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Wang Y, Jin RU, Xu J, Lin DC, Sun Z, Xu Y, Li QK, Zhang H. Harnessing technologies to unravel gastric cancer heterogeneity. Trends Cancer 2025:S2405-8033(25)00107-4. [PMID: 40425443 DOI: 10.1016/j.trecan.2025.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 04/14/2025] [Accepted: 04/21/2025] [Indexed: 05/29/2025]
Abstract
Gastric cancer arises from complex carcinogenic factor interactions, with limited treatment options due to the lack of targetable driver gene mutations and significant tumor heterogeneity. Recent studies have provided promising novel approaches to improve our understanding of gastric cancer heterogeneity through integrated characterization, combining genomics with emerging technologies. Delineating the molecular changes and targeting specific molecular subtypes will enhance the efficacy of gastric cancer treatment and improve clinical outcomes. This review provides a comprehensive overview of current technologies used in gastric cancer research, highlighting key discoveries and treatment strategies driven by these innovations. Finally, we discuss the emerging technology-guided directions and potential breakthroughs that could enhance the understanding of gastric cancer tumor heterogeneity, ultimately improving clinical outcomes.
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Affiliation(s)
- Yuefan Wang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
| | - Ramon U Jin
- Division of Oncology and Gastroenterology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Joanne Xu
- College of Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Ding Chiao Lin
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Zhenyu Sun
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Yuanwei Xu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Qing K Li
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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2
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Kawashima M, Yamada T, Miyasaka T, Kanaka S, Kuriyama S, Uehara K, Matsuda A, Ohta R, Sonoda H, Taniai N, Yoshida H. Impact of Minimal Residual Disease on Early Recurrence of Liver Metastatic Colorectal Cancer. Cancer Sci 2025; 116:1366-1374. [PMID: 40059633 PMCID: PMC12044645 DOI: 10.1111/cas.16442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/09/2024] [Accepted: 12/18/2024] [Indexed: 05/02/2025] Open
Abstract
For patients with resectable colorectal liver metastases (CRLM), the efficacy of adjuvant chemotherapy remains a subject of debate. Several studies have concluded that postoperative circulating tumor DNA (ctDNA) is a marker of minimal residual disease (MRD) and is a useful prognostic factor in patients with nonmetastatic colorectal cancer. However, few studies have explored its application in cases involving metastases. This was an observational study that included CRLM patients who underwent primary and liver tumor resection. By examining targeted sequencing of 50 genes commonly mutated in CRC, we identified at least one somatic mutation in each patient's metastatic liver tumor. Blood samples were obtained before and 1-month after surgery. Fifty-three patients were included, and recurrence was diagnosed in 39 patients. Of those, 13 patients experienced early relapse. ctDNA was detected in 45 patients before surgery and 11 after. All MRD-positive patients experienced recurrence. Among them, nine had early recurrence. MRD-positive patients had poorer recurrence free survival (RFS, p < 0.0001) and overall survival (OS, p < 0.0005). Nine of 13 patients with early recurrence had MRD; however, two of 40 patients without early recurrence also had MRD (p < 0.0001). Among 42 MRD-negative patients, adjuvant chemotherapy had no impact of RFS (p = 0.84) or OS (p = 0.54). MRD proved valuable in predicting the risk of postoperative recurrence in patients with CRLM, particularly because MRD positivity emerged as a significant risk factor for early recurrence. Furthermore, it appears that adjuvant chemotherapy may not effectively improve the prognosis for MRD-negative patients.
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Affiliation(s)
- Mampei Kawashima
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Takeshi Yamada
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | | | - Shintaro Kanaka
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Sho Kuriyama
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Kay Uehara
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Akihisa Matsuda
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Ryo Ohta
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Hiromichi Sonoda
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Nobuhiko Taniai
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
| | - Hiroshi Yoshida
- Department of Gastroenterological SurgeryNippon Medical SchoolTokyoJapan
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3
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Nasca V, Bergamo F, Foltran L, Antonuzzo L, Bencardino K, Dell'Aquila E, Corallo S, Spallanzani A, Brunetti O, Spada D, Tamberi S, Cella CA, Avallone A, Fornaro L, Di Donato S, Strippoli A, Puccini A, Tamburini E, Palermo F, Morano F, Pietrantonio F, Raimondi A. Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial. BMC Cancer 2025; 25:633. [PMID: 40200187 PMCID: PMC11980183 DOI: 10.1186/s12885-025-14063-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 04/01/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. TRIAL DESIGN TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1-14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1-5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. TRIAL REGISTRATION TRINITY is registered at ClinicalTrials.gov (NCT06253650).
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Affiliation(s)
- Vincenzo Nasca
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Francesca Bergamo
- Medical Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Luisa Foltran
- Centro Riferimento Oncologico (CRO) Aviano, National Cancer Institute IRCCS, Aviano, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Salvatore Corallo
- SC Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy
| | - Andrea Spallanzani
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | | | - Stefano Tamberi
- Oncology Unit, Ospedale Santa Maria Delle Croci, Ravenna, Italy
| | - Chiara Alessandra Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Istituto Europeo Di Oncologia IRCCS, Milan, Italy
| | - Antonio Avallone
- Istituto Nazionale Dei Tumori Napoli IRCCS Pascale, Naples, Italy
| | - Lorenzo Fornaro
- U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Antonia Strippoli
- Comprehensive Cancer Center, Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Alberto Puccini
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Emiliano Tamburini
- Department of Oncology and Palliative Care, Ospedale Cardinale Panico, Tricase, Italy
| | - Federica Palermo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
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Zhang H, Sun N, Li F, Wang Q, Sun Z, Zhang Y, Wang L, Zhao C, Fu Y. Construction of a modified TNM staging system and prediction model based on examined lymph node counts for gastric cancer patients at pathological stage N3. Front Oncol 2025; 15:1569736. [PMID: 40248208 PMCID: PMC12003143 DOI: 10.3389/fonc.2025.1569736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 03/13/2025] [Indexed: 04/19/2025] Open
Abstract
Background Examined lymph node (ELN) count is a critical factor affecting the number of metastatic lymph nodes (MLNs). The impact of the ELN number on survival and staging remains unclear. Methods This study included 4,291 stage N3 GC patients from the SEER database (training cohort) and 567 stage N3 GC patients from the FAHZZU database (validation cohort). The optimal ELN count and stage migration were investigated, and a modified TNM (mTNM) staging system including the ELN count was proposed. LASSO regression and random forest analyses were used to screen and evaluate the variables associated with survival, and an mTNM-based nomogram was constructed. The performance of the mTNM staging system and mTNM-based nomogram were compared with that of the 8th edition of the TNM staging system. Results The optimal threshold of the ELN count was identified as 21. An insufficient number of ELNs (≤ 21) was associated with poorer survival outcomes and led to stage migration in all N3 patients. A new mTNM staging system was proposed, integrating the ELN count into the TNM staging system (8th edition). LASSO regression analysis revealed that age, tumor size, adjuvant chemotherapy, adjuvant radiotherapy, and the mTNM system were associated with overall survival (OS) outcomes, and random forest analysis revealed that the mTNM system was the most important variable for predicting survival. An mTNM-based nomogram was constructed to predict 1-, 3-, and 5-year OS rates. Compared with the TNM staging system (8th edition), the mTNM staging system and mTNM-based nomogram showed superior prognosis discriminative ability, better predictive accuracy, and greater net improvement in survival outcomes. Conclusions The optimal ELN count for N3 GC patients was 21. The mTNM staging system and mTNM-based nomogram showed superior discriminative ability, predictive accuracy, and greater net benefit for OS outcomes.
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Affiliation(s)
- Hongyu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Nan Sun
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Feng Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiyang Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhao Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yawei Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunlin Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Kobayashi S, Nakamura Y, Hashimoto T, Bando H, Oki E, Karasaki T, Horinouchi H, Ozaki Y, Iwata H, Kato T, Miyake H, Ohba A, Ikeda M, Chiyoda T, Hasegawa K, Fujisawa T, Matsuura K, Namikawa K, Yajima S, Yoshino T, Hasegawa K. Japan society of clinical oncology position paper on appropriate clinical use of molecular residual disease (MRD) testing. Int J Clin Oncol 2025; 30:605-654. [PMID: 39920551 PMCID: PMC11946966 DOI: 10.1007/s10147-024-02683-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 12/09/2024] [Indexed: 02/09/2025]
Abstract
Although the 5-year relative survival rates for resectable solid tumors have improved over the past few years, the risk of postoperative recurrence necessitates effective monitoring strategies. Recent advancements in molecular residual disease (MRD) testing based on circulating tumor DNA (ctDNA) analysis have shown considerable promise in the context of predicting recurrence; however, significant barriers to widespread clinical implementation remain-mainly, low awareness among healthcare professionals, high costs, and lack of standardized assays and comprehensive evidence. This position paper, led by the Japan Society of Clinical Oncology, aims to establish a common framework for the appropriate clinical use of MRD testing in a tumor type-agnostic manner. It synthesizes currently available evidence, reviews region-specific clinical trends, addresses critical clinical questions related to MRD testing, and offers recommendations to guide healthcare professionals, biotechnology and pharmaceutical companies, and regulatory authorities. These recommendations were developed based on a voting process involving 15 expert members, ensuring a consensus-driven approach. These findings underscore the importance of collaborative efforts among various stakeholders in enhancing the clinical utility of MRD testing. This project aimed to foster consensus and provide clear guidelines to support the advancement of precision medicine in oncology and improve patient outcomes in the context of perioperative care.
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Affiliation(s)
- Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.
- Perioperative Treatment Development Promotion Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.
| | - Yoshiaki Nakamura
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.
- Translational Research Support Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.
- International Research Promotion Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.
| | - Tadayoshi Hashimoto
- Perioperative Treatment Development Promotion Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
- Translational Research Support Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
| | - Hideaki Bando
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
- Translational Research Support Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiro Karasaki
- Department of Thoracic Surgery, Respiratory Center, Toranomon Hospital, Tokyo, Japan
| | - Hidehito Horinouchi
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yukinori Ozaki
- Department of Breast Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroji Iwata
- Department of Advanced Clinical Research and Development, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hideaki Miyake
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Akihiro Ohba
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tatsuyuki Chiyoda
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Takao Fujisawa
- Translational Research Support Office, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kazuto Matsuura
- Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kenjiro Namikawa
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Shugo Yajima
- Department of Urology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
- Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Kiyoshi Hasegawa
- Department of Surgery, Graduate School of Medicine, Hepato-Biliary-Pancreatic Surgery Division, The University of Tokyo, Tokyo, Japan
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Guo X, Wang W, Cheng X, Song Q, Wang X, Wei J, Xu S, Lv X, Ji G. Diagnostic efficacy of an extracellular vesicle-derived lncRNA-based liquid biopsy signature for the early detection of early-onset gastric cancer. Gut 2025:gutjnl-2024-333657. [PMID: 40113244 DOI: 10.1136/gutjnl-2024-333657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Early-onset gastric cancer (EOGC) is a lethal malignancy. It differs from late-onset gastric cancer (LOGC) in clinical and molecular characteristics. The current strategies for EOGC detection have certain limitations in diagnostic performance due to the rising trend in EOGC. OBJECTIVE We developed a liquid biopsy signature for EOGC detection. DESIGN We use a systematic discovery approach by analysing genome-wide transcriptomic profiling data from EOGC (n=43), LOGC (n=31) and age-matched non-disease controls (n=37) tissue samples. An extracellular vesicle-derived long non-coding RNA (EV-lncRNA) signature was identified in blood samples from a training cohort (n=299), and subsequently confirmed by qPCR in two external validation cohorts (n=462 and n=438), a preoperative/postoperative cohort (n=66) and a gastrointestinal tumour cohort (n=225). RESULTS A three EV-lncRNA (NALT1, PTENP1 and HOTTIP) liquid biopsy signature was developed for EOGC detection with an area under the receiver operating characteristic curve (AUROC) of 0.924 (95% CI 0.889 to 0.953). This EV-lncRNA signature provided robust diagnostic performance in two external validation cohorts (Xi'an cohort: AUROC, 0.911; Beijing cohort: AUROC, 0.9323). Furthermore, the EV-lncRNA signature reliably identified resectable stage EOGC patients (stage I/II) and demonstrated better diagnostic performance than traditional GC-related biomarkers in distinguishing early-stage EOGC (stage I) from precancerous lesions. The low levels of this biomarker in postsurgery and other gastrointestinal tumour plasma samples indicated its GC specificity. CONCLUSIONS The newly developed EV-lncRNA signature effectively identified EOGC patients at a resectable stage with enhanced precision, thereby improving the prognosis of patients who would have otherwise missed the curative treatment window.
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Affiliation(s)
- Xin Guo
- Department of General Surgery, Xijing 986th Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weidong Wang
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xin Cheng
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiying Song
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xinxin Wang
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiangpeng Wei
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shenhui Xu
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaohui Lv
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Gang Ji
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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Gasparello J, Ceccon C, Angerilli V, Comunello T, Sabbadin M, D'Almeida Costa F, Antico A, Luchini C, Parente P, Bergamo F, Lonardi S, Fassan M. Liquid biopsy in gastric cancer: A snapshot of the current state of the art. THE JOURNAL OF LIQUID BIOPSY 2025; 7:100288. [PMID: 40027230 PMCID: PMC11863821 DOI: 10.1016/j.jlb.2025.100288] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 03/05/2025]
Abstract
Circulating tumor DNA (ctDNA) is nowadays considered a robust source to search for druggable tumoral genetic alterations, and in some specific settings liquid biopsy (LB) is already part of the diagnostics scenario and it has successfully implemented in the everyday practice. Three strengths make LB an extraordinary tool: i) to represent the complex molecular mosaicism that characterizes spatially heterogeneous malignancies; ii) to monitor in real-time the tumoral molecular landscape (i.e. to depict the longitudinal/temporal tumor evolution); iii) to ensure molecular profiling even in those cases in which tissue sampling is not feasible or not adequate. This review provides a snapshot of the current state of the art concerning ctDNA assay utility in gastric cancer (GC), testing its robustness as marker and seeking to understand the reasons for the delay in its application in clinical practice.
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Affiliation(s)
| | - Carlotta Ceccon
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Valentina Angerilli
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Pathology, Nijmegen, the Netherlands
| | - Tatiane Comunello
- Department of Pathology, A.C. Camargo Cancer Center, Sao Paulo, Brazil
| | - Marianna Sabbadin
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Antonio Antico
- Department of Clinical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | | | - Sara Lonardi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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8
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Liu Z, Shi Z, Jiang W, Shen Z, Chen W, Shen K, Sun Y, Tang Z, Wang X. Circulating tumor DNA analysis for prediction of prognosis and molecular insights in patients with resectable gastric cancer: results from a prospective study. MedComm (Beijing) 2025; 6:e70065. [PMID: 39830022 PMCID: PMC11742430 DOI: 10.1002/mco2.70065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 12/03/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
This study aimed to evaluate the prognostic value of plasma circulating tumor DNA (ctDNA) level in patients with resectable gastric cancer (GC). A total of 59 patients were prospectively enrolled, with their ctDNA detected and paired tumor tissue collected at various peri-operative time points. Patients with higher 1-month post-operative ctDNA levels demonstrated shorter overall survival status (hazard ratio [HR] = 5.30, p = 0.0022) and a higher risk of recurrence (HR = 3.85, p = 0.011). The model combining ctDNA with conventional serum tumor markers for GC, including carcinoembryonic antigen, carbohydrate antigen 19-9, and CA72-4, shows high predictive effectiveness for GC prognosis with an area under the curve of 0.940 (p = 0.002), which is higher than net ctDNA and other models without ctDNA. Patients with lower ctDNA levels were more likely to have positive stromal programmed cell death ligand 1 expression (p = 0.046). Additionally, DCAF4L2 mutation was identified as the crucial gene mutation in ctDNA suggesting poor prognosis of patients with GC. Overall, this study highlights that post-operative ctDNA can serve as an effective biomarker for prognostic prediction and recurrence surveillance in resectable GC.
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Affiliation(s)
- Zheng Liu
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
- Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Zhongyi Shi
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
| | - Wenchao Jiang
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
| | - Zhenbin Shen
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
| | - Weidong Chen
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
| | - Kuntang Shen
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
| | - Yihong Sun
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
- Department of General SurgeryZhongshan Hospital (Xiamen Branch)Fudan UniversityShanghaiChina
| | - Zhaoqing Tang
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
- Department of General SurgeryZhongshan Hospital (Xiamen Branch)Fudan UniversityShanghaiChina
| | - Xuefei Wang
- Department of Gastrointestinal SurgeryZhongshan HospitalFudan UniversityShanghaiChina
- Gastric Cancer CenterZhongshan HospitalFudan UniversityShanghaiChina
- Department of General SurgeryZhongshan Hospital (Xiamen Branch)Fudan UniversityShanghaiChina
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9
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Nakayama I, Nakamura Y, Shitara K. The immunotherapy challenge in locally advanced gastroesophageal cancer: VESTIGE trial's insights and future pathways. Ann Oncol 2025; 36:130-133. [PMID: 39627086 DOI: 10.1016/j.annonc.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 11/04/2024] [Indexed: 01/31/2025] Open
Affiliation(s)
- I Nakayama
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan
| | - Y Nakamura
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan
| | - K Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan.
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10
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Li J, Wu C, Song Y, Fan Y, Li C, Li H, Zhang S. Exploring the Clinical Value of Perioperative ctDNA-Based Detection of Molecular Residual Disease in Patients With Esophageal Squamous Cell Carcinoma. Thorac Cancer 2025; 16:e70017. [PMID: 39966084 PMCID: PMC11835505 DOI: 10.1111/1759-7714.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/03/2025] [Accepted: 02/08/2025] [Indexed: 02/20/2025] Open
Abstract
OBJECTIVE To explore the clinical value of molecular residual disease detection based on circulating tumor DNA (ctDNA-MRD) in the perioperative period of esophageal squamous cell carcinoma (ESCC) and to analyze the tumor escape mechanisms in MRD-positive cases. METHODS A total of 35 ESCC patients were prospectively enrolled. Preoperative and postoperative (1 month after surgery) blood and surgical tissue samples were analyzed. ctDNA variants were tracked in plasma to assess ctDNA-MRD, and whole-transcriptome sequencing was performed on MRD-positive and MRD-negative tissue samples. RESULTS Preoperative blood ctDNA was positive in 54.3% of patients, with a 31.6% positive predictive value for recurrence. One month postsurgery, the positive rate of ctDNA was 17.1%, with an 83.3% predictive value for recurrence. Both preoperative and postoperative ctDNA positivity were significant prognostic indicators (HR = 2.78, p < 0.05; HR = 4.42, p < 0.001). Multivariate analysis confirmed ctDNA as an independent prognostic factor (HR = 303.75, p < 0.001). Transcriptomic analysis revealed increased macrophage (W = 15 848; p < 0.01) and follicular helper T (Tfh) cell (W = 10 935; p < 0.01) levels in MRD-positive patients, suggesting a potential link to immune escape in tumors. CONCLUSIONS Plasma ctDNA measured 1 month postoperatively in ESCC patients can effectively detect MRD, and ctDNA-MRD serves as an independent risk factor for postoperative recurrence. The mechanism underlying MRD positivity may involve the polarization of Tfh cells and macrophages, aiding tumor cells in immune escape through the bloodstream.
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Affiliation(s)
- Jimin Li
- Department of Thoracic SurgeryCancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical SciencesTaiyuanChina
| | - Congcong Wu
- Department of Thoracic SurgeryCancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical SciencesTaiyuanChina
| | - Yongming Song
- Department of Thoracic SurgeryShanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanChina
| | - Yuhui Fan
- Department of Thoracic SurgeryShanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanChina
| | - Chao Li
- Department of Thoracic SurgeryShanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanChina
| | - Haibo Li
- Department of Thoracic SurgeryJincheng Second People's HospitalJinchengChina
| | - Shuangping Zhang
- Department of Thoracic SurgeryCancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical SciencesTaiyuanChina
- Department of Thoracic SurgeryYuncheng Central HospitalYunchengChina
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11
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Cheng L, Xu S, Wang Y, Li S, Li B, Li X. Circulating Tumor DNA Detection for Recurrence Monitoring of Stage I Non-Small Cell Lung Cancer Treated With Microwave Ablation. Thorac Cancer 2025; 16:e15534. [PMID: 39825733 PMCID: PMC11742128 DOI: 10.1111/1759-7714.15534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/29/2024] [Accepted: 01/05/2025] [Indexed: 01/20/2025] Open
Abstract
PURPOSE As microwave ablation continues to be used in patients with inoperable stage I non-small cell lung cancer (NSCLC), it is particularly important to monitor efficacy. Whether plasma ctDNA detection can predict its efficacy should be illustrated. METHODS We recruited 43 patients with inoperative stage I NSCLC, all of whom underwent biopsy-synchronous microwave ablation (MWA). Peripheral blood samples were collected at baseline (n = 43), within 1 h post-MWA (n = 28), and at the landmark time point (n = 26) for MRD detection. Clinical outcomes were analyzed using Kaplan-Meier survival analysis. RESULTS Patients with undetectable ctDNA at baseline (p = 0.042) and within 1 h after MWA (p = 0.023) had better clinical outcomes. In particular, patients with undetectable ctDNA at the 1-h post-MWA time point did not experience recurrence. Detection of ctDNA at the landmark time point is considered an independent risk factor for prognosis and is strongly correlated with clinical outcomes (p = 0.001), the median time to recurrence indicated by ctDNA was 4.9 months earlier compared to imaging. The clinical outcomes of patients with ctDNA clearance were similar to those with no ctDNA (p = 0.570). Risk stratification indicated that patients with persistent ctDNA had worse clinical outcomes compared to those who never had detectable ctDNA (p = 0.004). CONCLUSION Our findings suggest that ctDNA monitoring can assist in predicting clinical outcomes in stage I NSCLC treated with microwave ablation. Patients with undetectable ctDNA within 1 h after MWA are determined to be clinically cured. Risk stratification based on ctDNA test results helps to differentiate high-risk patients.
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Affiliation(s)
- Lin Cheng
- Department of Minimally Invasive Tumor Therapies CenterBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingChina
- Medical SchoolUniversity of Chinese Academy of SciencesBeijingChina
| | - Sheng Xu
- Department of Minimally Invasive Tumor Therapies CenterBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingChina
| | - Yu‐feng Wang
- Department of Minimally Invasive Tumor Therapies CenterBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingChina
| | - Sheng‐wei Li
- Department of Minimally Invasive Tumor Therapies CenterBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingChina
| | - Bin Li
- Department of Minimally Invasive Tumor Therapies CenterBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingChina
| | - Xiao‐Guang Li
- Department of Minimally Invasive Tumor Therapies CenterBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingChina
- Medical SchoolUniversity of Chinese Academy of SciencesBeijingChina
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12
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Iden CR, Mustafa SM, Øgaard N, Henriksen T, Jensen SØ, Ahlborn LB, Egebjerg K, Baeksgaard L, Garbyal RS, Nedergaard MK, Achiam MP, Andersen CL, Mau-Sørensen M. Circulating tumor DNA predicts recurrence and survival in patients with resectable gastric and gastroesophageal junction cancer. Gastric Cancer 2025; 28:83-95. [PMID: 39369091 PMCID: PMC11706848 DOI: 10.1007/s10120-024-01556-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 09/23/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Gastric and gastroesophageal junction (GEJ) cancer represents a significant global health challenge, with high recurrence rates and poor survival outcomes. This study investigates circulating tumor DNA (ctDNA) as a biomarker for assessing recurrence risk in patients with resectable gastric and GEJ adenocarcinomas (AC). METHODS Patients with resectable gastric and GEJ AC, undergoing perioperative chemotherapy and surgery, were prospectively enrolled. Serial plasma samples were collected at baseline, after one cycle of chemotherapy, after preoperative chemotherapy, and after surgery. ctDNA was assessed by a ddPCR test (TriMeth), which targets the gastrointestinal cancer-specific methylation patterns of the genes C9orf50, KCNQ5, and CLIP4. RESULTS ctDNA analysis was performed on 229 plasma samples from 86 patients. At baseline, ctDNA was detected in 56% of patients, which decreased to 37% following one cycle of chemotherapy, 25% after preoperative chemotherapy and 15% after surgical resection. The presence of ctDNA after one cycle of chemotherapy was associated with reduced recurrence-free survival (RFS) (HR = 2.54, 95% confidence interval (CI) 1.33-4.85, p = 0.005) and overall survival (OS) (HR = 2.23, 95% CI 1.07-4.62, p = 0.032). Similarly, ctDNA after surgery was associated with significantly shorter RFS (HR = 6.22, 95% CI 2.39-16.2, p < 0.001) and OS (HR = 6.37, 95% CI 2.10-19.3, p = 0.001). Multivariable regression analysis confirmed ctDNA after surgery as an independent prognostic factor (p < 0.001). CONCLUSION ctDNA analysis has the potential to identify patients at elevated risk of recurrence, thus providing personalized treatment strategies for patients with resectable gastric and GEJ cancer. Further validation in larger cohorts and ctDNA-guided interventions are needed for future clinical use.
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Affiliation(s)
- Cecilie Riis Iden
- Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Salah Mohammad Mustafa
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
- Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
| | - Nadia Øgaard
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
- Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
| | - Tenna Henriksen
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
- Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
| | - Sarah Østrup Jensen
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
- Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
| | - Lise Barlebo Ahlborn
- Department of Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Kristian Egebjerg
- Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Lene Baeksgaard
- Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Rajendra Singh Garbyal
- Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Mette Kjølhede Nedergaard
- Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Michael Patrick Achiam
- Department of Surgery & Transplantation, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Claus Lindbjerg Andersen
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
- Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
| | - Morten Mau-Sørensen
- Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
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Nixon AB, Navarro FCP, Zhou KI, Abbott C, McDaniel L, Howard L, Brady JC, Liu Y, Jia J, Niedzwiecki D, Strickler J, Boyle SM, Chen RO, Uronis H. Ultra-sensitive, tumor-informed ctDNA profiling in pembrolizumab-treated esophagogastric cancer patients predicts clinical responses. RESEARCH SQUARE 2024:rs.3.rs-5349536. [PMID: 39764133 PMCID: PMC11702795 DOI: 10.21203/rs.3.rs-5349536/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2025]
Abstract
To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables early prediction of treatment response and early detection of disease progression, we applied NeXT Personal, an ultra-sensitive bespoke tumor-informed liquid biopsy platform, to profile tumor samples from the KeyLargo study, a phase II trial in which metastatic esophagogastric cancer (mEGC) patients received capecitabine, oxaliplatin, and pembrolizumab. All 25 patients evaluated were ctDNA-positive at baseline. Minimal residual disease (MRD) events varied from 406,067 down to 1.5 parts per million (PPM) of ctDNA with a median limit of detection of 2.03 PPM. ctDNA dynamics were highly correlated with changes in tumor size (ρ = 0.59, p = 7.3×10-9). Lack of early molecular response (lack of ctDNA decrease) was associated with worse overall survival (OS) (HR 6.6, 95% CI 1.8-24.1, p = 0.005) and progression-free survival (PFS) (HR 15.4, 95% CI 2.7-87.0, p = 0.002). Lack of molecular clearance of ctDNA was associated with worse OS (HR 6.9, 95% CI 1.5-30.8, p = 0.012) and PFS (HR 19.2, 95% CI 2.4-152.8, p = 0.005). Molecular progression (ctDNA increase) preceded imaging-derived progression by a median lead time of 65 days. These results suggest that ultra-sensitive liquid biopsy approaches could improve treatment decision-making for mEGC patients receiving chemotherapy and immunotherapy.
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14
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Zhang X, Wang H, Li Y, Yan W, Chen Y, Song S, Liu N, Zhang C, Niu Z, Hou H. Neoadjuvant PD-(L)1 blockade with or without chemotherapy versus chemotherapy alone in mismatch repair-deficient, potentially resectable stage III-IV A gastric cancer patients: a single-center retrospective study. World J Surg Oncol 2024; 22:313. [PMID: 39593126 PMCID: PMC11590301 DOI: 10.1186/s12957-024-03601-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/19/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Currently, PD-(L)1 blockade-based neoadjuvant treatment has shown promising outcomes in patients with potentially resectable gastric cancer. In this real-world study, we aimed to retrospectively observe the efficacy including tumor response and event-free survival (EFS), and safety of PD-(L)1 blockade-based neoadjuvant treatment versus chemotherapy alone in potentially resectable gastric cancer patients with microsatellite instability-high (MSI-H) or mismatch-repair deficient (dMMR) status. METHODS We retrospectively collected the clinical data of patients with potentially resectable gastric cancer and MSI-H/dMMR status who received neoadjuvant treatment followed by D2 gastrectomy at the Affiliated Hospital of Qingdao University from January 2019 to June 2023. The outcomes of interest mainly included overall complete response (CR) rates, radiographical and pathological tumor response, treatment-related adverse events (TRAEs), and EFS. RESULTS In total, 30 patients were included in the analysis; 23 patients received neoadjuvant PD-(L)1 blockade plus chemotherapy or PD-(L)1 blockade monotherapy, and seven patients received neoadjuvant chemotherapy. In the PD-(L)1 blockade-based treatment group, 7 of 23 patients (30.4%, 95% CI 0.141-0.530) achieved pathological CR (pCR), while three patients with radiographical CR did not undergo surgery. In contrast, 1 of 7 (14.3%) patients in the neoadjuvant chemotherapy group achieved pCR. The overall CR rate was 43.5% (10 of 23, 95% CI 0.239-0.651) in the PD-(L)1 blockade-based treatment group and 14.3% (1 of 7, 95% CI 0.026-0.513) in the chemotherapy group. The neoadjuvant PD-(L)1 blockade-based treatment regimen was mild and well tolerated. By the latest follow-up, median EFS time was not reached in both cohorts. CONCLUSION In potentially resectable gastric cancer patients with MSI-H/dMMR status, PD-(L)1 blockade-based neoadjuvant treatment regimen provided promising clinical benefits and was well tolerated.
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Affiliation(s)
- Xuchen Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong, 266035, China
| | - Huiyun Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, Shandong, 266031, China
| | - Yi Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao, 266003, China
| | - Weihua Yan
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao University, No.16 Jiangsu Road, Qingdao, 266003, China
| | - Yunqing Chen
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao University, No.16 Jiangsu Road, Qingdao, 266003, China
| | - Shanai Song
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, Shandong, 266031, China
| | - Ning Liu
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, Shandong, 266031, China
| | - Chuantao Zhang
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, Shandong, 266031, China
| | - Zhaojian Niu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao, 266003, China.
| | - Helei Hou
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, Shandong, 266031, China.
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15
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Park SH, Lee HJ, Kim TI, Lee J, Han SY, Seo HI, Kim DU. Ultrashort Cell-Free DNA Fragments and Vimentin-Positive Circulating Tumor Cells for Predicting Early Recurrence in Patients with Biliary Tract Cancer. Diagnostics (Basel) 2024; 14:2462. [PMID: 39518429 PMCID: PMC11544859 DOI: 10.3390/diagnostics14212462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/24/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
Background/Objectives: Biliary tract cancer (BTC) is a rare but aggressive malignancy that requires surgical treatment. However, postoperative recurrence rates are high, and reliable predictors of recurrence are limited. This study aimed to investigate the effectiveness of cell-free DNA (cfDNA) and circulating tumor cells (CTCs) in predicting early recurrence after curative surgery and complete adjuvant therapy in patients with BTC. Methods: Twenty-four patients who underwent R0 and R1 resections and completed adjuvant therapy for BTC between September 2019 and March 2022 were followed up until March 2024. Patients were categorized into early recurrence (ER) and non-ER groups, using one year as the cutoff for recurrence. Results: The combination score derived from ultrashort fragments of cfDNA, vimentin-positive CTCs, and carbohydrate antigen (CA) 19-9 levels showed a statistically significant difference between the ER and non-ER groups (p-value < 0.001). The receiver operating characteristic curve from the combination score and CA 19-9 levels yielded areas under the curve of 0.891 and 0.750, respectively. Conclusions: Although further research is required, these findings suggest that cfDNA and CTCs may increase the accuracy of predicting postoperative recurrence in patients with BTC.
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Affiliation(s)
- Sung Hee Park
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (S.H.P.); (H.J.L.); (J.L.)
| | - Hye Ji Lee
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (S.H.P.); (H.J.L.); (J.L.)
| | - Tae In Kim
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (S.H.P.); (H.J.L.); (J.L.)
| | - Jonghyun Lee
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (S.H.P.); (H.J.L.); (J.L.)
| | - Sung Yong Han
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (S.H.P.); (H.J.L.); (J.L.)
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan 44955, Republic of Korea
| | - Hyung Il Seo
- Department of Surgery, Pusan National University College of Medicine, Yangsan 44955, Republic of Korea;
| | - Dong Uk Kim
- Department of Internal Medicine, Gumi Medical Center, CHA University, Gumi 39100, Republic of Korea;
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16
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Battaglin F, Lenz HJ. Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers. JCO Oncol Pract 2024; 20:1481-1490. [PMID: 39531845 PMCID: PMC11567053 DOI: 10.1200/op.24.00167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/11/2024] [Accepted: 05/01/2024] [Indexed: 11/16/2024] Open
Abstract
Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms. Here, we review the clinical applications, advantages, and limitations of ctDNA profiling for precision oncology in GI cancers.
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Affiliation(s)
- Francesca Battaglin
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
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17
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Martin TK, Dinerman A, Sudhaman S, Budde G, Palsuledesai CC, Krainock M, Liu MC, Smith E, Tapias L, Podgaetz E, Schwartz G. Early real-world experience monitoring circulating tumor DNA in resected early-stage non-small cell lung cancer. J Thorac Cardiovasc Surg 2024; 168:1349-1359.e2. [PMID: 38244856 DOI: 10.1016/j.jtcvs.2024.01.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 12/20/2023] [Accepted: 01/07/2024] [Indexed: 01/22/2024]
Abstract
OBJECTIVE The study objective was to evaluate the impact of monitoring circulating tumor DNA on the detection and management of recurrence in patients with resected early-stage non-small cell lung cancer. METHODS Between October 2021 and March 2023, postoperative circulating tumor DNA was monitored in patients with non-small cell lung cancer (N = 108). Longitudinal blood samples (n = 378 samples) were collected for prospective circulating tumor DNA analysis at 3-month intervals after curative-intent resection. A tumor-informed assay was used for the detection and quantification of circulating tumor DNA. The primary outcome measure was a circulating tumor DNA-positive result. The secondary outcome measure was changes in practice after a circulating tumor DNA-positive result. RESULTS The mean age of the patients in this cohort was 68.1 years. Of the 108 patients, 12 (11.1%) were circulating tumor DNA positive at least at 1 timepoint postsurgery, of whom 8 (66.7%) had a clinically evident recurrence and the remaining 4 had limited clinical follow-up. Of the 10 patients with recurrent disease, 8 demonstrated circulating tumor DNA positivity and the remaining 2 patients had brain-only metastases. Postoperative clinical care was altered in 100% (12/12) of circulating tumor DNA-positive patients, with 58.3% (7/12) receiving an early computed tomography scan and 100% (12/12) receiving an early positron emission tomography computed tomography scan as part of their surveillance strategy. Among the patients who received an early positron emission tomography scan, 66.6% (8/12) were positive for malignant features. CONCLUSIONS Routine monitoring of tumor-informed circulating tumor DNA after curative intent therapy improved patient risk stratification and prognostication.
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Affiliation(s)
- Travis K Martin
- Dignity Health East Valley General Surgery Residency, Chandler Regional Medical Center, Chandler, Ariz; Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Ft Worth, Tex.
| | - Aaron Dinerman
- Department of General Surgery, Baylor University Medical Center, Dallas, Tex
| | | | | | | | | | | | - Emy Smith
- Department of Thoracic Surgery, Baylor University Medical Center, Dallas, Tex
| | - Leonidas Tapias
- Department of Thoracic Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Eitan Podgaetz
- Department of Thoracic Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Gary Schwartz
- Department of Thoracic Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio
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18
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Perez-Wert P, Fernandez-Hernandez S, Gamez-Pozo A, Arranz-Alvarez M, Ghanem I, López-Vacas R, Díaz-Almirón M, Méndez C, Fresno Vara JÁ, Feliu J, Trilla-Fuertes L, Custodio A. Layer Analysis Based on RNA-Seq Reveals Molecular Complexity of Gastric Cancer. Int J Mol Sci 2024; 25:11371. [PMID: 39518924 PMCID: PMC11545517 DOI: 10.3390/ijms252111371] [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: 09/11/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Gastric adenocarcinoma (GA) is a significant global health issue with poor prognosis, despite advancements in treatment. Although molecular classifications, such as The Cancer Genome Atlas (TCGA), provide valuable insights, their clinical utility remains limited. We performed a multi-layered functional analysis using TCGA RNA sequencing data to better define molecular subtypes and explore therapeutic implications. We reanalyzed TCGA RNA-seq data from 142 GA patients with localized disease who received adjuvant chemotherapy. Our approach included probabilistic graphical models and recurrent sparse k-means/consensus cluster algorithms for layer-based analysis. Our findings revealed survival differences among TCGA groups, with the GS subtype showing the poorest prognosis. We identified twelve functional nodes and seven biological layers, each with distinct functions. The combined molecular layer (CML) classification identified three prognostic groups that align with TCGA subtypes. CML2 (GS-like) displayed gene expression related to lipid metabolism, correlating with worse survival. Transcriptomic heterogeneity within the CIN subtype revealed clusters tied to proteolysis and lipid metabolism. We identified a subset of CIN tumors with profiles similar to MSI, termed CIN-MSI-like. Claudin-18, a key gene in proteolysis, was overexpressed across TCGA subtypes, suggesting it is a potential therapeutic target. Our study advances GA biology, enabling refined stratification and personalized treatment. Further studies are needed to translate these findings into clinical practice.
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Affiliation(s)
- Pablo Perez-Wert
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
| | - Sara Fernandez-Hernandez
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Angelo Gamez-Pozo
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Marina Arranz-Alvarez
- IdiPAZ Biobank, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain;
| | - Ismael Ghanem
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
| | - Rocío López-Vacas
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Mariana Díaz-Almirón
- Biostatistics Unit, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain;
| | - Carmen Méndez
- Department of Pathology, Hospital Universitario La Paz, 28046 Madrid, Spain;
| | - Juan Ángel Fresno Vara
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - Jaime Feliu
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Universidad Autónoma de Madrid, 28046 Madrid, Spain
- Medicine Department, Universidad Autónoma de Madrid, 28046 Madrid, Spain
| | - Lucia Trilla-Fuertes
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Ana Custodio
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
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Vasiliadou I, Cattaneo C, Chan PYK, Henley-Smith R, Gregson-Williams H, Collins L, Wojewodka G, Guerrero-Urbano T, Jeannon JP, Connor S, Davis J, Pasto A, Mustapha R, Ng T, Kong A. Correlation of the treatment sensitivity of patient-derived organoids with treatment outcomes in patients with head and neck cancer (SOTO): protocol for a prospective observational study. BMJ Open 2024; 14:e084176. [PMID: 39389599 PMCID: PMC11474813 DOI: 10.1136/bmjopen-2024-084176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 08/19/2024] [Indexed: 10/12/2024] Open
Abstract
INTRODUCTION Organoids have been successfully used in several areas of cancer research and large living biobanks of patient-derived organoids (PDOs) have been developed from various malignancies. The characteristics of the original tumour tissue such as mutation signatures, phenotype and genetic diversity are well preserved in organoids, thus showing promising results for the use of this model in translational research. In this study, we aim to assess whether we can generate PDOs from head and neck squamous cell carcinoma (HNSCC) samples and whether PDOs can be used to predict treatment sensitivity in HNSCC patients as well as to explore potential biomarkers. METHODS AND ANALYSIS This is a prospective observational study at a single centre (Guy's and St Thomas' NHS Foundation Trust) to generate PDOs from patients' samples to assess treatment response and to correlate with patients' treatment outcomes. Patients will be included if they are diagnosed with HNSCC undergoing curative treatment (primary surgery or radiotherapy) or presenting with recurrent or metastatic cancers and they will be categorised into three groups (cohort 1: primary surgery, cohort 2: primary radiotherapy and cohort 3: recurrent/metastatic disease). Research tumour samples will be collected and processed into PDOs and chemosensitivity/radiosensitivity will be assessed using established methods. Moreover, blood and other biological samples (eg, saliva) will be collected at different time intervals during treatment and will be processed in the laboratory for plasma and peripheral blood mononuclear cell (PBMC) isolation. Plasma and saliva will be used for circulating tumour DNA analysis and PBMC will be stored for assessment of the peripheral immune characteristics of the patients as well as to perform co-culture experiments with PDOs. SOTO study (correlation of the treatment Sensitivity of patient-derived Organoids with Treatment Outcomes in patients with head and neck cancer) uses the collaboration of several specialties in head and neck cancer and has the potential to explore multiple areas of research with the aim of offering a valid and effective approach to personalised medicine for cancer patients. ETHICS AND DISSEMINATION This study was approved by North West-Greater Manchester South Research Ethics Committee (REC Ref: 22/NW/0023) on 21 March 2022. An informed consent will be obtained from all participants prior to inclusion in the study. Results will be disseminated via peer-reviewed publications and presentations at international conferences. TRIAL REGISTRATION NUMBER NCT05400239.
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Affiliation(s)
| | | | | | - Rhonda Henley-Smith
- Head and Neck Pathology, Guy's and St Thomas' Hospitals NHS Trust, London, UK
| | | | - Lisette Collins
- Head and Neck Pathology, Guy's and St Thomas' Hospitals NHS Trust, London, UK
| | | | | | | | - Steve Connor
- Head and Neck Radiology, Guy's and St Thomas' Hospitals NHS Trust, London, UK
| | - Jessica Davis
- Comprehensive Cancer Centre, King's College London, London, UK
| | - Anna Pasto
- Comprehensive Cancer Centre, King's College London, London, UK
| | - Rami Mustapha
- Comprehensive Cancer Centre, King's College London, London, UK
| | - Tony Ng
- Comprehensive Cancer Centre, King's College London, London, UK
| | - Anthony Kong
- Comprehensive Cancer Centre, King's College London, London, UK
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20
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Alsaab HO, Alzahrani MS, Bahauddin AA, Almutairy B. Circulating tumor DNA (ctDNA) application in investigation of cancer: Bench to bedside. Arch Biochem Biophys 2024; 758:110066. [PMID: 38906310 DOI: 10.1016/j.abb.2024.110066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/02/2024] [Accepted: 06/18/2024] [Indexed: 06/23/2024]
Abstract
Now, genomics forms the core of the precision medicine concept. Comprehensive investigations of tumor genomes have made it possible to characterize tumors at the molecular level and, specifically, to identify the fundamental processes that cause condition. A variety of kinds of tumors have seen better outcomes for patients as a result of the development of novel medicines to tackle these genetic-driving processes. Since therapy may exert selective pressure on cancers, non-invasive methods such as liquid biopsies can provide the opportunity for rich reservoirs of crucial and real-time genetic data. Liquid biopsies depend on the identification of circulating cells from tumors, circulating tumor DNA (ctDNA), RNA, proteins, lipids, and metabolites found in patient biofluids, as well as cell-free DNA (cfDNA), which exists in those with cancer. Although it is theoretically possible to examine biological fluids other than plasma, such as pleural fluid, urine, saliva, stool, cerebrospinal fluid, and ascites, we will limit our discussion to blood and solely cfDNA here for the sake of conciseness. Yet, the pace of wider clinical acceptance has been gradual, partly due to the increased difficulty of choosing the best analysis for the given clinical issue, interpreting the findings, and delaying proof of value from clinical trials. Our goal in this review is to discuss the current clinical value of ctDNA in cancers and how clinical oncology systems might incorporate procedures for ctDNA testing.
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Affiliation(s)
- Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, 21944, Saudi Arabia.
| | - Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia.
| | - Ammar A Bahauddin
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina Al-Munawarah, Saudi Arabia.
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
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21
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Jiang C, Zhang Y, Deng P, Lin H, Fu F, Deng C, Chen H. The Overlooked Cornerstone in Precise Medicine: Personalized Postoperative Surveillance Plan for NSCLC. JTO Clin Res Rep 2024; 5:100701. [PMID: 39188582 PMCID: PMC11345377 DOI: 10.1016/j.jtocrr.2024.100701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/15/2024] [Accepted: 06/25/2024] [Indexed: 08/28/2024] Open
Abstract
Non-small cell lung cancer recurrence after curative-intent surgery remains a challenge despite advancements in treatment. We review postoperative surveillance strategies and their impact on overall survival, highlighting recommendations from clinical guidelines and controversies. Studies suggest no clear benefit from more intensive imaging, whereas computed tomography scans reveal promise in detecting recurrence. For early-stage disease, including ground-glass opacities and adenocarcinoma in situ or minimally invasive adenocarcinoma, less frequent surveillance may suffice owing to favorable prognosis. Liquid biopsy, especially circulating tumor deoxyribonucleic acid, holds potential for detecting minimal residual disease. Clinicopathologic factors and genomic profiles can also provide information about site-specific metastases. Machine learning may enable personalized surveillance plans on the basis of multi-omics data. Although precision medicine transforms non-small cell lung cancer treatment, optimizing surveillance strategies remains essential. Tailored surveillance strategies and emerging technologies may enhance early detection and improve patients' survival, necessitating further research for evidence-based protocols.
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Affiliation(s)
- Chenyu Jiang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Yang Zhang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Penghao Deng
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Han Lin
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Fangqiu Fu
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Chaoqiang Deng
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Haiquan Chen
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
- Institute of Thoracic Oncology, Fudan University, Shanghai, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
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22
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Xie Z, Zhao W, He Y, Ke Y, Li Z, Zhang X. Mutational and transcriptional profile predicts the prognosis of stage IV gastric cancer - Prognostic factors for metastatic gastric cancer. Arab J Gastroenterol 2024; 25:275-283. [PMID: 39043541 DOI: 10.1016/j.ajg.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 03/27/2024] [Accepted: 05/05/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND AND STUDY AIMS The clinicopathological risk factors in the prognosis of stage IV gastric cancer have been comprehensively studied. However, the influencing factors of stage IV gastric cancer prognosis at genomic and transcriptional levels have not been well defined. PATIENTS AND METHODS The mutational and transcriptional data, along with demographic, clinicopathological and prognostic information of 44 stage IV gastric cancer patients were downloaded from the TCGA database. Univariate and multivariate analyses were performed to identify the significant risk factors and a Nomogram model was established to predict the patient prognosis. RESULTS TTN, TP53, FLG, LRP1B, SYNE1 and ARID1A were among the top mutated genes without hot-spot mutations. The mutational status of AHNAK2, ASCC3, DNAH3, DOP1A, MYLK, SIPA1L1, SORBS2, SYNE1 and ANF462 significantly stratified the patient prognosis. The transcription of several genes, such as AQP10, HOXC8/9/10, COL10A1/COL11A1, WNT7B, KRT17 and KLK6 was significantly up-regulated or down-regulated. Enrichment analysis on mutations and transcription revealed cell skeleton and membrane function, extracellular matrix function, HPV infection, and several cancer-related pathways as the main aberrancies. Univariate analyses revealed a series of significant factors stratifying patient prognosis, mainly including cancer location, several mutated genes and many up- or down-regulated genes. However, subsequent multivariate analysis revealed SYNE1 mutation, DNAH3 mutation, COMMD3 transcription level, and cancer location as the independent risk factors. A Nomogram model has been established with these significant risk factors to predict the patient prognosis. Further validation is needed to ensure the effectiveness of the model in real clinical practice. CONCLUSIONS Cancer location, along with the mutational status of SYNE1 and DNAH3 and the transcriptional level of COMMD3 were independent risk factors of stage IV gastric cancer. A Nomogram model was established with these factors for prognosis prediction.
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Affiliation(s)
- Zhengyong Xie
- General Surgery Department, General Hospital of Southern Theatre Command, PLA, No.111 Liuhua Road, Yuexiu District, Guangzhou 510010, Guangdong Province, China
| | - Wenzhen Zhao
- Department of 2nd Oncology, Guangdong Second Provincial General Hospital, Guangzhou 510317, Guangdong Province, China
| | - Yongzhong He
- Department of General Surgery, The Affiliated Hexian Memorial Hospital of Southern Medical University Guangzhou, Guangzhou 511400, Guangdong Province, China
| | - Yongli Ke
- General Surgery Department, General Hospital of Southern Theatre Command, PLA, No.111 Liuhua Road, Yuexiu District, Guangzhou 510010, Guangdong Province, China
| | - Zehang Li
- General Surgery Department, General Hospital of Southern Theatre Command, PLA, No.111 Liuhua Road, Yuexiu District, Guangzhou 510010, Guangdong Province, China
| | - Xuhui Zhang
- Department of 2nd Oncology, Guangdong Second Provincial General Hospital, Guangzhou 510317, Guangdong Province, China.
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23
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Hompe ED, Sachdeva UM. Updates in Translational Science for Esophageal and Gastric Cancers. Surg Oncol Clin N Am 2024; 33:571-581. [PMID: 38789199 DOI: 10.1016/j.soc.2023.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
In this article, the authors summarize the current state of translational science for esophageal and gastric cancers. The available targeted therapies, immunotherapies, and recently discovered molecular targets are reviewed. The authors introduce circulating tumor deoxyribonucleic acid and its promise as a biomarker to detect disease recurrence. The authors present patient-derived organoids as a new model for studying carcinogenesis and treatment responses. Finally, we discuss the implications of organoid models for precision oncology and describe exciting new work applying gene editing technology to organoids and studying tumor-microenvironment interactions using 3-dimensional co-culture systems.
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Affiliation(s)
- Eliza D Hompe
- Division of Thoracic Surgery, Massachusetts General Hospital, 55 Fruit Street, Austen 7, Boston, MA 02114, ISA
| | - Uma M Sachdeva
- Division of Thoracic Surgery, Massachusetts General Hospital, 55 Fruit Street, Austen 7, Boston, MA 02114, ISA; Department of Surgery, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
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24
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Shaker F, Razi S, Rezaei N. Circulating miRNA and circulating tumor DNA application as liquid biopsy markers in gastric cancer. Clin Biochem 2024; 129:110767. [PMID: 38705444 DOI: 10.1016/j.clinbiochem.2024.110767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Liquid biopsy has been investigated as a novel method to overcome the numerous challenges in gastric cancer (GC) management. This non-invasive, feasible, and easy-to-repeat method has been shown to be cost-effective and capable of increasing diagnostic sensitivity and prognostic assessment. Additionally, it is potentially accurate to aid decision-making and personalized treatment planning. MicroRNA (miRNA) and circulating tumor DNA (ctDNA) markers can enhance GC management in various aspects, including diagnosis (mainly earlier diagnosis and the ability to perform population-based screening), prognosis (more precise stratification of prognosis), and treatment (including more accurate prediction of treatment response and earlier detection of resistance to the treatment). Concerning the treatment-related application, miRNAs' mimics and antagonists (by using two main strategies of restoring tumor suppressor miRNAs and inhibiting oncogene miRNAs) have been shown to be effective therapeutic agents. However, these need to be further validated in clinical trials. Furthermore, novel delivery systems, such as lipid-based vectors, polymeric-based vectors, and exosome-based delivery, have been developed to enhance the performance of these agents. Moreover, this paper explores the current detection and measuring methods for these markers. These approaches are categorized into direct methods (e.g., Chem-NAT, HTG EdgeSeq, and Multiplex Circulating Fireplex) and indirect methods (e.g., Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), qPCR, microarray, and NGS) for miRNA detection. For ctDNA measurement, main core technologies like NGS, digital PCR, real-time PCR, and mass spectrometry are suggested.
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Affiliation(s)
- Farhad Shaker
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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25
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Bloom MD, Bashir B. Emerging role of circulating tumor DNA for early detection of recurrence in biliary tract cancers. J Gastrointest Oncol 2024; 15:1358-1362. [PMID: 38989432 PMCID: PMC11231843 DOI: 10.21037/jgo-24-224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 04/17/2024] [Indexed: 07/12/2024] Open
Affiliation(s)
- Matthew D. Bloom
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Babar Bashir
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Pharmacology, Physiology & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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26
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Liu Y, Lu XN, Guo HM, Bao C, Zhang J, Jin YN. Development and validation of a circulating tumor DNA-based optimization-prediction model for short-term postoperative recurrence of endometrial cancer. World J Clin Cases 2024; 12:3385-3394. [PMID: 38983398 PMCID: PMC11229938 DOI: 10.12998/wjcc.v12.i18.3385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/23/2024] [Accepted: 05/10/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Endometrial cancer (EC) is a common gynecological malignancy that typically requires prompt surgical intervention; however, the advantage of surgical management is limited by the high postoperative recurrence rates and adverse outcomes. Previous studies have highlighted the prognostic potential of circulating tumor DNA (ctDNA) monitoring for minimal residual disease in patients with EC. AIM To develop and validate an optimized ctDNA-based model for predicting short-term postoperative EC recurrence. METHODS We retrospectively analyzed 294 EC patients treated surgically from 2015-2019 to devise a short-term recurrence prediction model, which was validated on 143 EC patients operated between 2020 and 2021. Prognostic factors were identified using univariate Cox, Lasso, and multivariate Cox regressions. A nomogram was created to predict the 1, 1.5, and 2-year recurrence-free survival (RFS). Model performance was assessed via receiver operating characteristic (ROC), calibration, and decision curve analyses (DCA), leading to a recurrence risk stratification system. RESULTS Based on the regression analysis and the nomogram created, patients with postoperative ctDNA-negativity, postoperative carcinoembryonic antigen 125 (CA125) levels of < 19 U/mL, and grade G1 tumors had improved RFS after surgery. The nomogram's efficacy for recurrence prediction was confirmed through ROC analysis, calibration curves, and DCA methods, highlighting its high accuracy and clinical utility. Furthermore, using the nomogram, the patients were successfully classified into three risk subgroups. CONCLUSION The nomogram accurately predicted RFS after EC surgery at 1, 1.5, and 2 years. This model will help clinicians personalize treatments, stratify risks, and enhance clinical outcomes for patients with EC.
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Affiliation(s)
- Yuan Liu
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Xiao-Ning Lu
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hui-Ming Guo
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Chan Bao
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Juan Zhang
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Yu-Ni Jin
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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27
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Xu Y, Zhang P, Luo Z, Cen G, Zhang S, Zhang Y, Huang C. A predictive nomogram developed and validated for gastric cancer patients with triple-negative tumor markers. Future Oncol 2024; 20:919-934. [PMID: 37920954 DOI: 10.2217/fon-2023-0626] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2023] Open
Abstract
Aim: To predict the prognosis of gastric cancer patients with triple-negative tumor markers. Materials & methods: Prognostic factors of the nomogram were identified through univariate and multivariate Cox regression analyses. Calibration and receiver operating characteristic curves were used to assess accuracy. Decision curve analysis and concordance indexes were utilized to compare the nomogram with the pathological tumor, node, metastasis stage. Results: A nomogram incorporating log odds of positive lymph nodes, tumor size and lymphocyte-to-monocyte ratio was constructed. The calibration and receiver operating characteristic curves (area under the curve >0.85) showed high accuracy in predicting overall survival. The concordance indexes (0.832 vs 0.760; p < 0.001) and decision curve analysis demonstrated that the nomogram was superior to the pathological tumor, node, metastasis stage. Conclusion: A prediction and risk stratification nomogram has been developed and validated for gastric cancer patients with triple-negative tumor markers.
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Affiliation(s)
- Yitian Xu
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Pengshan Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Zai Luo
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Gang Cen
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Shaopeng Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Yuan Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chen Huang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
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Hashimoto T, Nakamura Y, Oki E, Kobayashi S, Yuda J, Shibuki T, Bando H, Yoshino T. Bridging horizons beyond CIRCULATE-Japan: a new paradigm in molecular residual disease detection via whole genome sequencing-based circulating tumor DNA assay. Int J Clin Oncol 2024; 29:495-511. [PMID: 38551727 PMCID: PMC11043144 DOI: 10.1007/s10147-024-02493-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 02/16/2024] [Indexed: 04/26/2024]
Abstract
Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.
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Affiliation(s)
- Tadayoshi Hashimoto
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yoshiaki Nakamura
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Junichiro Yuda
- Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Taro Shibuki
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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Zheng J, Qin C, Wang Q, Tian D, Chen Z. Circulating tumour DNA-Based molecular residual disease detection in resectable cancers: a systematic review and meta-analysis. EBioMedicine 2024; 103:105109. [PMID: 38614009 PMCID: PMC11021841 DOI: 10.1016/j.ebiom.2024.105109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 03/21/2024] [Accepted: 03/24/2024] [Indexed: 04/15/2024] Open
Abstract
BACKGROUND Circulating tumour DNA (ctDNA)-based molecular residual disease (MRD) detection technology has been widely used for recurrence evaluation, but there is no agreement on the efficacy of assessing recurrence and overall survival (OS) prognosis, as well as the sensitivity and specificity of landmark detection and longitudinal detection. METHODS We systematically searched Pubmed, Embase, Cochrane, and Scopus for prospective studies or randomized controlled trials that collected blood samples prospectively. The search period was from Jan 1, 2013, to Sept 10, 2023. We excluded retrospective studies. The primary endpoint was to assess the hazard ratio (HR) between circulating tumour DNA positive (ctDNA+) and negative (ctDNA-) for recurrence-free survival incidence (RFS), disease-free survival (DFS), progression-free survival (PFS), event-free survival (EFS), time to recurrence (TTR), distant metastasis-free survival (DMFS) or OS in patients with resectable cancers. We calculated the pooled HR of recurrence and OS and 95% confidence interval (CI) in patients with resected cancers using a random-effects model. Pooled sensitivity and specificity were estimated using the bivariate random effects model. FINDINGS This systematic review and meta-analysis returned 7578 records, yielding 80 included studies after exclusion. We found that the HR of recurrence across all included cancers between patients with ctDNA+ and ctDNA- was 7.48 (95% CI 6.39-8.77), and the OS was 5.58 (95% CI 4.17-7.48). We also found that the sensitivity, area under the summary receiver operating characteristic curve (AUSROC) and diagnostic odds ratio (DOR) of longitudinal tests were higher than that of landmark tests between patients with ctDNA+ and ctDNA- (0.74, 95% CI 0.68-0.80 vs 0.50, 95% CI 0.46-0.55; 0.88 vs. 0.80; 25.70, 95% CI 13.20-45.40 vs. 9.90, 95% CI 7.77-12.40). INTERPRETATION Postoperative ctDNA testing was a significant prognosis factor for recurrence and OS in patients with resectable cancers. However, the overall sensitivity of ctDNA-MRD detection could be better. Longitudinal monitoring can improve the sensitivity, AUSROC, and DOR. FUNDING Special fund project for clinical research of Qingyuan People's Hospital (QYRYCRC2023006), plan on enhancing scientific research in GMU (GZMU-SH-301).
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Affiliation(s)
- Jiachun Zheng
- Department of Respiratory and Critical Care Medicine, Affiliated Qingyuan Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Chuling Qin
- Guangzhou Medical University, Guangzhou, 511436, China
| | - Qianxi Wang
- Guangzhou Medical University, Guangzhou, 511436, China
| | - Dongbo Tian
- Department of Respiratory and Critical Care Medicine, Affiliated Qingyuan Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.
| | - Zisheng Chen
- Department of Respiratory and Critical Care Medicine, Affiliated Qingyuan Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.
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Frydendahl A, Rasmussen MH, Jensen SØ, Henriksen TV, Demuth C, Diekema M, Ditzel HJ, Wen SWC, Pedersen JS, Dyrskjøt L, Andersen CL. Error-Corrected Deep Targeted Sequencing of Circulating Cell-Free DNA from Colorectal Cancer Patients for Sensitive Detection of Circulating Tumor DNA. Int J Mol Sci 2024; 25:4252. [PMID: 38673836 PMCID: PMC11049993 DOI: 10.3390/ijms25084252] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Circulating tumor DNA (ctDNA) is a promising biomarker, reflecting the presence of tumor cells. Sequencing-based detection of ctDNA at low tumor fractions is challenging due to the crude error rate of sequencing. To mitigate this challenge, we developed ultra-deep mutation-integrated sequencing (UMIseq), a fixed-panel deep targeted sequencing approach, which is universally applicable to all colorectal cancer (CRC) patients. UMIseq features UMI-mediated error correction, the exclusion of mutations related to clonal hematopoiesis, a panel of normal samples for error modeling, and signal integration from single-nucleotide variations, insertions, deletions, and phased mutations. UMIseq was trained and independently validated on pre-operative (pre-OP) plasma from CRC patients (n = 364) and healthy individuals (n = 61). UMIseq displayed an area under the curve surpassing 0.95 for allele frequencies (AFs) down to 0.05%. In the training cohort, the pre-OP detection rate reached 80% at 95% specificity, while it was 70% in the validation cohort. UMIseq enabled the detection of AFs down to 0.004%. To assess the potential for detection of residual disease, 26 post-operative plasma samples from stage III CRC patients were analyzed. From this we found that the detection of ctDNA was associated with recurrence. In conclusion, UMIseq demonstrated robust performance with high sensitivity and specificity, enabling the detection of ctDNA at low allele frequencies.
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Affiliation(s)
- Amanda Frydendahl
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Mads Heilskov Rasmussen
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Sarah Østrup Jensen
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Tenna Vesterman Henriksen
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Christina Demuth
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Mathilde Diekema
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Henrik Jørn Ditzel
- Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark;
- Department of Oncology, Odense University Hospital, 5000 Odense, Denmark
| | | | - Jakob Skou Pedersen
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
- Bioinformatics Research Center, Faculty of Science, Aarhus University, 8000 Aarhus, Denmark
| | - Lars Dyrskjøt
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
| | - Claus Lindbjerg Andersen
- Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark; (A.F.); (S.Ø.J.); (T.V.H.); (C.D.); (M.D.); (J.S.P.); (L.D.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark
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Tian X, Liu X, Wang K, Wang R, Li Y, Qian K, Wang T, Zhao X, Liu L, Zhang PL, Xiong Y, Rui J, Chen R, Zhang Y. Postoperative ctDNA in indicating the recurrence risk and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer. Thorac Cancer 2024; 15:797-807. [PMID: 38409945 PMCID: PMC10995713 DOI: 10.1111/1759-7714.15251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/28/2024] Open
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC). METHODS We enrolled 58 NSCLC patients in a real-world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related and ultra-deep targeted NGS covering 338 genes, respectively. RESULTS ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease-free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy. CONCLUSION Postoperative ctDNA is a prognostic marker, and ctDNA-detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.
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Affiliation(s)
- Xiaoru Tian
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Xingsheng Liu
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Kai Wang
- Medical CenterGeneplus‐BeijingBeijingChina
| | - Ruotian Wang
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Yuanbo Li
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Kun Qian
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Tengteng Wang
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Xin Zhao
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Lei Liu
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | - Pei Long Zhang
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
| | | | - Jinqiu Rui
- Medical CenterGeneplus‐BeijingBeijingChina
| | | | - Yi Zhang
- Department of Thoracic SurgeryXuanwu Hospital Capital Medical UniversityBeijingChina
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32
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Díaz del Arco C, Fernández Aceñero MJ, Ortega Medina L. Liquid biopsy for gastric cancer: Techniques, applications, and future directions. World J Gastroenterol 2024; 30:1680-1705. [PMID: 38617733 PMCID: PMC11008373 DOI: 10.3748/wjg.v30.i12.1680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/01/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist's perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.
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Affiliation(s)
- Cristina Díaz del Arco
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - M Jesús Fernández Aceñero
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Luis Ortega Medina
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
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Sun Y, He S, Peng Y, Liu M, Xu D. A novel label-free capillary electrophoresis LED-induced fluorescence platform based on catalytic hairpin assembly for sensitive detection of multiple circulating tumor DNA. Analyst 2024; 149:1548-1556. [PMID: 38284430 DOI: 10.1039/d3an01993d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
Circulating tumor DNA (ctDNA) is a highly promising biomarker for the early diagnosis and treatment of gastric cancer (GC). However, there is still a lack of effective and practical ctDNA detection methods. In this work, a simple and economical capillary non-gel sieving electrophoresis-LED induced fluorescence detection (NGCE-LEDIF) platform coupled with catalytic hairpin assembly (CHA) as the signal amplification strategy is proposed for quantitative detection of PIK3CA E542K and TP53 (two types of ctDNA associated with GC). We have reasonably designed two pairs of programmable oligonucleotide hairpin probes for PIK3CA E542K and TP53. Using a one-pot reaction, the presence of ctDNA triggers the cyclic amplification of CHA, forming numerous thermodynamically stable H1/H2 double-strands. The H1/H2 double-stranded DNA catalyzed by PIK3CA E542K and TP53 can be easily separated by NGCE due to their different lengths, enabling simultaneous detection of both ctDNAs. Under optimal experimental conditions, the detection limits of this strategy for detecting GC-related biomarkers PIK3CA E542K and TP53 are 20.35 pM and 19.61 pM, respectively, and can achieve 730-fold signal amplification. This strategy has a good recovery in the serum matrix. The results of this study show that this strategy has significant advantages such as high selectivity, a simple process, no special instruments and equipment, no need for fluorescence modification of hairpin probes in advance, high automation, low cost, and minimal sample consumption. This provides a powerful method for the detection of trace cancer biomarkers in the serum matrix with good application prospects.
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Affiliation(s)
- Yanyan Sun
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, No 163, Xianlin Avenue, Nanjing, 210023, PR China.
| | - Si He
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, No 163, Xianlin Avenue, Nanjing, 210023, PR China.
| | - Yufei Peng
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, No 163, Xianlin Avenue, Nanjing, 210023, PR China.
| | - Min Liu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, No 163, Xianlin Avenue, Nanjing, 210023, PR China.
| | - Danke Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, No 163, Xianlin Avenue, Nanjing, 210023, PR China.
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Wang R, Yang Y, Lu T, Cui Y, Li B, Liu X. Circulating cell-free DNA-based methylation pattern in plasma for early diagnosis of esophagus cancer. PeerJ 2024; 12:e16802. [PMID: 38313016 PMCID: PMC10838104 DOI: 10.7717/peerj.16802] [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: 06/29/2023] [Accepted: 12/26/2023] [Indexed: 02/06/2024] Open
Abstract
With the increased awareness of early tumor detection, the importance of detecting and diagnosing esophageal cancer in its early stages has been underscored. Studies have consistently demonstrated the crucial role of methylation levels in circulating cell-free DNA (cfDNA) in identifying and diagnosing early-stage cancer. cfDNA methylation pertains to the methylation state within the genomic scope of cfDNA and is strongly associated with cancer development and progression. Several research teams have delved into the potential application of cfDNA methylation in identifying early-stage esophageal cancer and have achieved promising outcomes. Recent research supports the high sensitivity and specificity of cfDNA methylation in early esophageal cancer diagnosis, providing a more accurate and efficient approach for early detection and improved clinical management. Accordingly, this review aims to present an overview of methylation-based cfDNA research with a focus on the latest developments in the early detection of esophageal cancer. Additionally, this review summarizes advanced analytical technologies for cfDNA methylation that have significantly benefited from recent advancements in separation and detection techniques, such as methylated DNA immunoprecipitation sequencing (MeDIP-seq). Recent findings suggest that biomarkers based on cfDNA methylation may soon find successful applications in the early detection of esophageal cancer. However, large-scale prospective clinical trials are required to identify the potential of these biomarkers.
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Affiliation(s)
- Rui Wang
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Yue Yang
- Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, Jilin, China
| | - Tianyu Lu
- Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, Jilin, China
| | - Youbin Cui
- Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, Jilin, China
| | - Bo Li
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Xin Liu
- Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, Jilin, China
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Wilbur HC, Soares HP, Azad NS. Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations. Hepatology 2024:01515467-990000000-00725. [PMID: 38266282 DOI: 10.1097/hep.0000000000000760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/31/2023] [Indexed: 01/26/2024]
Abstract
Biliary tract cancers (BTC) are a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC. In this review, we assess the neoadjuvant and adjuvant clinical trials for the treatment of BTC and discuss the challenges and limitations of clinical trials, as well as future directions for the treatment of BTC.
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Affiliation(s)
- H Catherine Wilbur
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Heloisa P Soares
- Division of Oncology, Department of Internal Medicine Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Nilofer S Azad
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
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36
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Allan Z, Liu DS, Lee MM, Tie J, Clemons NJ. A Practical Approach to Interpreting Circulating Tumor DNA in the Management of Gastrointestinal Cancers. Clin Chem 2024; 70:49-59. [PMID: 38175583 DOI: 10.1093/clinchem/hvad188] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/19/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND There is accumulating evidence supporting the clinical use of circulating tumor DNA (ctDNA) in solid tumors, especially in different types of gastrointestinal cancer. As such, appraisal of the current and potential clinical utility of ctDNA is needed to guide clinicians in decision-making to facilitate its general applicability. CONTENT In this review, we firstly discuss considerations surrounding specimen collection, processing, storage, and analysis, which affect reporting and interpretation of results. Secondly, we evaluate a selection of studies on colorectal, esophago-gastric, and pancreatic cancer to determine the level of evidence for the use of ctDNA in disease screening, detection of molecular residual disease (MRD) and disease recurrence during surveillance, assessment of therapy response, and guiding targeted therapy. Lastly, we highlight current limitations in the clinical utility of ctDNA and future directions. SUMMARY Current evidence of ctDNA in gastrointestinal cancer is promising but varies depending on its specific clinical role and cancer type. Larger prospective trials are needed to validate different aspects of ctDNA clinical utility, and standardization of collection protocols, analytical assays, and reporting guidelines should be considered to facilitate its wider applicability.
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Affiliation(s)
- Zexi Allan
- Division of Cancer Research, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - David S Liu
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
- Upper Gastrointestinal Surgery Unit, Division of Surgery, Anaesthesia, and Procedural Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - Margaret M Lee
- Division of Personalised Oncology, the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Jeanne Tie
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
- Division of Personalised Oncology, the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
| | - Nicholas J Clemons
- Division of Cancer Research, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
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Han HS, Lee KW. Liquid Biopsy: An Emerging Diagnostic, Prognostic, and Predictive Tool in Gastric Cancer. J Gastric Cancer 2024; 24:4-28. [PMID: 38225764 PMCID: PMC10774753 DOI: 10.5230/jgc.2024.24.e5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/17/2024] Open
Abstract
Liquid biopsy, a minimally invasive procedure that causes minimal pain and complication risks to patients, has been extensively studied for cancer diagnosis and treatment. Moreover, it facilitates comprehensive quantification and serial assessment of the whole-body tumor burden. Several biosources obtained through liquid biopsy have been studied as important biomarkers for establishing early diagnosis, monitoring minimal residual disease, and predicting the prognosis and response to treatment in patients with cancer. Although the clinical application of liquid biopsy in gastric cancer is not as robust as that in other cancers, biomarker studies using liquid biopsy are being actively conducted in patients with gastric cancer. Herein, we aimed to review the role of various biosources that can be obtained from patients with gastric cancer through liquid biopsies, such as blood, saliva, gastric juice, urine, stool, peritoneal lavage fluid, and ascites, by dividing them into cellular and acellular components. In addition, we reviewed previous studies on the diagnostic, prognostic, and predictive biomarkers for gastric cancer using liquid biopsy and discussed the limitations of liquid biopsy and the challenges to overcome these limitations in patients with gastric cancer.
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Affiliation(s)
- Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
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Orășeanu A, Brisc MC, Maghiar OA, Popa H, Brisc CM, Șolea SF, Maghiar TA, Brisc C. Landscape of Innovative Methods for Early Diagnosis of Gastric Cancer: A Systematic Review. Diagnostics (Basel) 2023; 13:3608. [PMID: 38132192 PMCID: PMC10742893 DOI: 10.3390/diagnostics13243608] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/28/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023] Open
Abstract
From a global perspective, gastric cancer (GC) persists as a significant healthcare issue. In the Western world, the majority of cases are discovered at late stages, when the treatment is generally unsuccessful. There are no organized screening programs outside of Asia (Japan and Republic of Korea). Traditional diagnosis techniques (such as upper endoscopy), conventional tumor markers (CEA, CA19-9, and CA72-4), radiographic imaging, and CT scanning all have drawbacks. The gold standard for the earliest detection of cancer and related premalignant lesions is still endoscopy with a proper biopsy follow-up. Since there are currently no clinically approved biomarkers for the early diagnosis of GC, the identification of non-invasive biomarkers is expected to help improve the prognosis and survival rate of these patients. The search for new screening biomarkers is currently underway. These include genetic biomarkers, such as circulating tumor cells, microRNAs, and exosomes, as well as metabolic biomarkers obtained from biofluids. Meanwhile, cutting-edge high-resolution endoscopic technologies are demonstrating promising outcomes in the visual diagnosis of mucosal lesions with the aid of linked color imaging and machine learning models. Following the PRISMA guidelines, this study examined the articles in databases such as PubMed, resulting in 167 included articles. This review discusses the currently available and emerging methods for diagnosing GC early on, as well as new developments in the endoscopic detection of early lesions of the stomach.
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Affiliation(s)
- Alexandra Orășeanu
- Clinic of Gastroenterology, Bihor Clinical County Emergency Hospital, 410169 Oradea, Romania; (A.O.); (S.F.Ș.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
| | | | - Octavian Adrian Maghiar
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Horia Popa
- Clinical Emergency Hospital “Prof. Dr. Agrippa Ionescu”, 011356 Bucharest, Romania;
| | - Ciprian Mihai Brisc
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Sabina Florina Șolea
- Clinic of Gastroenterology, Bihor Clinical County Emergency Hospital, 410169 Oradea, Romania; (A.O.); (S.F.Ș.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
| | - Teodor Andrei Maghiar
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Ciprian Brisc
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
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Zavarykina TM, Lomskova PK, Pronina IV, Khokhlova SV, Stenina MB, Sukhikh GT. Circulating Tumor DNA Is a Variant of Liquid Biopsy with Predictive and Prognostic Clinical Value in Breast Cancer Patients. Int J Mol Sci 2023; 24:17073. [PMID: 38069396 PMCID: PMC10706922 DOI: 10.3390/ijms242317073] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
This paper introduces the reader to the field of liquid biopsies and cell-free nucleic acids, focusing on circulating tumor DNA (ctDNA) in breast cancer (BC). BC is the most common type of cancer in women, and progress with regard to treatment has been made in recent years. Despite this, there remain a number of unresolved issues in the treatment of BC; in particular, early detection and diagnosis, reliable markers of response to treatment and for the prediction of recurrence and metastasis, especially for unfavorable subtypes, are needed. It is also important to identify biomarkers for the assessment of drug resistance and for disease monitoring. Our work is devoted to ctDNA, which may be such a marker. Here, we describe its main characteristics and potential applications in clinical oncology. This review considers the results of studies devoted to the analysis of the prognostic and predictive roles of various methods for the determination of ctDNA in BC patients. Currently known epigenetic changes in ctDNA with clinical significance are reviewed. The possibility of using ctDNA as a predictive and prognostic marker for monitoring BC and predicting the recurrence and metastasis of cancer is also discussed, which may become an important part of a precision approach to the treatment of BC.
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Affiliation(s)
- Tatiana M. Zavarykina
- N.M. Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow 119334, Russia;
- “B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology of Ministry of Health of the Russian Federation, Moscow 117997, Russia; (S.V.K.); (G.T.S.)
| | - Polina K. Lomskova
- N.M. Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow 119334, Russia;
| | - Irina V. Pronina
- Institute of General Pathology and Pathophysiology, Moscow 125315, Russia;
| | - Svetlana V. Khokhlova
- “B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology of Ministry of Health of the Russian Federation, Moscow 117997, Russia; (S.V.K.); (G.T.S.)
| | - Marina B. Stenina
- “N.N. Blokhin National Medical Research Center of Oncology of Ministry of Health of the Russian Federation, Moscow 115522, Russia;
| | - Gennady T. Sukhikh
- “B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology of Ministry of Health of the Russian Federation, Moscow 117997, Russia; (S.V.K.); (G.T.S.)
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Min L, Chen J, Yu M, Yang K, Liu D. Utilizing circulating tumour DNA as a prognostic predictor of gastric cancer: a meta-analysis. Biomarkers 2023; 28:427-436. [PMID: 37036017 DOI: 10.1080/1354750x.2023.2201664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/05/2023] [Indexed: 04/11/2023]
Abstract
Background: Circulating tumour DNA (ctDNA) has demonstrated robust diagnostic accuracy in several digestive cancers. However, the prognostic role of ctCDNA in gastric cancer (GC) is still controversial. This systematic review and meta-analysis aimed to evaluate the prognostic value of ctDNA in GC.Methods: PubMed, Web of Science and Cochrane databases were searched to identify studies reporting the use of ctDNA to predict GC outcome and all relevant studies published until November 2022 were enrolled for our analysis. Data were extracted by two authors independently and statistic analysis was conducted by R program with 'meta' and 'metafor' packages.Results: A total of 34 qualified articles with 5091 subjects were incorporated into our meta-analysis. The corresponding Hazard ratio (HR) of overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS) were 2.74 (95% CI:2.24-3.35), 3.13 (95% CI:2.08-4.72) and 3.04 (95% CI:2.46-3.76), respectively, in GC patients.Conclusion: Blood-based ctDNA assay would be a potential novel biomarker for GC evaluation and prediction.Simple Summary: This is the integrated meta-analysis on the association of circulating tumour DNA (ctDNA) and prognosis of gastric cancer (GC) with an increasing number of studies exploring the prognostic value of GC in the last few years, which depicted that the detection of ctDNA could be a promising predictor in GC patients.
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Affiliation(s)
- Liang Min
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Jinghua Chen
- Department of Oncology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Meihong Yu
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
| | - Ke Yang
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Deliang Liu
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, China
- Research Center of Digestive Disease, Central South University, Changsha, China
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Seo SH, Park YS, Nam SK, Lee HS, Park DJ, Park KU. Concordance of circulating tumor DNA and matched formalin-fixed paraffin-embedded tumor tissue in gastric cancer as a predictor of recurrence. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2023; 19:45-51. [PMID: 38229488 DOI: 10.14216/kjco.23009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 10/24/2023] [Indexed: 01/18/2024]
Abstract
PURPOSE Combined analysis of the variant composition of circulating tumor DNA (ctDNA) from cell-free plasma and DNA from tumor tissue could provide insight into the implications of the genetic alterations responsible for the intratumoral and intertumoral heterogeneity of gastric cancer. We aimed to evaluate the usefulness of this approach in these patients. METHODS Cell-free plasma and formalin-fixed paraffin-embedded tumor tissue samples from 46 patients with gastric cancer were examined. Targeted deep sequencing was performed using a commercially available kit. RESULTS The cell-free DNA (cfDNA) concentration was higher in stage II-IV versus stage I patients and in larger versus smaller tumors. Only 12 of the 36 (33.3%) alterations in the tumor tissue samples were in concordance with those in the ctDNA samples. Two variants were in concordance in stage I samples and 10 in stage II-IV samples. Actionable variants that were detected in concordance were in the stage II-IV samples. Preoperative ctDNA positivity of actionable variants was significantly associated with cfDNA concentration, lymphatic invasion, N stage, and TNM stage. Cancer recurrence was significantly associated with tumor size, lymphatic/vascular invasion, TNM stage, and ctDNA-tumor tissue variant concordance. CONCLUSION Preoperative ctDNA genetic analysis using a multigene panel offers substantial clinical benefits when performed in conjunction with targeted deep sequencing of tumor tissue. Concordance between preoperative ctDNA and tumor tissue mutations may serve as a prognostic indicator in patients with gastric cancer.
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Affiliation(s)
- Soo Hyun Seo
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Young Suk Park
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo Kyung Nam
- Department of Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Kyoung Un Park
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Yuan S, Nie R, Huang Y, Chen Y, Wang S, Sun X, Li Y, Liu Z, Chen Y, Yao Y, Xu Y, Qiu H, Liang Y, Wang W, Liu Z, Zhao Q, Xu R, Zhou Z, Wang F. Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer. Cancer Commun (Lond) 2023; 43:1312-1325. [PMID: 37837629 PMCID: PMC10693304 DOI: 10.1002/cac2.12494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 09/24/2023] [Accepted: 10/03/2023] [Indexed: 10/16/2023] Open
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context. METHODS From 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors. RESULTS Compared with ctDNA-negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37-5.48; P = 0.003], while patients with positive post-ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08-72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival (RFS). Moreover, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index (0.78; 95% CI = 0.71-0.84) than the model without ctDNA (0.71; 95% CI = 0.64-0.79; P = 0.009). CONCLUSIONS Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue-based and circulating tumor features could achieve better risk prediction.
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Honoré N, van Marcke C, Galot R, Helaers R, Ambroise J, van Maanen A, Mendola A, Dahou H, Marbaix E, Van Eeckhout P, Longton E, Magremanne M, Schmitz S, Limaye N, Machiels JP. Tumor-agnostic plasma assay for circulating tumor DNA detects minimal residual disease and predicts outcome in locally advanced squamous cell carcinoma of the head and neck. Ann Oncol 2023; 34:1175-1186. [PMID: 37879442 DOI: 10.1016/j.annonc.2023.09.3102] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing. PATIENTS AND METHODS A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, β = 0.9). RESULTS We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011). CONCLUSIONS Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice.
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Affiliation(s)
- N Honoré
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - C van Marcke
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - R Galot
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - R Helaers
- Human Molecular Genetics, de Duve Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - J Ambroise
- Center for Applied Molecular Technologies, Institute of Clinical and Experimental Research, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - A van Maanen
- Statistical Support Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - A Mendola
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - H Dahou
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - E Marbaix
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - P Van Eeckhout
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - E Longton
- Department of Radiotherapy, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - M Magremanne
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Maxillo-facial Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - S Schmitz
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of ENT and Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - N Limaye
- Department of Genetics of Autoimmune Diseases and Cancer, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - J-P Machiels
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium.
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Mi J, Wang R, Han X, Ma R, Li H. Circulating tumor DNA predicts recurrence and assesses prognosis in operable gastric cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e36228. [PMID: 38050202 PMCID: PMC10695564 DOI: 10.1097/md.0000000000036228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/30/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Selecting the appropriate patient for further treatment after surgery for gastric cancer can improve the patient prognosis. Circulating tumor DNA (ctDNA) has the potential to predict recurrence and prognosis after gastric cancer surgery, but the results are still inconclusive. As the completed studies had small sample sizes and were inconsistent, a meta-analysis was conducted to assess the effect of ctDNA on recurrence and prognosis after gastric cancer surgery. METHODS PubMed, Embase, Scopus, and the Web of Science were searched for potentially eligible studies published up to April 7, 2023. Pooled relative risk (RR) and pooled hazard ratio (HR) were calculated to evaluate recurrence, recurrence-free survival (RFS), and overall survival (OS) following gastric cancer surgery. RESULTS A pooled analysis revealed that patients who were ctDNA positive before and after surgery were at a high risk of gastric cancer recurrence (RR = 1.79, 95% CI: 1.19-2.71; RR = 3.17, 95% CI: 2.36-4.25). The pooled data revealed that ctDNA-positive patients had a poorer RFS and OS (HR = 6.37, 95% CI: 2.70-15.01; HR = 4.58, 95% CI: 1.68-12.49). CONCLUSIONS ctDNA-positive patients were at a high risk of recurrence after gastric cancer surgery and had a poorer prognosis. Hence, ctDNA-positive patients needed close follow-up and further treatment.
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Affiliation(s)
- Junjie Mi
- Department of Gastroenterology, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Rong Wang
- Department of Gastroenterology, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Xiaofang Han
- Core Laboratory, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Ruijun Ma
- Department of Gastroenterology, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Huiying Li
- Fenyang College of Shanxi Medical University, Fenyang, China
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Alqahtani A, Alloghbi A, Coffin P, Yin C, Mukherji R, Weinberg BA. Prognostic utility of preoperative and postoperative KRAS-mutated circulating tumor DNA (ctDNA) in resected pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Surg Oncol 2023; 51:102007. [PMID: 37852124 DOI: 10.1016/j.suronc.2023.102007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/20/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease, with surgery being the only possible cure. However, despite surgery, the majority of patients experience recurrence. Recent evidence suggests that perioperative KRAS-mutated circulating tumor DNA (ctDNA) may have prognostic value. Therefore, we conducted a systematic review and meta-analysis to explore the prognostic significance of preoperative and postoperative KRAS-mutated ctDNA testing in resected PDAC. METHODS We searched PubMed/MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases for studies that reported the effect of preoperative and postoperative KRAS-mutated ctDNA on overall survival (OS) and/or relapse-free survival (RFS) in resected PDAC. We used a random-effects model to determine the pooled OS and RFS hazard ratios (HR) and their corresponding 95 % confidence intervals (CI). RESULTS We identified 15 studies (868 patients) eligible for analysis. In the preoperative setting, positive ctDNA correlated with worse RFS in 8 studies (HR, 2.067; 95 % CI, 1.346-3.174, P < 0.001) and worse OS in 10 studies (HR, 2.170; 95 % CI, 1.451-3.245, P < 0.001) compared to negative ctDNA. In the postoperative setting, positive ctDNA correlated with worse RFS across 9 studies (HR, 3.32; 95 % CI, 2.19-5.03, P < 0.001) and worse OS in 6 studies (HR, 6.62; 95 % CI, 2.18-20.16, P < 0.001) compared to negative ctDNA. CONCLUSION Our meta-analysis supports the utility of preoperative and postoperative KRAS-mutated ctDNA testing as a prognostic marker for resected PDAC. Further controlled studies are warranted to confirm these results and to investigate the potential therapeutic implications of positive KRAS-mutated ctDNA.
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Affiliation(s)
- Ali Alqahtani
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA; Medical Oncology Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Abdurahman Alloghbi
- Cancer Research Unit and Department of Oncology, King Khalid University, Abha, Saudi Arabia
| | - Philip Coffin
- Department of Internal Medicine, Georgetown University Medical Center, Washington, DC, 20057, USA
| | - Chao Yin
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA
| | - Reetu Mukherji
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA
| | - Benjamin A Weinberg
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA.
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Wei J, Guo X, Yang X, Liu J, Duan Q, Tan Y, Zhang Q, Sun T, Qi C, Li X, Ji G. Sintilimab plus fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as neoadjuvant therapy for resectable gastric cancer and biomarker exploration. Future Oncol 2023; 19:2395-2403. [PMID: 37990937 DOI: 10.2217/fon-2022-0929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023] Open
Abstract
At present, preoperative chemotherapy is the standard of care for the neoadjuvant treatment of potentially resectable gastric cancer (GC). However, because the efficacy and prognosis are not ideal, curative effects for this population are unsatisfactory. With the development of immune checkpoint inhibitors, the results of a few encouraging early trials of immunotherapeutic agents as neoadjuvant therapies for resectable GC have been reported. However, markers of the efficacy of immune checkpoint inhibitors remain unclear. This prospective single-center, single-arm observational study was designed to evaluate the efficacy of sintilimab plus the fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as a neoadjuvant treatment for localized GC. More importantly, this work assesses multiple dimensions and include ctDNA, the immune microenvironment and intestinal microbiome to explore correlations between biomarkers and neoadjuvant therapeutic efficacy. Clinical trial registration: ChiCTR2200061629 (www.chictr.org.cn/index.aspx).
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Affiliation(s)
- Jiangpeng Wei
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China
| | - Xin Guo
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China
| | - Xisheng Yang
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China
| | - Jinqiang Liu
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China
| | - Qianqian Duan
- The State Key Lab of Translational Medicine & Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Yuan Tan
- The State Key Lab of Translational Medicine & Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Qin Zhang
- The State Key Lab of Translational Medicine & Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Tingting Sun
- The State Key Lab of Translational Medicine & Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Chuang Qi
- The State Key Lab of Translational Medicine & Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Xiaohua Li
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China
| | - Gang Ji
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China
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Nawaf C, Shiang A, Chauhan PS, Chaudhuri AA, Agarwal G, Smith ZL. Circulating tumor DNA based minimal residual disease detection and adjuvant treatment decision-making for muscle-invasive bladder cancer guided by modern clinical trials. Transl Oncol 2023; 37:101763. [PMID: 37657155 PMCID: PMC10495651 DOI: 10.1016/j.tranon.2023.101763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 08/06/2023] [Accepted: 08/15/2023] [Indexed: 09/03/2023] Open
Abstract
Up to 430,000 cases of bladder cancer are diagnosed each year worldwide. A proposed method for non-invasive monitoring has been to utilize a "liquid biopsy." Liquid biopsy has been proposed as a non-invasive method of testing biomarkers in bodily fluids in order to detect and survey cancer. The liquid biopsy could be utilized to obtain information regarding circulating tumor cells, circulating cell-free tumor DNA, circulating cell-free tumor RNA, and more. It is currently being investigated to help guide adjuvant therapy and improve oncological outcomes. We highlight an array of exciting past and ongoing clinical trials regarding ctDNA and adjuvant therapy in regard to urothelial carcinoma which we believe to be amongst the leaders in the field.
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Affiliation(s)
- Cayce Nawaf
- Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America; Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis, MO, United States of America
| | - Alexander Shiang
- Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America; Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States of America
| | - Pradeep S Chauhan
- Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States of America
| | - Aadel A Chaudhuri
- Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States of America; Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States of America; Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis, MO, United States of America; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States of America; Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States of America.
| | - Gautum Agarwal
- Division of Urology, David Pratt Cancer Center, Mercy Hospital, 607 S New Ballas Rd, St. Louis, MO, United States of America.
| | - Zachary L Smith
- Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America; Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis, MO, United States of America.
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Chen Y, Zhang J, Han G, Tang J, Guo F, Li W, Xie L, Xu H, Zhang X, Tian Y, Pan L, Shu Y, Ma L, Chen X. Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study). Front Immunol 2023; 14:1232858. [PMID: 38022553 PMCID: PMC10644233 DOI: 10.3389/fimmu.2023.1232858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Background The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration https://www.clinicaltrials.gov, identifier NCT05494060.
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Affiliation(s)
- Yizhang Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Jiaguang Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gaohua Han
- Department of Oncology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Jie Tang
- Department of Oncology, Liyang People's Hospital, Changzhou, China
| | - Fen Guo
- Department of Oncology, Suzhou Municipal Hospital, Suzhou, China
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Soochow, Suzhow, China
| | - Li Xie
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Xu
- Department of Gastric Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinyi Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yitong Tian
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lanlan Pan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ling Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Oncology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
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陈 颖. [Research progress on circulating tumor DNA as a biomarker for minimal residual disease in solid tumors]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2023; 25:1072-1077. [PMID: 37905766 PMCID: PMC10621050 DOI: 10.7499/j.issn.1008-8830.2304040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 08/02/2023] [Indexed: 11/02/2023]
Abstract
Circulating tumor DNA (ctDNA) is emerging as a novel biomarker for tumor evaluation, offering advantages such as high sensitivity and specificity, minimal invasiveness, and absence of radiation. Currently, various techniques including gene sequencing and PCR are employed for ctDNA detection. The utilization of ctDNA for monitoring minimal residual disease (MRD) enables comprehensive assessment of tumor status and early identification of tumor recurrence, achieving a remarkable detection sensitivity of 0.01%. Therefore, ctDNA holds promise as a biomarker for early diagnosis, treatment response monitoring, and prognosis prediction in solid tumors. This article reviews the commonly used methods for detecting ctDNA and their advantages in evaluating tumor MRD and guiding clinical diagnosis and treatment.
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Affiliation(s)
- 颖 陈
- 汕头大学医学院深圳儿科临床学院,广东深圳518034
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Lv J, Wu J, Wu H, Ding P, Guo H, Yang P, Tian Y, Liu Y, Zhao Q. Study protocol of a phase II clinical trial evaluating the efficacy of neoadjuvant intraperitoneal and systemic albumin-bound paclitaxel combined with camrelizumab and S-1 in the treatment of patients with exfoliative cell-positive gastric cancer. Front Oncol 2023; 13:1201928. [PMID: 37841441 PMCID: PMC10571916 DOI: 10.3389/fonc.2023.1201928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/08/2023] [Indexed: 10/17/2023] Open
Abstract
Background Currently, gastric cancer with positive lavage cytology without gross peritoneal dissemination (GC-CY1) is a special type of metastatic form with poor prognosis. Consensus guidelines on treatment strategies for patients with GC-CY1 have not been established. This study involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of neoadjuvant intraperitoneal and systemic (NIPS) albumin-bound paclitaxel combined with Camrelizumab and S-1 in the treatment of GC-CY1 patients. Methods/design This is a prospective single-center exploratory study, and the primary endpoints of the trial are R0 resection rate and conversion rate of abdominal free cancer cells (FCCs), with secondary endpoints of 3-year progression-free survival (PFS); 3-year overall survival (OS); objective remission rate (ORR); disease control rate (DCR); safety and TRG classification. Discussion This study is the first to apply NIPS albumin-bound paclitaxel combined with Camrelizumab and S-1 to the conversion therapy of GC-CY1 patients. It is speculated that this combination of regimens will increase the negative conversion rate of FCCs by 20%, which will provide innovative insights into conversion treatment ideas for GC-CY1 patients to be managed in a more comprehensive and optimized manner. Clinical trial registration http://clinicaltrials.gov/, identifier NCT05410847.
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Affiliation(s)
- Jingxia Lv
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Jiaxiang Wu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Haotian Wu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Ping’an Ding
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Honghai Guo
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Peigang Yang
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Yuan Tian
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Yang Liu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Qun Zhao
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
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