importance Esophageal squamous cell carcinoma (ESCC) is a deadly disease with frequent recurrence. There are unmet needs for prognostic biomarkers for dynamically monitoring disease progression and detecting minimal residual disease. Objective To examine whether circulating tumor DNA is clinically useful as a prognostic biomarker for ESCC recurrence and patient survival. Design, Setting, and Participants This single-center, population-based cohort study consecutively enrolled 147 patients receiving curative (n = 74) or palliative (n = 73) treatment at the surgery and clinical oncology departments of Queen Mary Hospital in Hong Kong from August 1, 2016, to September 31, 2021. Patients were followed up for 2 years. Plasma samples were collected at different longitudinal time points for a prospective circulating tumor DNA (ctDNA) next-generation sequencing profiling study of 77 actionable genes. Intervention Patients were treated with up-front surgery, neoadjuvant chemoradiotherapy plus surgery with or without adjuvant therapy, or palliative chemotherapy (CT). Main Outcomes and Measures Detection of circulating tumor DNA (ctDNA), progression-free survival (PFS), and overall survival (OS). Results A total of 478 serial plasma samples from 147 patients with locoregional or metastatic ESCC were prospectively analyzed. Among the 74 patients in the curative group (median [range] age, 66 [46-85] years; 56 [76.0%] male), 44 (59.5%) relapsed and 36 (48.6%) died. For patients receiving curative surgical treatment, a high ctDNA level (hazard ratio [HR], 7.84; 95% CI, 1.87-32.97; P = .005) and ctDNA alterations (HR, 5.71; 95% CI, 1.81-17.97; P = .003) at 6 months postoperation were independently associated with poor OS. Among patients receiving neoadjuvant chemoradiotherapy, postneoadjuvant ctDNA alterations were associated with poor PFS (HR, 3.16; 95% CI, 1.17-8.52; P = .02). In the 73 patients in the palliative group (median [range] age, 63 [45-82] years; 63 [86.0%] male), 71 (97.3%) had disease relapse and 68 (93.2%) died. Detectable pre-CT NFE2L2 alterations were independently associated with PFS (HR, 2.99; 95% CI, 1.35-6.61; P = .007) and OS (HR, 28.39; 95% CI, 7.26-111.03; P = 1.52 × 10-6), whereas high ctDNA levels (HR, 2.41; 95% CI, 1.18-4.95; P = .02) and alterations in pre-cycle III ctDNA (HR, 1.99; 95% CI, 1.03-3.85; P = .04) showed weaker associations with PFS. Alterations in pre-CT ctDNA were independently associated with OS (HR, 4.46; 95% CI, 1.86-10.69; P = 7.97 × 10-4). Conclusions and Relevance The findings of this cohort study indicate that prognostic models incorporating ctDNA features are useful in ESCC. Both ctDNA level and NFE2L2 alterations pre-CT and before cycle III were found to be important prognostic factors in palliative groups, and ctDNA alterations after treatment and at 6 months after surgery may define high-risk groups for recurrence in the curative group. High-risk patients can benefit by a timely switch to the next therapeutic options.
Collapse
Affiliation(s)
- Hoi Yan Ng
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Josephine Mun Yee Ko
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Ka On Lam
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Dora Lai Wan Kwong
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Anthony Wing Ip Lo
- Division of Anatomical Pathology, Queen Mary Hospital, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Ian Yu Hong Wong
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Claudia Lai Yin Wong
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Siu Yin Chan
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Kwan Kit Chan
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Tsz Ting Law
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Wei Dai
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Henry Chun Hung Fong
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Faith Sin Fai Choy
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Chun Kit Lo
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Cancan Chen
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Simon Ying Kit Law
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| | - Maria Li Lung
- Department of Clinical Oncology, School of Clinical Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), People’s Republic of China
| |
Collapse
|
|
4
|
Richter F, Henssen C, Steiert TA, Meissner T, Mehdorn AS, Röcken C, Franke A, Egberts JH, Becker T, Sebens S, Forster M. Combining Solid and Liquid Biopsy for Therapy Monitoring in Esophageal Cancer. Int J Mol Sci 2023; 24:10673. [PMID: 37445849 DOI: 10.3390/ijms241310673] [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: 03/15/2023] [Revised: 06/15/2023] [Accepted: 06/17/2023] [Indexed: 07/15/2023] Open
Abstract
Esophageal cancer (EC) has one of the highest mortality rates among cancers, making it imperative that therapies are optimized and dynamically adapted to individuals. In this regard, liquid biopsy is an increasingly important method for residual disease monitoring. However, conflicting detection rates (14% versus 60%) and varying cell-free circulating tumor DNA (ctDNA) levels (0.07% versus 0.5%) have been observed in previous studies. Here, we aim to resolve this discrepancy. For 19 EC patients, a complete set of cell-free DNA (cfDNA), formalin-fixed paraffin-embedded tumor tissue (TT) DNA and leukocyte DNA was sequenced (139 libraries). cfDNA was examined in biological duplicates and/or longitudinally, and TT DNA was examined in technical duplicates. In baseline cfDNA, mutations were detected in 12 out of 19 patients (63%); the median ctDNA level was 0.4%. Longitudinal ctDNA changes were consistent with clinical presentation. Considerable mutational diversity was observed in TT, with fewer mutations in cfDNA. The most recurrently mutated genes in TT were TP53, SMAD4, TSHZ3, and SETBP1, with SETBP1 being reported for the first time. ctDNA in blood can be used for therapy monitoring of EC patients. However, a combination of solid and liquid samples should be used to help guide individualized EC therapy.
Collapse
Affiliation(s)
- Florian Richter
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany
| | - Clara Henssen
- Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany
| | | | - Tobias Meissner
- Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA
| | - Anne-Sophie Mehdorn
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany
| | - Jan-Hendrik Egberts
- Department of Surgery, Israelitisches Krankenhaus Hamburg, 22297 Hamburg, Germany
| | - Thomas Becker
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany
| | - Michael Forster
- Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany
| |
Collapse
|
|
5
|
Wang X, Yu N, Cheng G, Zhang T, Wang J, Deng L, Li J, Zhao X, Xu Y, Yang P, Bai N, Li Y, Bi N. Prognostic value of circulating tumour DNA during post-radiotherapy surveillance in locally advanced esophageal squamous cell carcinoma. Clin Transl Med 2022; 12:e1116. [PMID: 36437506 PMCID: PMC9702363 DOI: 10.1002/ctm2.1116] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/08/2022] [Accepted: 11/07/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation. METHODS Treatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T0 ), week 4 of RT/CRT (T1 ), 1-3 (T2 ) and 3-6 months post-RT/CRT (T3 ). ctDNA was analysed using next-generation sequencing of 474 cancer-relevant genes. RESULTS A total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40-78], 88% males, 95% stage III/IV), and the median follow-up time was 20.6 months (range: 12.2-33.3). During the post-RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post-RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T1 (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30-10.01) or T2 (HR: 5.45, 95% CI: 1.72-17.26) indicated inferior progression-free survival (PFS). ctDNA clearance between T0 -T1 (HR: 0.31, 95% CI: 0.08-1.13) or T0 -T2 (HR: 0.11; 95% CI: 0.02-0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T1 was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31-15.04). CONCLUSIONS ctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post-RT/CRT treatments for locoregional control in ESCC.
Collapse
Affiliation(s)
- Xin Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Nuo Yu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Guowei Cheng
- Department of Radiation OncologyCancer Hospital of HuanXingBeijingChina
| | - Tao Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jianyang Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jiao Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xiaotian Zhao
- Geneseeq Research InstituteNanjing Geneseeq Technology Inc.NanjingChina
| | - Yang Xu
- Geneseeq Research InstituteNanjing Geneseeq Technology Inc.NanjingChina
| | - Peng Yang
- Geneseeq Research InstituteNanjing Geneseeq Technology Inc.NanjingChina
| | - Na Bai
- Geneseeq Research InstituteNanjing Geneseeq Technology Inc.NanjingChina
| | - Yin Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| |
Collapse
|
|
6
|
Lam RCT, Johnson D, Lam G, Li MLY, Wong JWL, Lam WKJ, Chan KCA, Ma B. Clinical applications of circulating tumor-derived DNA in the management of gastrointestinal cancers - current evidence and future directions. Front Oncol 2022; 12:970242. [PMID: 36248993 PMCID: PMC9556664 DOI: 10.3389/fonc.2022.970242] [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: 06/15/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
Advances in Next Generation Sequencing (NGS) technologies have enabled the accurate detection and quantification of circulating tumor-derived (ct)DNA in most gastrointestinal (GI) cancers. The prognostic and predictive utility of ctDNA in patiets with different stages of colorectal (CRC), gastro-esophageal (GEC) and pancreaticobiliary cancers (PBC) are currently under active investigation. The most mature clinical data to date are derived from studies in the prognostic utility of personalized ctDNA-based NGS assays in the detection of minimal residual disease (MRD) and early recurrence after surgery in CRC and other GI cancers. These findings are being validated in several prospective studies which are designed to test if ctDNA could outperform conventional approaches in guiding adjuvant chemotherapy, and in post-operative surveillance in some GI cancers. Several adaptive studies using ctDNA as a screening platform are also being used to identify patients with actionable genomic alterations for clinical trials of targeted therapies. In the palliative setting, ctDNA monitoring during treatment has shown promise in the detection and tracking of clonal variants associated with acquired resistance to targeted therapies and immune-checkpoint inhibitors (ICI). Moreover, ctDNA may help to guide the therapeutic re-challenge of targeted therapies in patients who have prior exposure to such treatment. This review will examine the most updated research findings on ctDNA as a biomarker in CRC, GEC and PBCs. It aims to provide insights into how the unique strengths of this biomarker could be optimally leveraged in improving the management of these GI cancers.
Collapse
Affiliation(s)
- Rachel C. T. Lam
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - David Johnson
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir Y. K Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Gigi Lam
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Michelle L. Y. Li
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Joyce W. L. Wong
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - W. K. Jacky Lam
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - K. C. Allen Chan
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Brigette Ma
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir Y. K Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| |
Collapse
|
|
7
|
Hofste LSM, Geerlings MJ, von Rhein D, Tolmeijer SH, Weiss MM, Gilissen C, Hofste T, Garms LM, Janssen MJR, Rütten H, Rosman C, van der Post RS, Klarenbeek BR, Ligtenberg MJL. Circulating Tumor DNA-Based Disease Monitoring of Patients with Locally Advanced Esophageal Cancer. Cancers (Basel) 2022; 14:cancers14184417. [PMID: 36139577 PMCID: PMC9497103 DOI: 10.3390/cancers14184417] [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: 08/02/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary The standard of care for patients diagnosed with locally advanced esophageal cancer is neoadjuvant chemoradiotherapy followed by surgery. There is a high clinical need to monitor response to neoadjuvant treatment and recognize patients at risk for recurrence to enable individual treatment strategies. Ultradeep sequencing-based detection of circulating tumor DNA in preoperative plasma of patients with locally advanced esophageal cancer can predict which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery. Circulating tumor DNA-based prediction of the presence of distant metastasis might eventually be used to reconsider surgery and its associated morbidity in patients with detected circulating tumor DNA or stratify patients for adjuvant treatment. Abstract Patients diagnosed with locally advanced esophageal cancer are often treated with neoadjuvant chemoradiotherapy followed by surgery. This study explored whether detection of circulating tumor DNA (ctDNA) in plasma can be used to predict residual disease during treatment. Diagnostic tissue biopsies from patients with esophageal cancer receiving neoadjuvant chemoradiotherapy and surgery were analyzed for tumor-specific mutations. These tumor-informed mutations were used to measure the presence of ctDNA in serially collected plasma samples using hybrid capture-based sequencing. Plasma samples were obtained before chemoradiotherapy, and prior to surgery. The association between ctDNA detection and progression-free and overall survival was measured. Before chemoradiotherapy, ctDNA was detected in 56% (44/78) of patients and detection was associated with tumor stage and volume (p = 0.05, Fisher exact and p = 0.02, Mann-Whitney, respectively). After chemoradiotherapy, ctDNA was detected in 10% (8/78) of patients. This preoperative detection of ctDNA was independently associated with recurrent disease (hazard ratio 2.8, 95% confidence interval 1.1–6.8, p = 0.03, multivariable Cox-regression) and worse overall survival (hazard ratio 2.9, 95% confidence interval 1.2–7.1, p = 0.02, multivariable Cox-regression).Ultradeep sequencing-based detection of ctDNA in preoperative plasma of patients with locally advanced esophageal cancer may help to assess which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery.
Collapse
Affiliation(s)
- Lisa S. M. Hofste
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Maartje J. Geerlings
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Daniel von Rhein
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Sofie H. Tolmeijer
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Marjan M. Weiss
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Christian Gilissen
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Tom Hofste
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Linda M. Garms
- Department of Surgery, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Marcel J. R. Janssen
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Heidi Rütten
- Department of Radiation Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Camiel Rosman
- Department of Surgery, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Rachel S. van der Post
- Department of Pathology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Bastiaan R. Klarenbeek
- Department of Surgery, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Marjolijn J. L. Ligtenberg
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Pathology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Correspondence: ; Tel.: +31-0024-3617-749
| |
Collapse
|
|
8
|
Iacob R, Mandea M, Iacob S, Pietrosanu C, Paul D, Hainarosie R, Gheorghe C. Liquid Biopsy in Squamous Cell Carcinoma of the Esophagus and of the Head and Neck. Front Med (Lausanne) 2022; 9:827297. [PMID: 35572996 PMCID: PMC9098838 DOI: 10.3389/fmed.2022.827297] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/15/2022] [Indexed: 11/13/2022] Open
Abstract
Squamous cell carcinomas of the esophagus (ESCC) and of the head and neck (HNSCC) are two neoplasms that share common risk factors and have the same embryological origin, but a very different prognosis, the 5-year survival of HNSCC being almost double (40–50%) compared to the 5-year survival of ESCC (20%). Current guidelines emphasize the importance of screening for ESCC in patients diagnosed with head and neck cancers. A liquid biopsy is a novel tool for diagnosis, prognostic stratification, and personalized therapy. Liquid biopsy biomarkers for these two malignancies could help both their early detection, facilitate residual disease identification, and provide prognosis information. The present systematic review of the literature was aimed at describing the liquid biopsy biomarkers present in these two malignancies, with an emphasis on potential clinical applications.
Collapse
Affiliation(s)
- Razvan Iacob
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Matei Mandea
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
| | - Speranta Iacob
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Catalina Pietrosanu
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Professor Doctor Dorin Hociota Institute of Phonoaudiology and Functional ENT Surgery, Bucharest, Romania
| | - Doru Paul
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
| | - Razvan Hainarosie
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Professor Doctor Dorin Hociota Institute of Phonoaudiology and Functional ENT Surgery, Bucharest, Romania
- *Correspondence: Razvan Hainarosie
| | - Cristian Gheorghe
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| |
Collapse
|
|
9
|
Agulnik JS, Papadakis AI, Pepe C, Sakr L, Small D, Wang H, Kasymjanova G, Spatz A, Cohen V. Cell-Free Tumor DNA (ctDNA) Utility in Detection of Original Sensitizing and Resistant EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC). Curr Oncol 2022; 29:1107-1116. [PMID: 35200593 PMCID: PMC8871000 DOI: 10.3390/curroncol29020094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/17/2022] [Accepted: 02/10/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients. Methods: This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS® EGFR v2 qPCR (Roche) test. Results: Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (p = 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (p = 0.001). Conclusion: Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC.
Collapse
Affiliation(s)
- Jason S. Agulnik
- Peter Brojde Lung Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; (J.S.A.); (C.P.); (L.S.); (D.S.); (V.C.)
| | - Andreas I. Papadakis
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
| | - Carmela Pepe
- Peter Brojde Lung Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; (J.S.A.); (C.P.); (L.S.); (D.S.); (V.C.)
| | - Lama Sakr
- Peter Brojde Lung Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; (J.S.A.); (C.P.); (L.S.); (D.S.); (V.C.)
| | - David Small
- Peter Brojde Lung Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; (J.S.A.); (C.P.); (L.S.); (D.S.); (V.C.)
| | - Hangjun Wang
- Department of Pathology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
| | - Goulnar Kasymjanova
- Peter Brojde Lung Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; (J.S.A.); (C.P.); (L.S.); (D.S.); (V.C.)
- Correspondence:
| | - Alan Spatz
- OPTILAB-Montreal MUHC & Department of Laboratory Medicine, McGill University Health Center, Montreal, QC H3T 1E2, Canada;
| | - Victor Cohen
- Peter Brojde Lung Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; (J.S.A.); (C.P.); (L.S.); (D.S.); (V.C.)
| |
Collapse
|
|
10
|
Chidambaram S, Markar SR. Clinical utility and applicability of circulating tumor DNA testing in esophageal cancer: a systematic review and meta-analysis. Dis Esophagus 2022; 35:doab046. [PMID: 34286823 PMCID: PMC8832526 DOI: 10.1093/dote/doab046] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/15/2021] [Accepted: 06/21/2021] [Indexed: 12/11/2022]
Abstract
Esophageal cancer is an aggressive malignancy with a relatively poor prognosis even after multimodality therapy. Currently, patients undergo a series of investigations that can be invasive and costly or pose secondary risks to their health. In other malignancies, liquid biopsies of circulating tumor DNA (ctDNA) are used in clinical practice for diagnostic and surveillance purposes. This systematic review summarizes the latest evidence for the clinical applicability of ctDNA technology in esophageal cancer. A systematic review of the literature was performed using MEDLINE, EMBASE, the Cochrane Review and Scopus databases. Articles were evaluated for the use of ctDNA for diagnosis and monitoring of patients with esophageal cancer. Quality assessment of studies was performed using the QUADAS-2 tool. A meta-analysis was performed to assess the diagnostic accuracy of sequencing methodologies. We included 15 studies that described the use of ctDNA technology in the qualitative synthesis and eight studies involving 414 patients in the quantitative analysis. Of these, four studies assessed its utility in cancer diagnosis, while four studies evaluated its use for prognosis and monitoring. The pooled sensitivity and specificity for diagnostic studies were 71.0% (55.7-82.6%) and 98.6% (33.9-99.9%), while the pooled sensitivity and specificity for surveillance purposes were 48.9% (29.4-68.8%) and 95.5% (90.6-97.9%). ctDNA technology is an acceptable method for diagnosis and monitoring with a moderate sensitivity and high specificity that is enhanced in combination with current imaging methods. Further work should demonstrate the practical integration of ctDNA in the diagnostic and surveillance clinical pathway.
Collapse
Affiliation(s)
| | - Sheraz R Markar
- Department of Surgery and Cancer, Imperial College London, London, UK
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
11
|
Fujisawa R, Iwaya T, Endo F, Idogawa M, Sasaki N, Hiraki H, Tange S, Hirano T, Koizumi Y, Abe M, Takahashi T, Yaegashi M, Akiyama Y, Masuda M, Sasaki A, Takahashi F, Sasaki Y, Tokino T, Nishizuka SS. Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer. Carcinogenesis 2021; 42:1239-1249. [PMID: 34559206 DOI: 10.1093/carcin/bgab088] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/23/2021] [Indexed: 01/01/2023] Open
Abstract
We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses was evaluated by the ratio of the variant allele frequency of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50 or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 versus 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.
Collapse
Affiliation(s)
- Ryosuke Fujisawa
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan.,Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Takeshi Iwaya
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan.,Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Fumitaka Endo
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Masashi Idogawa
- Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Noriyuki Sasaki
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan.,Division of Biomedical Research & Development, Iwate Medical University Institute for Biomedical Sciences, Yahaba, Iwate, Japan
| | - Hayato Hiraki
- Division of Biomedical Research & Development, Iwate Medical University Institute for Biomedical Sciences, Yahaba, Iwate, Japan
| | - Shoichiro Tange
- Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Tomomi Hirano
- Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Yuka Koizumi
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan.,Division of Biomedical Research & Development, Iwate Medical University Institute for Biomedical Sciences, Yahaba, Iwate, Japan
| | - Masakazu Abe
- Division of Biomedical Research & Development, Iwate Medical University Institute for Biomedical Sciences, Yahaba, Iwate, Japan.,Department of Urology, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Tomoko Takahashi
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan.,Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Mizunori Yaegashi
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan.,Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Yuji Akiyama
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Mari Masuda
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Akira Sasaki
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan
| | - Fumiaki Takahashi
- Division of Medical Engineering, Department of Information Science, Iwate Medical University, Yahaba, Iwate, Japan
| | - Yasushi Sasaki
- Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.,Biology Division, Department of Liberal Arts and Sciences, Center for Medical Education, Sapporo Medical University, Sapporo, Japan
| | - Takashi Tokino
- Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Satoshi S Nishizuka
- Division of Biomedical Research & Development, Iwate Medical University Institute for Biomedical Sciences, Yahaba, Iwate, Japan
| |
Collapse
|
|
12
|
Yuan Z, Wang X, Geng X, Li Y, Tan F, Xue Q, Gao S, He J. Multi-region sequencing reveals genetic correlation between esophageal squamous cell carcinoma and matched cell-free DNA. Cancer Genet 2021; 258-259:93-100. [PMID: 34688997 DOI: 10.1016/j.cancergen.2021.08.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 07/23/2021] [Accepted: 08/28/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE This study aimed to determine if both ubiquitous and heterogeneous somatic mutations could be detected in circulating cell-free DNA (cfDNA) in patients with esophageal squamous cell carcinoma (ESCC). METHODS Paired multi-regional tumor tissues, cfDNA, and white blood cells (WBCs) were collected from five ESCC patients before treatment, as part of an ongoing prospective study (NCT02395705). Samples from Cohort 1 were sequenced by whole-exome sequencing and samples from Cohort 2 were sequenced by targeted capture sequencing. Somatic single-nucleotide variations (SNVs) were detected by comparing solid tumor or cfDNA with matched WBCs, with a minimum variant allele frequency (VAF) of 0.1% and P value <0.05. RESULTS Genomic DNA (gDNA) and plasma-derived cfDNA from 26 samples were sequenced successfully. In Cohort 1, a significant linear relationship between the tumor and cfDNA VAFs (R2= 0.78, P < 0.0001) was found. In Cohort 2, cfDNA could recover an average of 60.7% (31/51; range, 35.7-76.2%) of somatic mutations present in matched solid tumors. There was a significant positive correlation in VAFs between cfDNA and matched solid tumor tissues (R2= 0.92, P < 0.0001). CONCLUSIONS Both sequencing approaches revealed high intratumoral heterogeneity in ESCC, and enabled the detection of both ubiquitous and heterogeneous mutations in cfDNA.
Collapse
Affiliation(s)
- Zuyang Yuan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Xinfeng Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Xiao Geng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Yin Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.
| |
Collapse
|
|
13
|
Moati E, Taly V, Garinet S, Didelot A, Taieb J, Laurent-Puig P, Zaanan A. Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives. Cancers (Basel) 2021; 13:4743. [PMID: 34638228 PMCID: PMC8507552 DOI: 10.3390/cancers13194743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/06/2021] [Accepted: 09/18/2021] [Indexed: 12/21/2022] Open
Abstract
Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.
Collapse
Affiliation(s)
- Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
| | - Valerie Taly
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Simon Garinet
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Audrey Didelot
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| |
Collapse
|
|
14
|
Jonaitis P, Kiudelis V, Streleckiene G, Gedgaudas R, Skieceviciene J, Kupcinskas J. Novel Biomarkers in the Diagnosis of Benign and Malignant Gastrointestinal Diseases. Dig Dis 2021; 40:1-13. [PMID: 33647906 DOI: 10.1159/000515522] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/26/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Various noninvasive biomarkers have been used in the diagnosis, prognosis, and treatment of different gastrointestinal (GI) diseases for years. Novel technological developments and profound perception of molecular processes related to GI diseases over the last decade have allowed researchers to evaluate genetic, epigenetic, and many other potential molecular biomarkers in different diseases and clinical settings. Here, we present a review of recent and most relevant articles in order to summarize major findings on novel biomarkers in the diagnosis of benign and malignant GI diseases. SUMMARY Genetic variations, noncoding RNAs (ncRNAs), cell-free DNA (cfDNA), and microbiome-based biomarkers have been extensively analyzed as potential biomarkers in benign and malignant GI diseases. Multiple single-nucleotide polymorphisms have been linked with a number of GI diseases, and these observations are further being used to build up disease-specific genetic risk scores. Micro-RNAs and long ncRNAs have a large potential as noninvasive biomarkers in the management of inflammatory bowel diseases and GI tumors. Altered microbiome profiles were observed in multiple GI diseases, but most of the findings still lack translational clinical application. As of today, cfDNA appears to be the most potent biomarker for early detection and screening of GI cancers. Key Messages: Novel noninvasive molecular biomarkers show huge potential as useful tools in the diagnostics and management of different GI diseases. However, the use of these biomarkers in real-life clinical practice still remains limited, and further large studies are needed to elucidate the ultimate role of these potential noninvasive clinical tools.
Collapse
Affiliation(s)
- Paulius Jonaitis
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vytautas Kiudelis
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Greta Streleckiene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rolandas Gedgaudas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| |
Collapse
|
|
15
|
Yuan Z, Wang X, Geng X, Li Y, Mu J, Tan F, Xue Q, Gao S, He J. Liquid biopsy for esophageal cancer: Is detection of circulating cell-free DNA as a biomarker feasible? Cancer Commun (Lond) 2020; 41:3-15. [PMID: 33264481 PMCID: PMC7819547 DOI: 10.1002/cac2.12118] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/19/2020] [Accepted: 11/19/2020] [Indexed: 12/25/2022] Open
Abstract
Esophageal cancer (EC) is a common cancer and is histopathologically classified into esophageal squamous cell carcinoma and esophageal adenocarcinoma. EC is a worldwide public health issue because of late diagnosis and lack of effective therapy. In contrast to standard tumor biopsies, liquid biopsies are emerging as a tool which is minimally invasive that can complement or even substitute more classical approaches. Specifically, cell-free DNA (cfDNA) has shown promise in cancer-related clinical applications. Indeed, cfDNA has been shown to be an effective circulating biomarker for non-invasive cancer diagnosis and monitoring of cancer patients. Although the clinical application of cfDNA has been reported on other cancers, few studies have evaluated its use in EC. Here, we review this relevant literature and discuss limitations and advantages of its application in the diagnosis and monitoring of EC.
Collapse
Affiliation(s)
- Zuyang Yuan
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Xinfeng Wang
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Xiao Geng
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Yin Li
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Juwei Mu
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Fengwei Tan
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Qi Xue
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Shugeng Gao
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| | - Jie He
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021P. R. China
| |
Collapse
|
|
16
|
Jia R, Zhao CH, Li PS, Liu RR, Zhang Y, Chen HE, Chang LP, Gong YH, Guan YF, Yi X, Xu JM. Post-radiation circulating tumor DNA as a prognostic factor in locally advanced esophageal squamous cell carcinoma. Oncol Lett 2020; 21:68. [PMID: 33365079 PMCID: PMC7716704 DOI: 10.3892/ol.2020.12329] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 10/20/2020] [Indexed: 12/15/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly malignant and deadly tumor. Radiation therapy is one of the primary treatments for locally advanced ESCC. However, the biomarkers for prognosis of definitive radiation remain undefined. Peripheral blood circulating tumor (ct)DNA provides information of tumor genetic alterations and has been confirmed as a potential non-invasive biomarker for several types of cancer. The present study investigated the clinical implications of ctDNA detection in patients with ESCC and receiving definitive radiation therapy. Patients with locally advanced ESCC were retrospectively recruited. Plasma samples were collected before, during and following radiation therapy. Next-generation sequencing was performed to identify somatic mutations in 180 genes. A total of 69 baseline and post-radiation plasma samples were collected from 25 patients. A total of 59 non-silent single nucleotide variants were present in 33 genes. All pre-radiation and 58.3% (14/24) of post-radiation samples had at least one mutation. Patients with lymph node metastases (LNM) exhibited a higher number of pre-radiation mutations compared with those without LNM. The variables, progression-free survival (PFS) and overall survival (OS) of the patients with one baseline mutation were not significantly different compared with that in patients with more than one baseline mutation. Patients with initial ctDNA-positive post-radiation samples exhibited significantly reduced PFS (P=0.047) and OS (P=0.005) compared with that in patients with ctDNA-negative samples. The post-radiation plasma ctDNA status was an independent prognostic factor from univariate and multivariate analyses. Dynamic monitoring of ctDNA during follow-up was examined. The results indicated that ctDNA was a predictive and prognostic marker in patients with ESCC and receiving definitive radiation therapy, which may guide subsequent treatment.
Collapse
Affiliation(s)
- Ru Jia
- Department of Gastrointestinal Oncology, The Fifth Medical Centre, Chinese People's Liberation Army General Hospital, Fengtai, Beijing 100071, P.R. China
| | - Chuan-Hua Zhao
- Department of Gastrointestinal Oncology, The Fifth Medical Centre, Chinese People's Liberation Army General Hospital, Fengtai, Beijing 100071, P.R. China
| | - Pan-Song Li
- Geneplus-Beijing Institute, Changping, Beijing 102206, P.R. China
| | - Rong-Rui Liu
- Department of Gastrointestinal Oncology, The Fifth Medical Centre, Chinese People's Liberation Army General Hospital, Fengtai, Beijing 100071, P.R. China
| | - Yun Zhang
- Department of Gastrointestinal Oncology, The Fifth Medical Centre, Chinese People's Liberation Army General Hospital, Fengtai, Beijing 100071, P.R. China
| | - Hai-E Chen
- Department of Gastrointestinal Oncology, The Fifth Medical Centre, Chinese People's Liberation Army General Hospital, Fengtai, Beijing 100071, P.R. China
| | - Lian-Peng Chang
- Geneplus-Beijing Institute, Changping, Beijing 102206, P.R. China
| | - Yu-Hua Gong
- Geneplus-Beijing Institute, Changping, Beijing 102206, P.R. China
| | - Yan-Fang Guan
- Geneplus-Beijing Institute, Changping, Beijing 102206, P.R. China
| | - Xin Yi
- Geneplus-Beijing Institute, Changping, Beijing 102206, P.R. China
| | - Jian-Ming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Centre, Chinese People's Liberation Army General Hospital, Fengtai, Beijing 100071, P.R. China
| |
Collapse
|
|
17
|
van der Wilk BJ, Eyck BM, Doukas M, Spaander MCW, Schoon EJ, Krishnadath KK, Oostenbrug LE, Lagarde SM, Wijnhoven BPL, Looijenga LHJ, Biermann K, van Lanschot JJB. Residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer: locations undetected by endoscopic biopsies in the preSANO trial. Br J Surg 2020; 107:1791-1800. [PMID: 32757307 PMCID: PMC7689829 DOI: 10.1002/bjs.11760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/06/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022]
Abstract
Background Active surveillance has been proposed for patients with oesophageal cancer in whom there is a complete clinical response after neoadjuvant chemoradiotherapy (nCRT). However, endoscopic biopsies have limited negative predictive value in detecting residual disease. This study determined the location of residual tumour following surgery to improve surveillance and endoscopic strategies. Methods The present study was based on patients who participated in the prospective preSANO trial with adenocarcinoma or squamous cell carcinoma of the oesophagus or oesophagogastric junction treated in four Dutch hospitals between 2013 and 2016. Resection specimens and endoscopic biopsies taken during clinical response evaluations after nCRT were reviewed by two expert gastrointestinal pathologists. The exact location of residual disease in the oesophageal wall was determined in resection specimens. Endoscopic biopsies were assessed for the presence of structures representing the submucosal layer of the oesophageal wall. Results In total, 119 eligible patients underwent clinical response evaluations after nCRT followed by standard surgery. Residual tumour was present in endoscopic biopsies from 70 patients, confirmed on histological analysis of the resected organ. Residual tumour was present in the resection specimen from 27 of the other 49 patients, despite endoscopic biopsies being negative. Of these 27 patients, residual tumour was located in the mucosa in 18, and in the submucosa beneath tumour‐free mucosa in eight. One patient had tumour in muscle beneath tumour‐free mucosa and submucosa. Conclusion Most residual disease after nCRT missed by endoscopic biopsies was located in the mucosa. Active surveillance could be improved by more sampling and considering submucosal biopsies.
Collapse
Affiliation(s)
| | - B M Eyck
- Departments of Surgery, Rotterdam, the Netherlands
| | - M Doukas
- Pathology, Rotterdam, the Netherlands
| | - M C W Spaander
- Gastroenterology and Hepatology Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - E J Schoon
- Departments of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands
| | - K K Krishnadath
- Amsterdam University Medical Centres - location AMC, University of Amsterdam, Amsterdam Cancer Centre, Amsterdam, the Netherlands
| | | | - S M Lagarde
- Departments of Surgery, Rotterdam, the Netherlands
| | | | - L H J Looijenga
- Pathology, Rotterdam, the Netherlands.,Department of Pathology, Princess Maxima Centre for Paediatric Oncology, Utrecht, the Netherlands
| | | | | |
Collapse
|
|
18
|
Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12061352. [PMID: 32466419 PMCID: PMC7352685 DOI: 10.3390/cancers12061352] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/12/2020] [Accepted: 05/23/2020] [Indexed: 12/27/2022] Open
Abstract
(1) Background: Early predictive markers to track treatment responses are needed for advanced esophageal squamous cell carcinoma (ESCC) patients. We examined the prognostication and risk stratification role of liquid biopsy serial monitoring for this deadly cancer. (2) Methods: Circulating tumor cells (CTCs) and plasma cell-free DNA (cfDNA) were isolated from 60 ESCC patients treated by chemotherapy (CT) at five serial timepoints: baseline (CTC1/cfDNA1), CT pre-cycle III (CTC2/cfDNA2), CT post-cycle IV, end of CT and relapse. (3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (≥3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis. In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis. (4) Conclusions: CTC counts at pre-cycle III are independently associated with response at interim reassessment and PFS. Combined changes of CTC counts and cfDNA levels from baseline to pre-cycle III are independently associated with OS. Longitudinal liquid biopsy serial monitoring provides complementary information for prediction and prognosis for CT responses in advanced ESCC.
Collapse
|
|
19
|
Chu LY, Peng YH, Weng XF, Xie JJ, Xu YW. Blood-based biomarkers for early detection of esophageal squamous cell carcinoma. World J Gastroenterol 2020; 26:1708-1725. [PMID: 32351288 PMCID: PMC7183865 DOI: 10.3748/wjg.v26.i15.1708] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 03/13/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive system worldwide, especially in China. Due to the lack of effective early detection methods, ESCC patients often present at an advanced stage at the time of diagnosis, which seriously affects the prognosis of patients. At present, early detection of ESCC mainly depends on invasive and expensive endoscopy and histopathological biopsy. Therefore, there is an unmet need for a non-invasive method to detect ESCC in the early stages. With the emergence of a large class of non-invasive diagnostic tools, serum tumor markers have attracted much attention because of their potential for detection of early tumors. Therefore, the identification of serum tumor markers for early detection of ESCC is undoubtedly one of the most effective ways to achieve early diagnosis and treatment of ESCC. This article reviews the recent advances in the discovery of blood-based ESCC biomarkers, and discusses the origins, clinical applications, and technical challenges of clinical validation of various types of biomarkers.
Collapse
Affiliation(s)
- Ling-Yu Chu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xue-Fen Weng
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| |
Collapse
|
|
20
|
Randrian V, Adenis A, Desrame J, Barbier E, Di Fiore F, Lièvre A, Dahan L, Laurent-Puig P, Mineur L, Breysacher G, Roquin G, Louafi S, Lopez A, Louvet C, Borg C, Metges JP, Faroux R, Gaba L, Manfredi S, Tougeron D. Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI)-PRODIGE 62: A multicentre, randomised, non-comparative phase II study. Dig Liver Dis 2020; 52:347-350. [PMID: 31899122 DOI: 10.1016/j.dld.2019.11.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 12/11/2022]
Abstract
Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but no randomised studies are available. OESIRI is a multicentre, randomised, open-label phase II trial designed to evaluate efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU versus paclitaxel as second-line therapy in patients with mESCC. The main inclusion criteria are histologically proven mESCC in progression after first-line platinum-based chemotherapy. Patients with initial resectable disease can be included if recurrence occurred within 6 months. The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. In addition, circulating tumour DNA will be monitored to assess its prognostic value.
Collapse
Affiliation(s)
- Violaine Randrian
- Gastroenterology Department, Centre Hospitalo-Universitaire de Poitiers, University of Poitiers, Poitiers, France
| | - Antoine Adenis
- Medical Oncology Department, Institut Régional Du Cancer de Montpellier (ICM), Université de Montpellier, France
| | - Jérôme Desrame
- Medical Oncology Department, Hôpital Privé Jean du Cancer de Mermoz, Lyon, France
| | - Emilie Barbier
- FFCD EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Dijon, France
| | | | - Astrid Lièvre
- Gastroenterology Department, Centre Hospitalo-Universitaire Pontchaillou, Rennes 1 University, Rennes, France
| | - Laetitia Dahan
- Digestive Oncology Department, AP-HM, La Timone Hospital, Aix-Marseille Université, Marseille, France
| | - Pierre Laurent-Puig
- Biology Department, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, Paris, France
| | - Laurent Mineur
- Digestive Oncology Department, Institut Sainte Catherine, Avignon, France
| | | | - Guillaume Roquin
- Gastroenterology & Digestive Oncology Department, Centre Hospitalo-Universitaire d'Angers, Angers, France
| | - Samy Louafi
- Gastroenterology Department, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France; Gastroenterology Department, Groupe Hospitalier Nord Essonne, Longjumeau, France
| | - Anthony Lopez
- Gastroenterology and Hepatology Department, Centre Hospitalo-Universitaire de Nancy, Vandoeuvre-lès-Nancy, France
| | - Christophe Louvet
- Medical Oncology Department, Institut Mutualiste Montsouris, Paris, France
| | - Christophe Borg
- Medical Oncology Department, Centre Hospitalo-Universitaire de Besançon, Besançon, France
| | - Jean Philippe Metges
- Medical Oncology Department, Centre Hospitalier Régional Universitaire de Brest-Hôpital Morvan, Brest, France
| | - Roger Faroux
- Gastroenterology Department, Centre Hospitalier de La Roche-sur-Yon, La Roche-sur-Yon, France
| | - Lila Gaba
- FFCD EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Dijon, France
| | - Sylvain Manfredi
- Gastroenterology Department, Centre Hospitalo-Universitaire de Dijon, EPICAD INSERM LNC-UMR 1231, University of Bourgogne-Franche Comté, Dijon, France
| | - David Tougeron
- Gastroenterology Department, Centre Hospitalo-Universitaire de Poitiers, University of Poitiers, Poitiers, France.
| |
Collapse
|
|
21
|
Azad TD, Chaudhuri AA, Fang P, Qiao Y, Esfahani MS, Chabon JJ, Hamilton EG, Yang YD, Lovejoy A, Newman AM, Kurtz DM, Jin M, Schroers-Martin J, Stehr H, Liu CL, Hui ABY, Patel V, Maru D, Lin SH, Alizadeh AA, Diehn M. Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer. Gastroenterology 2020; 158:494-505.e6. [PMID: 31711920 PMCID: PMC7010551 DOI: 10.1053/j.gastro.2019.10.039] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 10/24/2019] [Accepted: 10/30/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy. METHODS We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6-8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy). RESULTS The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P < .0001), formation of distant metastases (hazard ratio, 32.1; P < .0001), and shorter disease-specific survival times (hazard ratio, 23.1; P < .0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P < .001 for comparison of either technique to combined analysis). CONCLUSIONS In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.
Collapse
Affiliation(s)
- Tej D. Azad
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Aadel A. Chaudhuri
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, USA
| | - Penny Fang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yawei Qiao
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mohammad S. Esfahani
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Jacob J. Chabon
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Emily G. Hamilton
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Yi D. Yang
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Alex Lovejoy
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Aaron M. Newman
- Stanford Cancer Institute, Stanford University, Stanford, California, USA,Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA
| | - David M. Kurtz
- Stanford Cancer Institute, Stanford University, Stanford, California, USA,Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Michael Jin
- Stanford Cancer Institute, Stanford University, Stanford, California, USA,Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Joseph Schroers-Martin
- Stanford Cancer Institute, Stanford University, Stanford, California, USA,Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Henning Stehr
- Department of Radiation Oncology, Stanford University, Stanford, California, USA,Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Chih Long Liu
- Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Angela Bik-Yu Hui
- Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Viren Patel
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dipen Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Steven H. Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ash A. Alizadeh
- Stanford Cancer Institute, Stanford University, Stanford, California, USA,Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Maximilian Diehn
- Department of Radiation Oncology, Stanford University, Stanford, California; Stanford Cancer Institute, Stanford University, Stanford, California; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.
| |
Collapse
|
|
22
|
Matsuoka T, Yashiro M. Precision medicine for gastrointestinal cancer: Recent progress and future perspective. World J Gastrointest Oncol 2020; 12:1-20. [PMID: 31966910 PMCID: PMC6960076 DOI: 10.4251/wjgo.v12.i1.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 10/12/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.
Collapse
Affiliation(s)
- Tasuku Matsuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| |
Collapse
|
|
23
|
Said R, Guibert N, Oxnard GR, Tsimberidou AM. Circulating tumor DNA analysis in the era of precision oncology. Oncotarget 2020; 11:188-211. [PMID: 32010431 PMCID: PMC6968778 DOI: 10.18632/oncotarget.27418] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.
Collapse
Affiliation(s)
- Rabih Said
- Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Oncology, St. George Hospital University Medical Center, University of Balamand, Beirut, Lebanon
- Co-authorship
| | - Nicolas Guibert
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Thoracic Oncology, Toulouse University Hospital, Toulouse, France
- Co-authorship
| | - Geoffrey R. Oxnard
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Apostolia M. Tsimberidou
- Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
24
|
Smith RA, Lam AK. Liquid Biopsy for Investigation of Cancer DNA in Esophageal Squamous Cell Carcinoma. Methods Mol Biol 2020; 2129:203-215. [PMID: 32056180 DOI: 10.1007/978-1-0716-0377-2_16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Early detection of cancer and the monitoring of cancer recurrence in treated patients are significant challenges in esophageal squamous cell carcinoma (ESCC). Liquid biopsy is the identification of tumor biomarkers from minimally invasive samples of biological fluids, including urine, blood, stool, saliva, or cerebrospinal fluid. Liquid biopsy offers a potential solution to the problems of detection and surveillance as DNA shed from cancer cells as cell-free DNA or in exosomes can be detected in body fluids. By detecting these DNAs, we can identify the presence of cancer-associated mutations for basic detection, as well as to obtain information on the recurrence and evolution of disease following initial treatment. These sources of information have the potential to significantly improve the management of patients with ESCC. In this chapter, we detail a method for the isolation of cell-free DNA from blood plasma and DNA associated with exosomes in blood from patients with esophageal squamous cell carcinomas.
Collapse
Affiliation(s)
- Robert A Smith
- Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
| | - Alfred K Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| |
Collapse
|
|
25
|
Hagi T, Kurokawa Y, Takahashi T, Saito T, Yamashita K, Tanaka K, Makino T, Yamasaki M, Nakajima K, Mori M, Doki Y. Molecular Barcode Sequencing for Highly Sensitive Detection of Circulating Tumor DNA in Patients with Esophageal Squamous Cell Carcinoma. Oncology 2019; 98:222-229. [DOI: 10.1159/000504808] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 11/14/2019] [Indexed: 11/19/2022]
|
|
26
|
Meng P, Wei J, Geng Y, Chen S, Terpstra MM, Huang Q, Zhang Q, Su Z, Yu W, Su M, Kok K, van den Berg A, Gu J. Targeted sequencing of circulating cell-free DNA in stage II-III resectable oesophageal squamous cell carcinoma patients. BMC Cancer 2019; 19:818. [PMID: 31429737 PMCID: PMC6701116 DOI: 10.1186/s12885-019-6025-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 08/08/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the potential of cell-free DNA (cfDNA) as a disease biomarker in oesophageal squamous cell carcinoma (ESCC) that can be used for treatment response evaluation and early detection of tumour recurrence. METHODS Matched tumour tissue, pre- and post-surgery plasma and WBCs obtained from 17 ESCC patients were sequenced using a panel of 483 cancer-related genes. RESULTS Somatic mutations were detected in 14 of 17 tumour tissues. Putative harmful mutations were observed in genes involved in well-known cancer-related pathways, including PI3K-Akt/mTOR signalling, Proteoglycans in cancer, FoxO signalling, Jak-STAT signalling, Chemokine signalling and Focal adhesion. Forty-six somatic mutations were found in pre-surgery cfDNA in 8 of 12 patients, with mutant allele frequencies (MAF) ranging from 0.24 to 4.91%. Three of the 8 patients with detectable circulating tumour DNA (ctDNA) had stage IIA disease, whereas the others had stage IIB-IIIB disease. Post-surgery cfDNA somatic mutations were detected in only 2 of 14 patients, with mutant allele frequencies of 0.28 and 0.36%. All other somatic mutations were undetectable in post-surgery cfDNA, even in samples collected within 3-4 h after surgery. CONCLUSION Our study shows that somatic mutations can be detected in pre-surgery cfDNA in stage IIA to IIIB patients, and at a lower frequency in post-surgery cfDNA. This indicates that cfDNA could potentially be used to monitor disease load, even in low disease-stage patients.
Collapse
Affiliation(s)
- Pei Meng
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, 9700RB Groningen, Netherlands
| | - Jiacong Wei
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
- Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700RB Groningen, Netherlands
| | - Yiqun Geng
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
| | - Shaobin Chen
- Department of Thoracic surgery, Cancer Hospital of Shantou University, Shantou, 515041 Guangdong China
| | - Miente Martijn Terpstra
- Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700RB Groningen, Netherlands
| | - Qiongyi Huang
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
| | - Qian Zhang
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
| | - Zuoqing Su
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
| | - Wanchun Yu
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
| | - Min Su
- Department of Pathology & Institute of Clinical Pathology, Shantou University Medical College, Shantou, 515041 Guangdong China
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700RB Groningen, Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, 9700RB Groningen, Netherlands
| | - Jiang Gu
- Provincial Key laboratory of Infectious Diseases and Molecular Pathology, Department of Pathology and Pathophysiology, Collaborative and Creative Centre, Shantou University Medical College, Shantou, 515041 Guangdong China
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, 610066 China
| |
Collapse
|
|
27
|
Egyud M, Tejani M, Pennathur A, Luketich J, Sridhar P, Yamada E, Ståhlberg A, Filges S, Krzyzanowski P, Jackson J, Kalatskaya I, Jiao W, Nielsen G, Zhou Z, Litle V, Stein L, Godfrey T. Detection of Circulating Tumor DNA in Plasma: A Potential Biomarker for Esophageal Adenocarcinoma. Ann Thorac Surg 2019; 108:343-349. [PMID: 31059681 PMCID: PMC6676214 DOI: 10.1016/j.athoracsur.2019.04.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 02/07/2019] [Accepted: 04/01/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Recent literature has demonstrated the potential of "liquid biopsy" and detection of circulating tumor (ct)DNA as a cancer biomarker. However, to date there is a lack of data specific to esophageal adenocarcinoma (EAC). This study was conducted to determine how detection and quantification of ctDNA changes with disease burden in patients with EAC and evaluate its potential as a biomarker in this population. METHODS Blood samples were obtained from patients with stage I to IV EAC. Longitudinal blood samples were collected from a subset of patients. Imaging studies and pathology reports were reviewed to determine disease course. Tumor samples were sequenced to identify mutations. Mutations in plasma DNA were detected using custom, barcoded, patient-specific sequencing libraries. Mutations in plasma were quantified, and associations with disease stage and response to therapy were explored. RESULTS Plasma samples from a final cohort of 38 patients were evaluated. Baseline plasma samples were ctDNA positive for 18 patients (47%) overall, with tumor allele frequencies ranging from 0.05% to 5.30%. Detection frequency of ctDNA and quantity of ctDNA increased with stage. Data from longitudinal samples indicate that ctDNA levels correlate with and precede evidence of response to therapy or recurrence. CONCLUSIONS ctDNA can be detected in plasma of EAC patients and correlates with disease burden. Detection of ctDNA in early-stage EAC is challenging and may limit diagnostic applications. However, our data demonstrate the potential of ctDNA as a dynamic biomarker to monitor treatment response and disease recurrence in patients with EAC.
Collapse
Affiliation(s)
- Matthew Egyud
- Department of Surgery, Boston University/Boston Medical Center, Boston, Massachusetts
| | | | - Arjun Pennathur
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - James Luketich
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Praveen Sridhar
- Department of Surgery, Boston University/Boston Medical Center, Boston, Massachusetts
| | - Emiko Yamada
- Department of Surgery, Boston University/Boston Medical Center, Boston, Massachusetts
| | - Anders Ståhlberg
- Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Stefan Filges
- Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | | | - Jennifer Jackson
- Department of Surgery, Boston University/Boston Medical Center, Boston, Massachusetts
| | | | - Wei Jiao
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Gradon Nielsen
- Department of Medicine, University of Rochester, Rochester, New York
| | - Zhongren Zhou
- Department of Pathology, University of Rochester, Rochester, New York
| | - Virginia Litle
- Department of Surgery, Boston University/Boston Medical Center, Boston, Massachusetts
| | - Lincoln Stein
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Tony Godfrey
- Department of Surgery, Boston University/Boston Medical Center, Boston, Massachusetts.
| |
Collapse
|
|
28
|
Koldby KM, Mortensen MB, Detlefsen S, Pfeiffer P, Thomassen M, Kruse TA. Tumor-specific genetic aberrations in cell-free DNA of gastroesophageal cancer patients. J Gastroenterol 2019; 54:108-121. [PMID: 30242476 DOI: 10.1007/s00535-018-1508-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/04/2018] [Indexed: 02/04/2023]
Abstract
The applicability of liquid biopsies is studied intensively in all types of cancer and analysis of circulating tumor DNA (ctDNA) has recently been implemented clinically for mutation detection in lung cancer. ctDNA may provide information about tumor quantity and mutations present in the tumor, and as such have many potential applications in diagnosis and treatment of cancer. It has been suggested that ctDNA analysis may overcome the issue of intra-tumor heterogeneity faced by tissue biopsies and serve as an additional diagnostic tool. Furthermore, liquid biopsies are potentially helpful for monitoring of treatment response as well as detection of minimal residual disease and relapse. Gastroesophageal cancers (GEC) have high mortality rates and the majority of patients present with advanced stage at diagnosis or succumb due to disease recurrence even after radical resection of the primary tumor. Biomarkers that can help optimize treatment strategy are thus highly desirable. The present study is a review of published data on ctDNA in GEC patients. We identified 25 studies in which tumor-specific genetic aberrations were investigated in plasma or serum and discuss these in relation to the methods applied for ctDNA analysis. The methods used for ctDNA detection greatly influence the sensitivity of the analysis and, therefore, the potential clinical applications. We found that studies of ctDNA in GEC, although limited in number, are promising for several applications such as genetic profiling of tumors and monitoring of disease progression. However, more studies are needed to establish if and how this analysis can be clinically implemented.
Collapse
Affiliation(s)
- Kristina Magaard Koldby
- Department of Clinical Genetics, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark. .,Human Genetics, Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, Odense, Denmark.
| | - Michael Bau Mortensen
- Department of Surgery, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, Odense, Denmark
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark.,Human Genetics, Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, Odense, Denmark
| | - Torben A Kruse
- Department of Clinical Genetics, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark.,Human Genetics, Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, Odense, Denmark
| |
Collapse
|
|
29
|
Abstract
Genetic material derived from tumours is constantly shed into the circulation of cancer patients both in the form of circulating free nucleic acids and within circulating cells or extracellular vesicles. Monitoring cancer-specific genomic alterations, particularly mutant allele frequencies, in circulating nucleic acids allows for a non-invasive liquid biopsy for detecting residual disease and response to therapy. The advent of molecular targeted treatments and immunotherapies with increasing effectiveness requires corresponding effective molecular biology methods for the detection of biomarkers such as circulating nucleic acid to monitor and ultimately personalise therapy. The use of polymerase chain reaction (PCR)-based methods, such as droplet digital PCR, allows for a very sensitive analysis of circulating tumour DNA, but typically only a limited number of gene mutations can be detected in parallel. In contrast, next-generation sequencing allows for parallel analysis of multiple mutations in many genes. The development of targeted next-generation sequencing cancer gene panels optimised for the detection of circulating free DNA now provides both the flexibility of multiple mutation analysis coupled with a sensitivity that approaches or even matches droplet digital PCR. In this review, we discuss the advantages and disadvantages of these current molecular technologies in conjunction with how this field is evolving in the context of melanoma diagnosis, prognosis, and monitoring of response to therapy.
Collapse
|
|
30
|
Yang W, Han Y, Zhao X, Duan L, Zhou W, Wang X, Shi G, Che Y, Zhang Y, Liu J, Zhang H, Zhao Q, Hong L, Fan D. Advances in prognostic biomarkers for esophageal cancer. Expert Rev Mol Diagn 2018; 19:109-119. [PMID: 30582379 DOI: 10.1080/14737159.2019.1563485] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Wanli Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Yu Han
- Department of Otolaryngology, Xijing Hospital, Air Force Military Medical University, Xi’an, China
| | - Xinhui Zhao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Lili Duan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Wei Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Xiaoqian Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Gaokai Shi
- The First Brigade of Student, Air Force Military Medical University, Xi’an, China
| | - Yinggang Che
- The First Brigade of Student, Air Force Military Medical University, Xi’an, China
| | - Yujie Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Jinqiang Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Hongwei Zhang
- Department of Digestive Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, China
| | - Qingchuan Zhao
- Department of Digestive Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, China
| | - Liu Hong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| |
Collapse
|
|
31
|
Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence. Sci Rep 2018; 8:14941. [PMID: 30297788 PMCID: PMC6175817 DOI: 10.1038/s41598-018-33027-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 09/20/2018] [Indexed: 12/18/2022] Open
Abstract
Oesophageal cancer (OC) has high mortality. This study aims at determining the feasibility of liquid biopsies for genomic profiling in early stage OC, comparing two different technologies for mutational analysis in circulating cell -free DNA (ccfDNA) and evaluating the clinical impact of these somatic alterations during primary staging. In 25 patients with locally advanced OC, endoscopic tumour biopsies and simultaneous blood samples were taken during primary staging. Genomic DNA from biopsies and ccfDNA were analysed for mutations using a 12 gene panel next-generation sequencing (NGS) assay as well as digital droplet PCR (ddPCR). Genetic data was correlated with patients' outcome. In 21 of the tested biopsies (84%) at least one somatic mutation was detected by NGS. Mutations detected by NGS were detectable by ddPCR with similar allele frequencies. In three out of the 21 patients with proven mutations, the same mutations were also detectable in ccfDNA using NGS (14%). In contrast, ddPCR detected mutations in ccfDNA of five additional patients (8/21, 38%). Post-surgical outcome analysis was performed for those patients who had received complete tumour resection (n = 16). Five of them suffered from an early relapse within the first year after surgery, including four with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed a higher sensitivity for ddPCR compared to NGS in detecting mutated ccfDNA in OC. Detection of somatically altered ccfDNA during primary staging seems to be indicative for post-surgical tumour recurrence.
Collapse
|
|
32
|
Fang YF, Geng Q. Research progress and prospects of esophageal cancer in era of precision medicine. Shijie Huaren Xiaohua Zazhi 2017; 25:2829-2837. [DOI: 10.11569/wcjd.v25.i32.2829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer (EC) is a common digestive system carcinoma, and China has the highest incidence of EC in the world. The prognosis of EC is poor; the five-year survival rate of EC in developing countries is extremely low because the clinical symptoms are often found too late, which makes the patients cannot be cured. In the era of precision medicine, new concepts and technologies are applied to the screening, diagnosis, and treatment of EC. Therefore, it becomes possible to formulate a personalized and accurate disease prevention and treatment program for each patient, so as to achieve maximum therapeutic effect, minimize side effects, and ultimately achieve the goal of improving the prognosis of EC. This article reviews the recent research progress and prospects of EC in the era of precision medicine with regard to disease screening, diagnosis, and treatment.
Collapse
Affiliation(s)
- Yi-Fan Fang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| |
Collapse
|
|
33
|
Clinical value of ctDNA in upper-GI cancers: A systematic review and meta-analysis. Biochim Biophys Acta Rev Cancer 2017; 1868:394-403. [PMID: 28801248 DOI: 10.1016/j.bbcan.2017.08.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 08/05/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND The recent expanding technical possibilities to detect tumor derived mutations in blood, so-called circulating tumor DNA (ctDNA), has rapidly increased the interest in liquid biopsies. This review and meta-analysis explores the clinical value of ctDNA in malignancies of the upper gastro-intestinal tract. METHODS PubMed, Cochrane and Embase databases were searched to identify studies reporting the diagnostic, prognostic or predictive value of ctDNA in patients with esophageal, gastric and pancreatic cancer, until January 2017. The diagnostic accuracy and, using random-effect pair-wise meta-analyses, the prognostic value of ctDNA was assessed. RESULTS A total of 34 studies met the inclusion criteria. For esophageal and gastric cancer, amplification of oncogenes in blood, such as HER2 and MYC, can be relevant for diagnostic purposes, and to predict treatment response in certain patient subpopulations. Given the limited number of studies assessing the role of ctDNA in esophageal and gastric cancer, the meta-analysis estimated the diagnostic accuracy and predictive value of ctDNA in pancreatic cancer only (n=10). The pooled sensitivity and specificity of ctDNA as a diagnostic tool in pancreatic cancer were 28% and 95%, respectively. Patients with pancreatic cancer and detectable ctDNA demonstrated a worse overall survival compared to patients with undetectable ctDNA (HR 1.92, 95% confidence interval (CI) 1.15-3.22, p=0.01). CONCLUSION The presence of ctDNA is significantly associated with a poor prognosis in patients with pancreatic cancer. The use of ctDNA in clinical practice is promising, although standardization of sequencing techniques and further development of high-sensitive detection methods is needed.
Collapse
|
|
34
|
Mehrotra M, Singh RR, Chen W, Huang RS, Almohammedsalim AA, Barkoh BA, Simien CM, Hernandez M, Behrens C, Patel KP, Routbort MJ, Broaddus RR, Medeiros LJ, Wistuba II, Kopetz S, Luthra R. Study of Preanalytic and Analytic Variables for Clinical Next-Generation Sequencing of Circulating Cell-Free Nucleic Acid. J Mol Diagn 2017; 19:514-524. [DOI: 10.1016/j.jmoldx.2017.03.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 02/10/2017] [Accepted: 03/06/2017] [Indexed: 12/19/2022] Open
|
|
35
|
Harada K, Mizrak Kaya D, Shimodaira Y, Song S, Baba H, Ajani JA. Translating genomic profiling to gastrointestinal cancer treatment. Future Oncol 2017; 13:919-934. [PMID: 28067073 DOI: 10.2217/fon-2016-0422] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Next-generation sequencing enables faster, cheaper and more accurate whole-genome sequencing, allowing genome profiling and discovery of molecular features. As molecular targeted drugs are developed, treatment can be tailored according to molecular subtype. Gastric and colorectal cancers have each been divided into four subtypes according to molecular features. Profiling of the esophageal cancer genome is underway and its classification is anticipated. To date, identification of HER2 expression in gastric adenocarcinoma and KRAS, NRAS and BRAF mutations in colon cancer have proved essential for treatment decisions. However, to overcome therapy resistance and improve prognosis, further individualized therapy is required. Here, we summarize the treatment options for gastrointestinal cancer according to genomic profiling and discuss future directions.
Collapse
Affiliation(s)
- Kazuto Harada
- Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.,Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Dilsa Mizrak Kaya
- Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Yusuke Shimodaira
- Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| |
Collapse
|
|
36
|
Yazbeck R, Jaenisch SE, Watson DI. From blood to breath: New horizons for esophageal cancer biomarkers. World J Gastroenterol 2016; 22:10077-10083. [PMID: 28028355 PMCID: PMC5155166 DOI: 10.3748/wjg.v22.i46.10077] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/05/2016] [Accepted: 10/30/2016] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer is a lethal cancer encompassing adenocarcinoma and squamous cell carcinoma sub-types. The global incidence of esophageal cancer is increasing world-wide, associated with the increased prevalence of associated risk factors. The asymptomatic nature of disease often leads to late diagnosis and five-year survival rates of less than 15%. Current diagnostic tools are restricted to invasive and costly endoscopy and biopsy for histopathology. Minimally and non-invasive biomarkers of esophageal cancer are needed to facilitate earlier detection and better clinical management of patients. This paper summarises recent insights into the development and clinical validation of esophageal cancer biomarkers, focussing on circulating markers in the blood, and the emerging area of breath and odorant biomarkers.
Collapse
|
|
37
|
Liang J, She Y, Zhu J, Wei L, Zhang L, Gao L, Wang Y, Xing J, Guo Y, Meng X, Li P. Development and validation of an ultra-high sensitive next-generation sequencing assay for molecular diagnosis of clinical oncology. Int J Oncol 2016; 49:2088-2104. [PMID: 27826616 DOI: 10.3892/ijo.2016.3707] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 09/07/2016] [Indexed: 11/06/2022] Open
Abstract
Dramatic improvements in the understanding of oncogenes have spurred the development of molecular target therapies, which created an exigent need for comprehensive and rapid clinical genotyping. Next-generation sequencing (NGS) assay with increased performance and decreased cost is becoming more widely used in clinical diagnosis. However, the optimization and validation of NGS assay remain a challenge, especially for the detection of somatic variants at low mutant allele fraction (MAF). In the present study, we developed and validated the Novogene Comprehensive Panel (NCP) based on targeted capture for NGS analysis. Due to the high correlation between SNV/INDEL detection performance and target coverage, here we focused on these two types of variants for our deep sequencing strategy. To validate the capability of NCP in single-nucleotide variant (SNV) and small insert and deletion (INDEL) detection, we implemented a practical validation strategy with pooled cell lines, deep sequencing of pooled samples (>2000X average unique coverage across target region) achieving >99% sensitivity and high specificity (positive predictive value, PPV >99%) for all types of variations with expected MAF >5%. Furthermore, given the high sensitivity and that false positive may exist in this assay, we confirmed its accuracy of variants with MAF <5% using 35 formalin-fixed and paraffin-embedded (FFPE) tumor specimens by Quantstudio 3D Digital PCR (dPCR; Life Technologies) and obtained a high consistency (32 of 35 mutations detected by NGS were verified). We also used the amplification refractory mutation system (ARMS) to verify the variants with a MAF in a broad range of 2-63% detected in 33 FFPE samples and reached a 100% PPV for this assay. As a potential clinical diagnosis tool, NCP can robustly and comprehensively analyze clinical-related genes with high sensitivity and low cost.
Collapse
Affiliation(s)
- Jiao Liang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, P.R. China
| | - Yaoguang She
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jiaqi Zhu
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Longgang Wei
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Lanying Zhang
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Lianju Gao
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Yan Wang
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Jing Xing
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Yang Guo
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Xuehong Meng
- Novogene Bioinformatics Institute, Beijing 100083, P.R. China
| | - Peiyu Li
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| |
Collapse
|
|
38
|
Wu A, Lim M. Issues to Consider in Designing Immunotherapy Clinical Trials for Glioblastoma Management. ACTA ACUST UNITED AC 2016. [DOI: 10.4236/jct.2016.78060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|