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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [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: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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Du XY, Xia RJ, Shen LW, Ma JG, Yao WQ, Xu W, Lin ZP, Ma LB, Niu GQ, Fan RF, Xu SM, Yan L. Quadruple therapy with immunotherapy and chemotherapy as first-line conversion treatment for unresectable advanced gastric adenocarcinoma: A case report. World J Gastrointest Oncol 2025; 17:102258. [DOI: 10.4251/wjgo.v17.i4.102258] [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: 10/13/2024] [Revised: 01/20/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND The treatment of gastric cancer remains highly challenging, particularly in cases of unresectable locally advanced or metastatic disease. Although chemotherapy and immunotherapy have shown some efficacy in such patients, significant limitations persist in extending survival and enhancing safety. To address these challenges, we designed an innovative first-line quadruple conversion therapy regimen that integrates a programmed cell death protein 1 (PD-1) inhibitor with chemotherapy, and we successfully implemented this therapy regimen in the treatment of a patient with unresectable locally advanced gastric adenocarcinoma.
CASE SUMMARY We report the case of a 55-year-old male who was diagnosed with unresectable locally advanced gastric adenocarcinoma and presented with intermittent epigastric pain and multiple lymph node metastases in the abdominal cavity, with the metastasis being notably large in size. The tumor tissue was negative for human epidermal growth factor receptor 2 by immunohistochemistry. Considering the patient's status, the multidisciplinary team decided to administer sintilimab in combination with albumin-bound paclitaxel (nab-paclitaxel), S-1, and oxaliplatin as a quadruple drug conversion therapy. After 4 cycles of conversion therapy, the patient's epigastric pain was significantly alleviated, his stool color normalized, the volume of the primary tumor and lymph node metastases was markedly reduced, and the tumor marker levels decreased to within the normal range. The patient subsequently underwent laparoscopic total gastrectomy with abdominal lymph node dissection, and postoperative pathological biopsy revealed a pathological complete response and R0 resection, after which the patient recovered to an excellent physical status.
CONCLUSION To the best of our knowledge, this is the first reported case of unresectable locally advanced gastric adenocarcinoma successfully treated with quadruple therapy with a PD-1 inhibitor and chemotherapy as a first-line conversion regimen. This first-line conversion therapy with the quadruple regimen may be effective and safe for unresectable locally advanced gastric adenocarcinoma.
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Affiliation(s)
- Xiao-Yu Du
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Department of Medicine, Northwest Minzu University, Lanzhou 730050, Gansu Province, China
| | - Ren-Jie Xia
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Department of Medicine, Northwest Minzu University, Lanzhou 730050, Gansu Province, China
| | - Li-Wen Shen
- Department of Medical Support Center, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Jian-Guo Ma
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Wei-Qing Yao
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Department of Medicine, Northwest Minzu University, Lanzhou 730050, Gansu Province, China
| | - Wei Xu
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Zhi-Peng Lin
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Liang-Bin Ma
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Guo-Qiang Niu
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Rui-Fang Fan
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Shu-Mei Xu
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Long Yan
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
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Song J, Zhu J, Jiang Y, Guo Y, Liu S, Qiao Y, Du Y, Li J. Advancements in immunotherapy for gastric cancer: Unveiling the potential of immune checkpoint inhibitors and emerging strategies. Biochim Biophys Acta Rev Cancer 2025; 1880:189277. [PMID: 39938663 DOI: 10.1016/j.bbcan.2025.189277] [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: 06/10/2024] [Revised: 01/08/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.
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Affiliation(s)
- Jiawei Song
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China; Department of Experimental Surgery, Xijing Hospital, Xi'an 710038, China
| | - Jun Zhu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yu Jiang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yajie Guo
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Shuai Liu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yihuan Qiao
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yongtao Du
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Jipeng Li
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China; Department of Experimental Surgery, Xijing Hospital, Xi'an 710038, China.
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Qin S, Bai Y, Li J, Pan H, Luo S, Qu Y, Ye F, Yang L, Liu T, Li W, Chen X, Yang J, Ying J, Lin X, Zhao L, Liang X, Mao Y, Guo R, Zuo Y, Bordia S, Li S. First-Line Pembrolizumab Plus Chemotherapy for HER2-Negative Advanced Gastric Cancer: China Subgroup Analysis of the Randomized Phase 3 KEYNOTE-859 Study. Adv Ther 2025; 42:1892-1906. [PMID: 40025394 PMCID: PMC11929688 DOI: 10.1007/s12325-024-03069-4] [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: 08/27/2024] [Accepted: 11/08/2024] [Indexed: 03/04/2025]
Abstract
INTRODUCTION Results of the global, randomized, phase 3 KEYNOTE-859 study (N = 1579) showed that first-line pembrolizumab plus chemotherapy produced a statistically significant and clinically meaningful improvement in overall survival (OS) with manageable toxicity versus placebo plus chemotherapy in patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction cancer. This subgroup analysis was conducted to investigate outcomes in patients enrolled in mainland China. METHODS Adults with previously untreated advanced or metastatic HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma were randomly assigned (1:1) to receive pembrolizumab or placebo with fluoropyrimidine- and platinum-containing chemotherapy. The primary outcome was OS. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR), all assessed per RECIST v1.1 by blinded independent central review, and safety. RESULTS Overall, 236 patients were enrolled in mainland China (126 pembrolizumab plus chemotherapy; 110 placebo plus chemotherapy). Median time from randomization to database cutoff (October 3, 2022) was 24.7 months (range 15.3-38.9). Median OS was 15.9 months (95% confidence interval [CI] 13.2-19.2) for pembrolizumab plus chemotherapy versus 12.2 months (95% CI 10.6-14.1) for placebo plus chemotherapy (hazard ratio [HR], 0.68; 95% CI 0.50-0.91). Median PFS was 8.1 months (95% CI 6.9-9.6) for pembrolizumab plus chemotherapy versus 5.7 months (95% CI 4.5-6.5) for placebo plus chemotherapy (HR, 0.65; 95% CI 0.48-0.88). ORR was 69.0% for pembrolizumab plus chemotherapy versus 45.5% for placebo plus chemotherapy; median DOR was 8.2 months (range 1.2+ to 34.6+) versus 5.5 months (range 1.3+ to 31.2+), respectively. Grade 3-5 treatment-related adverse events occurred in 82 patients (65.6%) treated with pembrolizumab plus chemotherapy and 54 patients (49.1%) treated with placebo plus chemotherapy. CONCLUSION Consistent with efficacy in the overall population from KEYNOTE-859, first-line pembrolizumab plus chemotherapy showed improved efficacy, versus placebo plus chemotherapy, and manageable safety in patients enrolled in mainland China. TRIAL REGISTRATION Clinicaltrials.gov: NCT03675737.
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Affiliation(s)
- Shukui Qin
- GI Cancer Center, Nanjing Tianyinshan Hospital of China Pharmaceutical University, No 3789, Jieyin Road, Jiangning District, Nanjing, 210000, Jiangsu, China.
- Cancer Center of People's Liberation Army, Nanjing, China.
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Jin Li
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongming Pan
- Zhejiang University School of Medicine, Sir Run Shaw Hospital, Hangzhou, China
| | - Suxia Luo
- The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Yanli Qu
- Cancer Hospital Affiliated to Xinjiang Medical University, Xinjiang, China
| | - Feng Ye
- The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Lin Yang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianshu Liu
- Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Wei Li
- The First Hospital of Jilin University, Changchun, China
| | - Xi Chen
- The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Fuzhou, China
| | - Jianwei Yang
- Fujian Provincial Cancer Hospital, Fuzhou, China
| | - Jieer Ying
- Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiaoyan Lin
- Fujian Medical University Union Hospital, Fuzhou, China
| | - Lin Zhao
- Peking Union Medical College Hospital, Beijing, China
| | | | | | | | - Yi Zuo
- MSD China, Beijing, China
| | | | - Shouguo Li
- Zhongshan Hospital Affiliated to Xiamen University, Xiamen, China
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Sigler GI, Murtha J, Varley PR. Diagnostic Advances and Novel Therapeutics in Peritoneal Metastasis. Surg Oncol Clin N Am 2025; 34:173-194. [PMID: 40015798 DOI: 10.1016/j.soc.2024.12.005] [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: 03/01/2025]
Abstract
Appropriate assessment of disease burden in patients with peritoneal surface malignancy (PSM) is critical for treatment decision-making, and conventional cross-sectional imaging (computed tomography and/or MRI) often underestimates burden of disease. Advances in imaging for PSM include novel functional imaging modalities that target cells unique to the tumor microenvironment. Novel alternative methods of diagnosis and disease monitoring are also potentially applicable to management of PSM. These include forms of "liquid biopsy" targeting circulating tumor DNA. Novel regional therapies include both new therapeutic agents (immune-based and nanoparticle-based), as well as new methods of delivery such as pressurized intraperitoneal aerosolized chemotherapy.
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Affiliation(s)
- Gregory I Sigler
- Division of Surgical Oncology, Department of General Surgery, Complex General Surgical Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Mail Code 7375, Madison, WI 53792, USA
| | - Jacqueline Murtha
- Department of General Surgery, General Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Mail Code 7375, Madison, WI 53792, USA
| | - Patrick R Varley
- Division of Surgical Oncology, Department of General Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Mail Code 7375, Madison, WI 53792, USA; William S. Middleton Memorial Veterans Affairs Hospital, Madison, WI, USA.
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Mansoor H, Gohar M, Attaria A, Karim FF, Naeem U, Khan M, Iqbal J. Evaluating comparative effectiveness of pembrolizumab-based therapy versus chemotherapy in treatment of gastric carcinoma: a systematic review and meta-analysis of randomized controlled trials. Clin Exp Med 2025; 25:98. [PMID: 40153063 DOI: 10.1007/s10238-025-01610-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/24/2025] [Indexed: 03/30/2025]
Abstract
Gastric cancer, especially cancer of the gastro-esophageal junction, ranks among the first five cancers in the world with the highest mortality rates. It has poor survival rates for the advanced stages. Traditional chemotherapy, while standard, often results in significant side effects and limited efficacy. The objective of this meta-analysis and systemic review is to ascertain if pembrolizumab-based therapies for advanced gastric cancer are more effective and safer than standard chemotherapy. The focus consisted of RCTs with adults suffering from gastric carcinoma who received pembrolizumab every 3 weeks (200 mg) intra-related dose or with at least comparable chemotherapy regimen. Outcomes assessed are as follows: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). All potential sources regarding the search of outcome measures were applied: Google Scholar, Scopus, PubMed, and Cochrane library, and last search in June 2024 was carried out. Out of 568 articles screened, four RCTs comprising 2,831 patients met the inclusion criteria. Analysis indicated that pembrolizumab alone did not significantly improve OS compared to chemotherapy (HR 0.87). However, when combined with chemotherapy, pembrolizumab dramatically enhanced OS (HR 0.80) and PFS (HR 0.78). ORR was superior in the pembrolizumab plus chemotherapy group (RR 1.24), while pembrolizumab monotherapy showed no significant difference from chemotherapy alone. Safety analysis revealed a higher frequency of adverse events in the pembrolizumab-based therapy groups compared to chemotherapy. Pembrolizumab together with chemotherapy improves greater survival and higher levels of response rate in patients with severe gastric cancer, especially with high PD-L1 expression. But it has rather more adverse events, allowing patient monitoring with care.
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Affiliation(s)
| | - Maheen Gohar
- Liaquat University of Health Sciences, Jamshoro, Pakistan
| | - Asma Attaria
- Jinnah Sindh Medical University, Karachi, Pakistan
| | | | | | - Mohsin Khan
- Jinnah Sindh Medical University, Karachi, Pakistan
| | - Javed Iqbal
- Nursing Department, Communicable Disease Center, Hamad Medical Corporation, P.O Box 3050, Doha, Qatar.
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Groen-van Schooten TS, Cabeza-Segura M, Ferreira RM, Martínez-Ciarpaglini C, Barros R, Santos-Antunes J, Costa A, Fernández-Figueroa EA, Lino-Silva L, Hernandez-Guerrero AI, Ruiz-García E, Caballero C, Boggino H, Gauna C, Cantero D, Freile B, Esteso F, O Connor J, Riquelme A, Owen G, Riquelme E, Roa JC, Latorre G, Garrido M, Ruiz-Pace F, Diez García M, Alsina M, Lordick F, Farrés J, Carbonell-Asins JA, Villagrasa R, Pereira R, Pouw RE, Jimenez-Martí E, Miralles A, Dientsmann R, Figueiredo C, Carneiro F, Cervantes A, Derks S, Fleitas T. Immune profiling of gastric adenocarcinomas in EU and LATAM countries identifies global differences in immune subgroups and microbiome influence. Br J Cancer 2025:10.1038/s41416-025-02979-6. [PMID: 40113862 DOI: 10.1038/s41416-025-02979-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/04/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) patients from European (EU) and especially Latin American (LATAM) countries are underrepresented in previous large-scale multi-omic studies that have identified clinically relevant subgroups. The LEGACY study aimed to profile the molecular and immunological features of GCs from EU and LATAM countries. METHODS Tumor biopsies from 95 EU and 56 LATAM GCs were profiled with immunohistochemistry (CD3, CD8, FOXP3, PD-L1, MSI and HER2), Nanostring mRNA expression analyses, and microbiome sequencing. RESULTS Immune profiling identified four distinct immune clusters: a T cell dominant cluster with enriched activation pathways, a macrophage dominant cluster and an immune excluded microenvironment which were equally distributed among the countries. A fourth cluster of mostly Mexican patients consisted of excessive T cell numbers accompanied by enhanced cytokine signaling in absence of enhanced antigen presentation and cytotoxicity signatures and a strong association with H. pylori infection. DISCUSSION Both EU and LATAM countries have GCs with a T cell inflamed microenvironment that might benefit from checkpoint inhibition. We identified a highly inflamed GC subgroup that lacked antigen presentation and cytotoxicity associated with H. pylori CagA-positive strains, suggesting their contribution to tumor immune tolerance. Future studies are needed to unravel whether these cancers benefit from immunotherapy as well.
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Affiliation(s)
- Tessa S Groen-van Schooten
- Department of Medical Oncology, Amsterdam University Medical Center (UMC) location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, Netherlands
- Oncode Institute, Amsterdam, Netherlands
| | - Manuel Cabeza-Segura
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Rui M Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | | | - Rita Barros
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
| | - João Santos-Antunes
- Department of Gastroenterology, Unidade Local de Saúde São João, Porto, Portugal
| | - Andreia Costa
- Department of Oncology, Unidade Local de Saúde São João, Porto, Portugal
| | - Edith A Fernández-Figueroa
- Núcleo B de Innovación en Medicina de Precisión, Instituto Nacional de Medicina Genómica, Ciudad de, México, México
| | - Leonardo Lino-Silva
- Head of Division. Surgical Pathology, National Cancer Institute (INCan), Mexico City, Mexico
| | | | - Erika Ruiz-García
- Departamento de Tumores de Tubo Digestivo, Instituto Nacional de Cancerología, Ciudad de, México, México
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Ciudad de México, México
| | | | - Hugo Boggino
- Department of Pathology, GENPAT, Asunción, Paraguay
| | - Cinthia Gauna
- Medical Oncology Department, Instituto de Previsión Social, Asunción, Paraguay
| | - Daniel Cantero
- Department of Gastroenterology, Instituto de Previsión Social, Asunción, Paraguay
| | - Berenice Freile
- Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina
| | - Federico Esteso
- Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina
| | - Juan O Connor
- Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina
| | - Arnoldo Riquelme
- Department of Gastroenterology, Faculty of Medicine. Pontificia Universidad Catolica de Chile. Center for Prevention and Control of Cancer (CECAN), Santiago, Chile
| | - Gareth Owen
- Faculty of Biological Sciences & Faculty of Medicine. Pontificia Universidad Católica de Chile, Millennium Institute for Immunology and Immunotherapy, Center for Prevention and Control of Cancer (CECAN), Advance Center for Chronic Disease (ACCDIS), Santiago, Chile
| | - Erick Riquelme
- Department of Respiratory Diseases, Faculty of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, Faculty of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gonzalo Latorre
- Department of Gastroenterology, Faculty of Medicine. Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Marcelo Garrido
- Facultad de Ciencia de la Salud, Centro de Oncología de Precision, Universidad Mayor, Huechuraba, Chile
| | - Fiorella Ruiz-Pace
- Oncology Data Science, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Marc Diez García
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Maria Alsina
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
- Hospital Universitario de Navarra, Navarrabiomed-IdiSNA, Pamplona, Spain
| | - Florian Lordick
- Department of Medicine (Oncology, Gastroenterology, Hepatology, and Pulmonology), University of Leipzig Medical Center, Comprehensive Cancer Center Central Germany (CCCG), Leipzig, Germany
| | | | | | - Rossana Villagrasa
- Department of Gastroenterology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Rita Pereira
- Department of Gastroenterology, Instituto de Previsión Social, Asunción, Paraguay
| | - Roos E Pouw
- Gastroenterology Department. Amsterdam UMC, Amsterdam, The Netherlands
| | - Elena Jimenez-Martí
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Ana Miralles
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Rodrigo Dientsmann
- Oncology Data Science, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
| | - Fatima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
| | - Andrés Cervantes
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
- CiberOnc. Carlos III Institute, Madrid, Spain
| | - Sarah Derks
- Department of Medical Oncology, Amsterdam University Medical Center (UMC) location Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
- Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, Netherlands.
- Oncode Institute, Amsterdam, Netherlands.
| | - Tania Fleitas
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain.
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Veas Rodriguez J, Piñol M, Sorolla MA, Parisi E, Sorolla A, Santacana M, Ruiz M, Parra G, Bernabeu M, Iglesias M, Aracil C, Escartin A, Vilardell F, Matias-Guiu X, Salud A, Montal R. Comprehensive immunophenotyping of gastric adenocarcinoma identifies an inflamed class of tumors amenable to immunotherapies. J Immunother Cancer 2025; 13:e010024. [PMID: 40102027 PMCID: PMC11927434 DOI: 10.1136/jitc-2024-010024] [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] [Accepted: 02/22/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Gastric adenocarcinoma (GAC) imposes a considerable global health burden. Molecular profiling of GAC from the tumor microenvironment perspective through a multi-omics approach is eagerly awaited in order to allow a more precise application of novel therapies in the near future. METHODS To better understand the tumor-immune interface of GAC, we identified an internal cohort of 82 patients that allowed an integrative molecular analysis including mutational profiling by whole-exome sequencing, RNA gene expression of 770 genes associated with immune response, and multiplex protein expression at spatial resolution of 34 immuno-oncology targets at different compartments (tumorous cells and immune cells). Molecular findings were validated in 595 GAC from the TCGA and ACRG external cohorts with available multiomics data. Prediction of response to immunotherapies of the discovered immunophenotypes was assessed in 1039 patients with cancer from external cohorts with available transcriptome data. RESULTS Unsupervised clustering by gene expression identified a subgroup of GAC that includes 52% of the tumors, the so-called Inflamed class, characterized by high tumor immunogenicity and cytotoxicity, particularly in the tumor center at protein level, with enrichment of PIK3CA and ARID1A mutations and increased presence of exhausted CD8+ T cells as well as co-inhibitory receptors such as PD1, CTLA4, LAG3, and TIGIT. The remaining 48% of tumors were called non-inflamed based on the observed exclusion of T cell infiltration, with an overexpression of VEGFA and higher presence of TP53 mutations, resulting in a worse clinical outcome. A 10-gene RNA signature was developed for the identification of tumors belonging to these classes, demonstrating in evaluated datasets comparable clinical utility in predicting response to current immunotherapies when tested against other published gene signatures. CONCLUSIONS Comprehensive immunophenotyping of GAC identifies an inflamed class of tumors that complements previously proposed tumor-based molecular clusters. Such findings may provide the rationale for exploring novel immunotherapeutic approaches for biomarker-enriched populations in order to improve GAC patient's survival.
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Affiliation(s)
- Joel Veas Rodriguez
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Miquel Piñol
- Department of Pathology, Oncological Pathology Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Maria Alba Sorolla
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Eva Parisi
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Anabel Sorolla
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Maria Santacana
- Scientific and Technical Service of Immunohistochemistry, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Maria Ruiz
- Scientific and Technical Service of Biobank, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Genís Parra
- CNAG-Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Mario Bernabeu
- CNAG-Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Mar Iglesias
- Department of Pathology, Hospital del Mar, University Pompeu Fabra, Hospital del Mar Research Institute, CIBERONC, Barcelona, Spain
| | - Carles Aracil
- Department of Gastroenterology, Clinical and Experimental Research in Digestive and Hematological Pathology Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Alfredo Escartin
- Department of Surgery, Experimental Surgery Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Felip Vilardell
- Department of Pathology, Oncological Pathology Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Xavier Matias-Guiu
- Department of Pathology, Oncological Pathology Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Antonieta Salud
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
| | - Robert Montal
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova - IRBLleida, Lleida, Spain
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9
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Kikuchi Y, Oshima Y, Fujisaki M, Tsuru M, Urakami H, Nagaoka S, Futawatari N, Yajima S, Shimada H. Comparison of the prognostic effect of taxane regimens combined with ramucirumab before nivolumab for advanced gastric cancer. Int J Clin Oncol 2025:10.1007/s10147-025-02737-x. [PMID: 40095335 DOI: 10.1007/s10147-025-02737-x] [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: 09/13/2024] [Accepted: 03/02/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Ramucirumab with either solvent-based or nanoparticle albumin-bound paclitaxel is a standard second-line treatment for advanced gastric cancer. Reportedly, nanoparticle albumin-bound paclitaxel has activated the immune system, but the efficacy of taxane-based agents before nivolumab remains unclear. Therefore, we investigated the prognostic effect of ramucirumab with solvent-based or nanoparticle albumin-bound paclitaxel as second-line therapy, followed by nivolumab as third-line therapy. METHODS This retrospective study enrolled 115 patients with gastric cancer treated with ramucirumab in combination with solvent-based paclitaxel or nanoparticle albumin-bound paclitaxel from 2017 to 2019 at six hospitals. All patients received nivolumab as a third-line therapy. Ramucirumab + solvent-based paclitaxel and ramucirumab + nanoparticle albumin-bound paclitaxel were administered to 57 and 58 patients, respectively. RESULTS The progression-free survival of the ramucirumab + solvent-based paclitaxel group was slightly better than that of the ramucirumab + nanoparticle albumin-bound paclitaxel group but with no statistically significant difference (5.3 months vs. 4.2 months). Contrary, the overall survival of the ramucirumab + nanoparticle albumin-bound paclitaxel group was slightly better than the ramucirumab + solvent-based paclitaxel group but with no statistically significant difference (19.0 months vs. 12.5 months). The multivariate analysis of progression-free survival revealed that ramucirumab + nanoparticle albumin-bound paclitaxel was an independent risk factor for poor prognosis, whereas ramucirumab + nanoparticle albumin-bound paclitaxel was an independent factor for good overall survival. CONCLUSIONS Ramucirumab + nanoparticle albumin-bound paclitaxel may prolong overall survival when administered before nivolumab, despite its limited effect on progression-free survival.
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Affiliation(s)
- Yoshinori Kikuchi
- Department of Clinical Oncology, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yoko Oshima
- Division of General and Gastroenterological Surgery, Department of Surgery (Omori), Toho University, Tokyo, Japan.
| | - Muneharu Fujisaki
- Department of Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Mao Tsuru
- NTT Medical Center Tokyo, Tokyo, Japan
| | - Hidejiro Urakami
- National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Sakae Nagaoka
- Department of Gastroesophageal Surgery, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Nobue Futawatari
- Department of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Satoshi Yajima
- Division of General and Gastroenterological Surgery, Department of Surgery (Omori), Toho University, Tokyo, Japan
| | - Hideaki Shimada
- Division of General and Gastroenterological Surgery, Department of Surgery (Omori), Toho University, Tokyo, Japan
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Wang Y, Lu J, Chong X, Wang C, Chen X, Peng Z, Gu Y, Wang Y, Wang X, Li J, Gong J, Qi C, Yuan J, Lu Z, Lu M, Zhou J, Cao Y, Chen Y, Zhang C, Hou Z, Kou H, Shen L, Zhang X. PD-1 antibody camrelizumab plus apatinib and SOX as first-line treatment in patients with AFP-producing gastric or gastro-esophageal junction adenocarcinoma (CAP 06): a multi-center, single-arm, phase 2 trial. Signal Transduct Target Ther 2025; 10:100. [PMID: 40082418 PMCID: PMC11906745 DOI: 10.1038/s41392-025-02193-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 02/18/2025] [Accepted: 02/25/2025] [Indexed: 03/16/2025] Open
Abstract
Alpha-fetoprotein-producing gastric or gastro-esophageal junction (AFP-G/GEJ) cancer, a rare gastric cancer subtype, exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer. The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown. This multi-center, single-arm, phase 2 trial (ClinicalTrials.gov NCT04609176) evaluated the antitumor activity, safety, and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin (SOX), followed by maintenance treatment with camrelizumab plus apatinib, as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma. Primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 in the full analysis set. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response, time to response, and safety. Between December 4, 2020, and August 4, 2023, 36 patients were enrolled and treated. The trial met its primary endpoint with a confirmed ORR of 66.7% (95% CI: 49.0-81.4). The DCR was 88.9% (95% CI: 73.9-96.9). With a median follow-up of 11.7 months (range: 3.2-37.9), the median PFS reached 7.8 months (95% CI: 4.9-12.3) and the median OS reached 18.0 months (95% CI: 10.5-NR). No new safety concerns were identified. In exploratory analysis, patients with durable clinical benefit exhibited higher pre-treatment (PD-1+) CD8+ T cell densities and effective scores. First-line treatment with camrelizumab plus apatinib and SOX, followed by maintenance treatment with camrelizumab plus apatinib, is effective and safe in AFP-G/GEJ adenocarcinoma. Further studies are necessary to validate these findings.
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Affiliation(s)
- Yakun Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jialin Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaoyi Chong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Chang Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhi Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanhong Gu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Yizhuo Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Xicheng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jifang Gong
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Changsong Qi
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Early Drug Development Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jiajia Yuan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhihao Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ming Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jun Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanshuo Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yang Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Cheng Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhiguo Hou
- Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
| | - Hongyi Kou
- Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Xiaotian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, China.
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11
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Ji X, Wang G, Pan D, Xu S, Lei X. Efficacy and safety of pembrolizumab in advanced gastric and gastroesophageal junction cancer: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:173. [PMID: 40087572 PMCID: PMC11908035 DOI: 10.1186/s12876-025-03754-w] [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: 11/26/2024] [Accepted: 03/03/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Pembrolizumab, a PD-1 inhibitor, has shown potential for treating advanced gastric and gastroesophageal junction (GEJ) cancer. This meta-analysis evaluates its efficacy and safety, alone or combined with chemotherapy, in this population. METHODS A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched up to October 31, 2024. Twelve studies comprising 4,069 patients were included. The primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR), adverse events (AEs), and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Pembrolizumab combined with chemotherapy significantly improved OS (MD = 1.92 months; 95% CI: 0.94 to 2.91) and ORR (MD = 11.05%; 95% CI: 6.29 to 15.82) compared to chemotherapy alone. Pembrolizumab monotherapy did not show a significant effect on OS (MD = 0.24 months; 95% CI: -1.15 to 1.63) and was associated with a significant reduction in PFS (MD = -2.28 months; 95% CI: -2.85 to -1.71) compared to chemotherapy alone. For safety, pembrolizumab monotherapy significantly reduced the risk of AEs (OR = 0.68; 95% CI: 0.57 to 0.81) and grade ≥ 3 AEs (OR = 0.39; 95% CI: 0.30 to 0.51) compared to chemotherapy. Pembrolizumab combined with chemotherapy did not significantly alter the risk of AEs (OR = 1.01; 95% CI: 0.90 to 1.13) or grade ≥ 3 AEs (OR = 1.12; 95% CI: 0.99 to 1.27) compared to chemotherapy alone. CONCLUSION Pembrolizumab combined with chemotherapy improves survival and response rates with a manageable safety profile in advanced gastric and GEJ cancers. Monotherapy shows limited efficacy, highlighting the need for combination strategies and patient selection.
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Affiliation(s)
- Xiaoying Ji
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Guoping Wang
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Dandan Pan
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Shanxia Xu
- Quzhou Zhong Da Lang Yuan Nursing Home, Quzhou, Zhejiang, 324000, China
| | - Xinming Lei
- The Quzhou Afliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China.
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12
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Ziogou A, Giannakodimos A, Giannakodimos I, Schizas D, Charalampakis N. Effect of Helicobacter Pylori infection on immunotherapy for gastrointestinal cancer: a narrative review. Immunotherapy 2025:1-14. [PMID: 40087147 DOI: 10.1080/1750743x.2025.2479410] [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: 09/17/2024] [Accepted: 03/11/2025] [Indexed: 03/16/2025] Open
Abstract
Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.
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Affiliation(s)
- Afroditi Ziogou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, Greece
| | | | - Ilias Giannakodimos
- Departement of Urology, Attikon University Hospital of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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13
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Kang YK, Kim HD, Cho H, Park YS, Lee JS, Ryu MH. Phase 2 study of neoadjuvant durvalumab plus docetaxel, oxaliplatin, and S-1 with surgery and adjuvant durvalumab plus S-1 for resectable locally advanced gastric cancer. J Immunother Cancer 2025; 13:e010635. [PMID: 40081945 PMCID: PMC11907044 DOI: 10.1136/jitc-2024-010635] [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] [Accepted: 02/01/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Based on the phase 3 PRODIGY study, neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) have emerged as a viable treatment option for Asian patients with resectable locally advanced gastric cancer (LAGC). This phase 2 study evaluated the efficacy and safety of combining neoadjuvant durvalumab with DOS, followed by surgery and adjuvant durvalumab plus S-1 chemotherapy, for resectable LAGC. METHODS Patients with LAGC with cT2/3N+or cT4Nany tumors were enrolled in this study. Patients with proficient mismatch repair protein (pMMR) tumors received three cycles of neoadjuvant durvalumab plus DOS, administered every 3 weeks, followed by surgery and adjuvant S-1 plus durvalumab (main study arm). The primary endpoints were the rate of pathologic complete regression (pCR) and safety. An exploratory arm evaluated patients with deficient mismatch repair protein (dMMR) tumors, who received three cycles of neoadjuvant durvalumab and tremelimumab, followed by surgery and adjuvant durvalumab. RESULTS In the main study arm, 50 pMMR patients were enrolled, and received at least one dose of neoadjuvant treatment. The median age was 63 years, with 72.0% being men. 18 and 32 patients presented with clinical stage II and III tumors, respectively. 49 (98.0%) underwent surgery, with 45 achieving R0 resection. A pCR rate of 30.0% was observed, meeting the prespecified primary efficacy endpoint. With a median follow-up of 21.8 months, the 3-year progression-free survival and overall survival rates were 69.9% and 88.1%, respectively. 10% of patients experienced predefined unacceptable severe toxicities, including febrile neutropenia (n=3) and persistent G4 neutropenia (n=2) lasting more than 7 days, thereby meeting the primary safety endpoint. Nine patients with dMMR tumors were enrolled in the exploratory arm. All nine underwent surgery, with a pCR rate of 22.2%. CONCLUSIONS This study met its primary efficacy and safety endpoints. The combination of neoadjuvant durvalumab plus DOS, followed by surgery and adjuvant durvalumab plus S-1 chemotherapy, warrants further investigation in a phase 3 trial for Asian patients with LAGC. CLINICAL TRIAL INFORMATION 04221555.
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Affiliation(s)
- Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Hyungwoo Cho
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea (the Republic of)
| | - Jong Seok Lee
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
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14
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Moehler M, Oh DY, Kato K, Arkenau T, Tabernero J, Lee KW, Rha SY, Hirano H, Spigel D, Yamaguchi K, Wyrwicz L, Disel U, Pazo-Cid RA, Fornaro L, Xu Y, Sheng T, Yang S, Kadva A, Cruz-Correa M, Xu RH. First-Line Tislelizumab Plus Chemotherapy for Advanced Gastric Cancer with Programmed Death-Ligand 1 Expression ≥ 1%: A Retrospective Analysis of RATIONALE-305. Adv Ther 2025:10.1007/s12325-025-03133-7. [PMID: 40075025 DOI: 10.1007/s12325-025-03133-7] [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: 11/27/2024] [Accepted: 01/31/2025] [Indexed: 03/14/2025]
Abstract
INTRODUCTION Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5%. The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against first-line treatment with programmed cell death protein-1 inhibitors in this setting in patients with a PD-L1 combined positive score < 1 or TAP score < 1%, due to an unfavorable benefit-risk profile. Thus, we retrospectively analyzed data from RATIONALE-305 in patients with a PD-L1 TAP score ≥ 1%. METHODS Adult patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC were randomized to tislelizumab 200 mg or placebo with ICC every 3 weeks. Efficacy and safety outcomes of tislelizumab plus ICC versus placebo plus ICC were retrospectively assessed in those with a PD-L1 TAP score ≥ 1%. RESULTS At the final analysis cutoff (February 28, 2023), 432 patients received tislelizumab plus ICC and 453 received placebo plus ICC, and had a PD-L1 TAP score ≥ 1%. Clinically meaningful improvements to OS were observed with tislelizumab plus ICC compared with placebo plus ICC [15.0 months (95% confidence interval [CI] 13.3-16.7) vs. 12.8 months (95% CI 12.1-14.1), respectively; stratified hazard ratio 0.77 (95% CI 0.67-0.90)]. Progression-free survival, overall response rate, duration of response, and disease control rate, were also improved. OS improvements were maintained at a 3-year data cutoff (February 28, 2024). Tislelizumab plus ICC had an acceptable safety profile with no new safety signals. CONCLUSIONS Tislelizumab plus ICC is an effective and tolerable first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC with a PD-L1 TAP score ≥ 1%. TRIAL REGISTRATION NUMBER NCT03777657.
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Affiliation(s)
- Markus Moehler
- Department of Medicine, University Medical Center of Johannes Gutenberg University, Mainz, Germany
| | - Do-Youn Oh
- Department of Hemato-Oncology, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tobias Arkenau
- Department of Oncology, Sarah Cannon Research, London, UK
| | - Josep Tabernero
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea
| | - Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - David Spigel
- Department of Oncology, Tennessee Oncology, Nashville, TN, USA
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Lucjan Wyrwicz
- Department of Oncology and Radiotherapy, Maria Sklodowska-Curie National Cancer Research Institute, Warsaw, Poland
| | - Umut Disel
- Department of Medical Oncology, Acibadem Adana Hospital, Adana, Turkey
| | - Roberto A Pazo-Cid
- Medical Oncology Department, Hospital Universitario Miguel Servet, Saragossa, Spain
| | - Lorenzo Fornaro
- Department of Medical Oncology, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Yaling Xu
- Clinical Development, BeiGene (Shanghai) Co., Ltd, Shanghai, China
| | - Tao Sheng
- Biostatistics, BeiGene USA, Inc., Emeryville, CA, USA
| | - Silu Yang
- Clinical Biomarkers, BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Alysha Kadva
- Clinical Development, BeiGene USA, Inc., San Mateo, CA, USA
| | - Marcia Cruz-Correa
- School of Medicine, University of Puerto Rico, Pan American Center for Oncology Trials, San Juan, Puerto Rico
| | - Rui-Hua Xu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng East Road, Guangzhou, 510060, People's Republic of China.
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15
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Alsina Maqueda M, Teijo Quintáns A, Cuatrecasas M, Fernández Aceñero MJ, Fernández Montes A, Gómez Martín C, Jiménez Fonseca P, Martínez Ciarpaglini C, Rivera Herrero F, Iglesias Coma M. Biomarkers in gastroesophageal cancer 2025: an updated consensus statement by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). Clin Transl Oncol 2025:10.1007/s12094-025-03865-6. [PMID: 40072752 DOI: 10.1007/s12094-025-03865-6] [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: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 03/14/2025]
Abstract
Gastroesophageal carcinomas, including gastroesophageal adenocarcinoma (GEA) and esophageal squamous cell carcinoma (ESCC), pose a global health challenge due to their heterogeneity. The approach to diagnosis and treatment should first differentiate between GEA and ESCC. Over the past decade, therapies for metastatic or advanced GEA/ESCC have expanded, with several new therapeutic targets alongside trastuzumab for metastatic HER2-positive GEA. Four key biomarkers are essential for targeted therapy: HER2 overexpression/amplification, deficient mismatch repair/microsatellite instability (dMMR/MSI), PD-L1, and Claudin18.2 expression. Immunohistochemistry is the recommended method for these biomarkers evaluation. In addition, the assessment of biomarkers like FGFR2b is likely to become routine in the near future. Experts from the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) have formed a consensus to optimize biomarker detection and usage in clinical practice. Their recommendations aim to improve personalized treatment strategies for GEA and ESCC patients, integrating new diagnostic insights into routine care.
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Affiliation(s)
- Maria Alsina Maqueda
- Medical Oncology Department, Unidad de Oncología Médica Traslacional, Hospital Universitario de Navarra, Navarrabiomed - Centro de Investigación Sanitaria de Navarra, Pamplona, Spain.
| | - Ana Teijo Quintáns
- Pathology Department, Gastrointestinal and Neuroendocrine Tumors Research Group, Hospital Universitario 12 de Octubre, Research Institute (Imas12), Madrid, Spain
| | - Miriam Cuatrecasas
- Pathology Department, Hospital Clinic de Barcelona, Biomedical Research Institute IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Maria Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, Surgical Pathology Department, Hospital Clínico Universitario San Carlos, nstituto de Investigación Sanitaria Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain
- , Madrid, Spain
| | - Ana Fernández Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Carlos Gómez Martín
- Gastrointestinal Cancer and Early Clinical-Translational Research Units, Medical Oncology Division, 12 de Octubre University Hospital, Madrid, Spain
| | - Paula Jiménez Fonseca
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Carolina Martínez Ciarpaglini
- Pathology Department, Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
| | - Fernando Rivera Herrero
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - Mar Iglesias Coma
- Pathology Department, Hospital del Mar, Pompeu Fabra University, Hospital del Mar Research Institute, Barcelona, Spain.
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16
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Tian Y, Shi W, Wang J, Zhang W, Xia L, Gao L, Qiu H, Yu Z, Zhang Y, Chen Y. Exosomal PD-L1 and lactate versus tissue PD-L1 as biomarkers for clinical outcomes of PD-1 Blockade plus chemotherapy in metastatic esophagogastric signet ring cell carcinoma. Exp Hematol Oncol 2025; 14:34. [PMID: 40075410 PMCID: PMC11905711 DOI: 10.1186/s40164-025-00615-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/15/2025] [Indexed: 03/14/2025] Open
Abstract
In this investigator-initiated, prospective, exploratory study, biomarkers predictive of clinical outcomes of first-line immune checkpoint inhibitor (ICI, nivolumab or pembrolizumab) plus XELOX(oxaliplatin and capecitabine) were identified in human epidermal growth factor receptor 2 (HER2)-negative patients with metastatic esophagogastric signet ring cell carcinoma. The findings showed an objective response rate (ORR) of 51.5% and a disease control rate of 86.8%, the median progression-free survival (PFS) for the entire cohort was 6.63 months. PD-L1 expression level in tumor tissues could not identify a high PD-L1 group that significantly benefited from ICI plus XELOX in terms of the ORR and PFS. By contrast, the patients expressing low exosomal PD-L1 or lactate in peripheral blood plasma before treatment initiation demonstrated a significantly increased ORR and prolonged PFS compared to that with high exosomal PD-L1 or lactate, patients with combining predictor of exosomal PD-L1 and lactate lower than - 0.249 was associated with a better ORR (82.1% vs. 30.0%, P < 0.001) and a longer median PFS (13.83 vs. 5.50 months, P < 0.001) compared to those with combining predictor ≥-0.249. The results also revealed that exosomal PD-L1 levels in peripheral blood plasma before the treatment were significantly correlated with the frequency of CD8+ T cells (P = 0.007), and in patients after receiving ICI plus XELOX, high exosomal PD-L1 level was associated with more PD-1+ Treg cells, high exosomal lactate level was associated with less CD8+ T cells and more Treg cells. Thus, the levels of PD-L1 and lactate in exosomes may affect the balance between Treg cells and CD8+T cells, leading to treatment resistance to ICI plus XELOX. Compared to PD-L1 expression level in tumor tissues, exosomal PD-L1 and lactate levels could more accurately predict clinical outcomes of HER2-negative patients with metastatic esophagogastric signet ring cell carcinoma receiving first-line PD-1 blockade plus chemotherapy.
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Affiliation(s)
- Yuanyuan Tian
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Oncology, The First Affiliated Hospital of Henan University, No. 357, West Gate Street, Kaifeng, 475000, China
| | - Wei Shi
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing Wang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wenjie Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lingling Xia
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hu Qiu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenhua Yu
- School of Physics Science and Technology, Wuhan University, Wuhan, China
| | - Yongfeng Zhang
- Pathology Department, The First Affiliated Hospital of Henan University of Science and Technology, 24, Jinghua Road, 471000, Luoyang, China.
| | - Yongshun Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
- Cancer Center, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Shenzhen, 518033, China.
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17
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Chen HZ, Kim NH, Nishizaki D, Nesline MK, Conroy JM, DePietro P, Pabla S, Kato S, Kurzrock R. PD-1 transcriptomic landscape across cancers and implications for immune checkpoint blockade outcome. NPJ Genom Med 2025; 10:21. [PMID: 40069238 PMCID: PMC11897377 DOI: 10.1038/s41525-025-00465-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/20/2025] [Indexed: 03/15/2025] Open
Abstract
Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor and a target for cancer immune checkpoint inhibitors (ICI). We investigated PD-1 transcript expression across cancer types and its correlations to clinical outcomes. Using a reference population, PD-1 expression was calculated as percentiles in 489 of 514 patients (31 cancer types) with advanced/metastatic disease. PD-1 RNA expression varied across and within cancer types; pancreatic and liver/bile duct malignancies displayed the highest rates of high PD-1 (21.82% and 21.05%, respectively). Elevated CTLA-4, LAG-3, and TIGIT RNA expression were independently correlated with high PD-1. Although high PD-1 was not associated with outcome in immunotherapy-naïve patients (n = 272), in patients who received ICIs (n = 217), high PD-1 transcript expression was independently correlated with prolonged survival (hazard ratio 0.40; 95%CI, 0.18-0.92). This study identifies PD-1 as an important biomarker in predicting ICI outcomes, and advocates for comprehensive immunogenomic profiling in cancer management.
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Affiliation(s)
- Hui-Zi Chen
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
| | - Na Hyun Kim
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
| | - Daisuke Nishizaki
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | | | | | | | | | - Shumei Kato
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Razelle Kurzrock
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
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18
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Kim HD, Jung S, Bang YH, Kim J, Kim HJ, Lee HE, Hyung J, Yoo C, Kim WT, Yoon MJ, Lee H, Ryou JH, Jeon H, Yanai H, Lee JS, Lee G, Ryu MH. Blood TCTP as a potential biomarker associated with immunosuppressive features and poor clinical outcomes in metastatic gastric cancer. J Immunother Cancer 2025; 13:e010455. [PMID: 40032602 DOI: 10.1136/jitc-2024-010455] [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] [Accepted: 02/16/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND No established biomarker exists for specific myeloid cell populations or in gastric cancer. This study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with an immune checkpoint inhibitor and/or cytotoxic chemotherapy. METHODS Plasma samples were prospectively collected from the cohorts of patients with gastric cancer treated with first-line fluoropyrimidine plus platinum chemotherapy (n=143, cohort 1) and third-line nivolumab (n=165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. External single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics datasets were employed to validate the findings. RESULTS Patients with high plasma TCTP levels (TCTP-high group) exhibited poor progression-free survival (PFS) and overall survival (OS) with first-line chemotherapy compared with those with low levels (TCTP-low group) in cohort 1 (HR: 1.73 for PFS; 1.77 for OS). In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/natural killer (NK) cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. scRNA-seq analyses identified a myeloid subset with high TPT1 (encoding TCTP) expression and TCTP-related molecules, enriched with inhibitory myeloid inflammation gene signatures and providing inhibitory signals to T/NK cells (Macrophage-chemokine). Spatial transcriptomics analyses revealed a tumor-cell-enriched cluster co-localized with the Macrophage-chemokine subset, which exhibited the highest TPT1 expression and a positive correlation between its abundance and average TPT1 levels. In nivolumab-treated patients (cohort 2), the high TCTP group was associated with poor survival outcomes (HR: 1.39 for PFS; 1.47 for OS). CONCLUSIONS Plasma TCTP is a prognostic biomarker, reflecting clinically relevant immunosuppressive myeloid signals in patients with gastric cancer.
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Affiliation(s)
- Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Seyoung Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of)
| | - Yeong Hak Bang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Jiae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Hee Jeong Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Hyung Eun Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Jaewon Hyung
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | | | | | | | | | | | - Hideyuki Yanai
- Department of Inflammology, The University of Tokyo, Bunkyo-ku, Japan
| | - Jeong Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of)
| | | | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
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19
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He Y, Hong Q, Chen S, Zhou J, Qiu S. Reprogramming tumor-associated macrophages in gastric cancer: a pathway to enhanced immunotherapy. Front Immunol 2025; 16:1558091. [PMID: 40098971 PMCID: PMC11911521 DOI: 10.3389/fimmu.2025.1558091] [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: 01/09/2025] [Accepted: 02/12/2025] [Indexed: 03/19/2025] Open
Abstract
Gastric cancer (GC) remains a significant global health concern due to its poor prognosis and limited therapeutic options, particularly in advanced stages. Tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), plays a key role in tumor progression, immune evasion, and therapy resistance. TAMs exhibit plasticity, shifting between pro-inflammatory M1 and immunosuppressive M2 phenotypes, with the latter predominating in GC and contributing to poor outcomes. Recent therapeutic advancements focus on targeting TAMs, including inhibiting M2 polarization, reprogramming TAMs to M1 phenotypes, and combining TAM-targeted approaches with immune checkpoint inhibitors. Innovations in nanotechnology, metabolic reprogramming, and targeting key pathways such as interleukin-6 and C-C motif ligand 2/C-C motif chemokine receptor 2 further enhance these strategies. However, challenges remain, including the spatial and functional heterogeneity of TAMs within the TME and the need for selective targeting to avoid disrupting immune homeostasis. Ongoing research on TAM origins, functions, and interactions within the TME is crucial for developing precise and effective therapies. These advances hold promise not only for improving outcomes in GC but also for addressing other cancers with similarly complex microenvironments.
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Affiliation(s)
| | | | | | | | - Shengliang Qiu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang
Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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20
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Cammarota A, Woodford R, Smyth EC. Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight. Drugs 2025; 85:361-383. [PMID: 39843758 DOI: 10.1007/s40265-024-02132-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/24/2025]
Abstract
The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.
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Affiliation(s)
- Antonella Cammarota
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- Department of Medical Sciences, Humanitas University, Via Rita Levi Montalcini, Pieve Emanuele, Milan, Italy
| | - Rachel Woodford
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- National Health and Medical Research Council Clinical Trials Centre (NHMRC CTC), University of Sydney, Parramatta Road, Camperdown, Australia
| | - Elizabeth C Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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21
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Komori A, Hironaka S, Kadowaki S, Mitani S, Furuta M, Kawakami T, Makiyama A, Takegawa N, Sugiyama K, Hirano H, Ando T, Matsushima T, Chida A, Kashiwada T, Komoda M, Matsumoto T, Oda H, Yabusaki H, Kawakami H, Yamazaki K, Boku N, Hyodo I, Yoshimura K, Muro K. Prevalence and clinicopathological features of microsatellite instability-high metastatic or recurrent gastric and esophagogastric junction cancer: WJOG13320GPS. Gastric Cancer 2025; 28:301-308. [PMID: 39738793 DOI: 10.1007/s10120-024-01579-2] [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: 10/01/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Microsatellite instability (MSI)-high tumors represent a distinct, small-fraction subtype in esophagogastric junction cancer or gastric cancer (GC), yet their clinical significance remains poorly understood. This study aimed to investigate the prevalence and clinicopathological features of chemotherapy-naïve metastatic or recurrent MSI-high GC as a prescreening study for a phase II trial of nivolumab plus ipilimumab. METHODS Key inclusion criteria included metastatic or recurrent adenocarcinoma of GC, ECOG performance status of 0 or 1, and no prior systemic therapy for metastatic or recurrent disease. MSI status was tested using multiplex PCR fragment analysis (MSI Testing Kit, FALCO). The primary endpoint was the prevalence of MSI-high GC. RESULTS Between October 2020 and October 2022, 930 eligible patients from 75 centers in Japan were analyzed. The prevalence of MSI-high GC was 5.6% (95% CI 4.2-7.3). MSI-high GC was more frequently observed in females than males (9.6% vs 3.8%, p < 0.001), patients aged ≥ 70 years compared to those < 70 years (8.0% vs 2.8%, p < 0.001), in the lower stomach than other locations (10.5% vs 3.2%, p < 0.001), HER2-negative tumors than HER2-positive tumors (6.5% vs 1.8%, p = 0.02), and in patients without liver metastasis than those with liver metastasis (6.9% vs 2.2%, p = 0.004). CONCLUSIONS The prevalence of MSI-high tumors among chemotherapy-naïve patients with unresectable GC was 5.6%. These tumors were associated with female sex, older age, lower stomach, HER2-negative, and absence of liver metastasis. These findings would help assuming MSI-high tumors and may have significant implications for clinical practice and studies targeting this GC subtype.
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Affiliation(s)
- Azusa Komori
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Shuichi Hironaka
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Mitaka, Japan.
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Seiichiro Mitani
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Mitsuhiro Furuta
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Takeshi Kawakami
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Naoki Takegawa
- Department of Gastroenterology, Hyogo Cancer Center, Akashi, Japan
| | - Keiji Sugiyama
- Department of Medical Oncology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
| | - Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji Campus, Chuo-Ku, Japan
| | - Takayuki Ando
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Tomohiro Matsushima
- Department of Gastroenterology, Saitama Prefectural Cancer Center, Ina, Japan
| | - Akihiko Chida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tomomi Kashiwada
- Department of Medical Oncology, Saga-Ken Medical Centre Koseikan, Saga, Japan
| | - Masato Komoda
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Toshihiko Matsumoto
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Hisanobu Oda
- Division of Integrative Medical Oncology, Saiseikai Kumamoto Hospital, Kumamoto, Japan
| | - Hiroshi Yabusaki
- Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Narikazu Boku
- Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Kenichi Yoshimura
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
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22
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de la Fouchardière C, Cammarota A, Svrcek M, Alsina M, Fleitas-Kanonnikoff T, Lordick Obermannová R, Wagner AD, Yap Wei Ting D, Enea D, Petrillo A, Smyth EC. How do I treat dMMR/MSI gastro-oesophageal adenocarcinoma in 2025? A position paper from the EORTC-GITCG gastro-esophageal task force. Cancer Treat Rev 2025; 134:102890. [PMID: 39933210 DOI: 10.1016/j.ctrv.2025.102890] [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: 12/16/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
In less than a decade, immune checkpoint inhibitors (ICIs) have transformed the management of mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI) cancers. However, beyond colorectal cancer (CRC), much of the evidence is mostly derived from non-randomized phase II studies or post-hoc analyses of broader clinical trials. dMMR/MSI tumours represent a specific subgroup of gastro-esophageal adenocarcinomas (GEA), accounting for approximately 9 % of cases, with a higher prevalence in early-stage compared to advanced-stage disease and older female patients. These tumours are predominantly sporadic, often linked to MLH1 promoter methylation, and rarely exhibit HER2 overexpression/ERBB2 amplification or other oncogenic drivers. The treatment landscape for early stage dMMR/MSI GEA is likely to change substantially soon, as ICIs have shown high pathological complete response (pCR) rates in small phase II trials, raising questions on optimisation of neoadjuvant therapy, and paving the way for organ preservation. The standard of treatment for untreated patients with advanced dMMR/MSI GEA is chemotherapy + ICI irrespectively of PDL-1 status. However, the role of chemotherapy-free regimen consisting of CTLA-4 plus PD-1 inhibitors remains undetermined. This review addresses these and other emerging questions, offering expert opinions and insights into the future therapeutic landscape for dMMR/MSI GEA.
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Affiliation(s)
- Christelle de la Fouchardière
- Institut PAOLI-CALMETTES, 232 Boulevard Sainte-Marguerite 13009, Marseille, France; Unicancer GI (UCGI) Group, Paris, France; EORTC-GITC Group, Brussels, Belgium.
| | - Antonella Cammarota
- EORTC-GITC Group, Brussels, Belgium; Hepatobiliary Immunopathology Lab, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Magali Svrcek
- Sorbonne Université, AP-HP, Saint-Antoine Hospital, Department of Pathology, France; LIMICS, UMRS 1142, Campus des Cordeliers 75006, Paris, France
| | - Maria Alsina
- EORTC-GITC Group, Brussels, Belgium; Hospital Universitario de Navarra, Navarrabiomed - IdiSNA, c. de Irunlarrea 3 31008, Pamplona, Spain
| | - Tania Fleitas-Kanonnikoff
- EORTC-GITC Group, Brussels, Belgium; Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain
| | - Radka Lordick Obermannová
- EORTC-GITC Group, Brussels, Belgium; Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Faculty of Medicine, Masaryk University, Czech Republic
| | - Anna Dorothea Wagner
- EORTC-GITC Group, Brussels, Belgium; Anna Dorothea Wagner, Department of Oncology, Division of Medical Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), 1011, Lausanne, Switzerland
| | | | - Diana Enea
- Sorbonne Université, AP-HP, Saint-Antoine Hospital, Department of Pathology, France
| | - Angelica Petrillo
- EORTC-GITC Group, Brussels, Belgium; Medical Oncology Unit, Ospedale del Mare, Naples, Italy
| | - Elizabeth C Smyth
- EORTC-GITC Group, Brussels, Belgium; Oxford NIHRBiomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK
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Abe H, Urabe M, Yagi K, Yamashita H, Seto Y, Ushiku T. Expression of therapy target molecules in esophagogastric junction and Barrett's adenocarcinoma. Gastric Cancer 2025; 28:264-274. [PMID: 39663311 DOI: 10.1007/s10120-024-01573-8] [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: 07/25/2024] [Accepted: 11/30/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND Recently, novel molecular targeted therapies have been developed for gastric and esophageal adenocarcinomas. We examined the status of therapeutic target molecules in esophagogastric junction (EGJ) and Barrett's adenocarcinoma. METHODS Tissue microarrays were constructed from 114 cases of non-Barrett's EGJ adenocarcinoma and 30 cases of Barrett's adenocarcinoma. Immunohistochemistry for mismatch repair proteins, PD-L1, HER2, CLDN18, FGFR2b, and EBER-ISH was performed. When HER2 immunohistochemistry was 2 + , gene amplification was examined using in situ hybridization. RESULTS EBER positivity, mismatch repair deficiency, PD-L1 combined positive score (CPS) ≥ 1, CLDN18 expression ≥ 75%, FGFR2b expression, and HER2 positivity were observed in 7 (6.1%), 11 (9.6%), 70 (61.4%), 38 (33.3%), 6 (5.3%), and 11 (9.6%) cases of EGJ adenocarcinoma as well as in 0 (0%), 0 (0%), 23 (76.7%), 7 (23.3%), 2 (6.7%), and 6 (20.0%) cases of Barrett's adenocarcinoma, respectively. PD-L1 CPS ≥ 1 cases had longer recurrence-free survival (P = 0.001) and overall survival (P = 0.003) than CPS < 1 cases. Other target molecules were not associated with survival. A total of 93/114 (81.6%) cases of EGJ adenocarcinoma and 26/30 (86.7%) cases of Barrett's adenocarcinomas expressed at least one target molecule. CONCLUSIONS Most EGJ and Barrett's adenocarcinomas may be eligible for molecular targeted therapy. Appropriate patient stratification based on these molecular tests will be important for precision medicine of the EGJ and Barrett's adenocarcinoma.
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Affiliation(s)
- Hiroyuki Abe
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Masayuki Urabe
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Gastrointestinal Surgery Division, Department of Surgery, Japanese Red Cross Omori Hospital, Tokyo, Japan
| | - Koichi Yagi
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroharu Yamashita
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Esophageal/Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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24
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Jiang W, Zhang B, Xu J, Xue L, Wang L. Current status and perspectives of esophageal cancer: a comprehensive review. Cancer Commun (Lond) 2025; 45:281-331. [PMID: 39723635 PMCID: PMC11947622 DOI: 10.1002/cac2.12645] [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: 07/01/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.
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Affiliation(s)
- Wei Jiang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
| | - Bo Zhang
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jiaqi Xu
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Liyan Xue
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Luhua Wang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
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25
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He J, Zhang B, Zhou S, Yang Y, Han Z, Wu T, Qiao Q, Yang H, He X, Wang N. Phase II study of perioperative camrelizumab and XELOX for locally advanced gastric or gastroesophageal junction adenocarcinoma. Cancer Sci 2025; 116:736-743. [PMID: 39656600 PMCID: PMC11875781 DOI: 10.1111/cas.16425] [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: 05/17/2024] [Revised: 11/15/2024] [Accepted: 11/24/2024] [Indexed: 12/17/2024] Open
Abstract
Immune checkpoint inhibitors combined with chemotherapy have shown promising efficacy in treating gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the neoadjuvant setting. This phase II trial (NCT05715632) aimed to investigate the efficacy and safety of perioperative camrelizumab plus XELOX in patients with locally advanced G/GEJ adenocarcinoma. Treatment-naive patients with cT3-4aN1-3 M0 resectable locally advanced G/GEJ adenocarcinoma were recruited to receive camrelizumab (200 mg, intravenously) on Day 1 combined with XELOX (oxaliplatin at 130 mg/m2 on Day 1 and capecitabine at 1000 mg/m2 on Days 1-14) every 3 weeks for four cycles, followed by surgery and adjuvant camrelizumab combined with XELOX every 3 weeks for four cycles. The primary endpoint was the pathological complete response (pCR; ypT0N0) rate. From September 2020 to January 2023, 46 patients were enrolled, and all patients completed neoadjuvant therapy. Among them, 43 underwent D2 resection. In the intention-to-treat population, pCR was achieved in nine patients (19.6%, 95% confidence interval [CI]: 9.9%-34.4%), and the major pathological response was achieved in 25 patients (54.3%, 95% CI: 39.2%-68.8%). The objective response rate was 69.6%, of which 12 patients achieved a complete response and 20 patients achieved a partial response. The 1-year event-free survival and disease-free survival rates were both 93.1%. Treatment-related adverse events (TRAEs) occurred in 42 (91.3%) patients, and grade 3 TRAEs occurred in nine (19.6%) patients. No grades 4-5 TRAEs were observed. Perioperative camrelizumab combined with XELOX showed promising pathological response with an acceptable safety profile in patients with resectable locally advanced G/GEJ adenocarcinoma.
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Affiliation(s)
- Jiaxing He
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Bo Zhang
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Shuai Zhou
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Ying Yang
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Zhuo Han
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Tao Wu
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Qing Qiao
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Haicheng Yang
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Xianli He
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
| | - Nan Wang
- Department of General SurgeryAir Force Medical University Tangdu HospitalXi'anChina
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26
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Su R, Sun X, Luo Y, Gu L, Wang F, Dong A, Yamamoto M, Tsukamoto T, Nomura S, Zhao Z, Dai C, Deng G, Zhuang B, He Y, Zhang C, Yin S. SUSD2 + cancer-associated fibroblasts in gastric cancer mediate the effect of immunosuppression and predict overall survival and the effectiveness of neoadjuvant immunotherapy. Gastric Cancer 2025; 28:245-263. [PMID: 39656339 DOI: 10.1007/s10120-024-01572-9] [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: 07/24/2024] [Accepted: 11/25/2024] [Indexed: 02/21/2025]
Abstract
BACKGROUND The expression patterns and functions of Sushi Domain Containing 2 (SUSD2) differ among various malignancies. This research aims to investigate the expression of SUSD2 and the role of the SUSD2+ cancer-associated fibroblasts (CAFs) for immunotherapy in gastric cancer. METHODS The expression of SUSD2 and specific markers (CD4, CD8, PD-1, TIGIT, TIM-3 and CD163) was determined using immunohistochemistry and multiplex immunofluorescence (mIHC) on paraffin sections. Flow cytometry and western blot were used to assess the expression of SUSD2 in fibroblasts from fresh samples. Also, analysis of single-cell and bulk RNA sequencing was employed to confirm the presence and characterize the function of SUSD2+ CAFs. The predictive power of indicators for neoadjuvant immunotherapy was evaluated via ROC curve analysis. Animal experiment was employed to validate the immunosuppressive effect of SUSD2+ CAFs. RESULTS SUSD2 is mainly expressed on fibroblasts within the tumors and the high infiltration of SUSD2+ CAFs went together with a poor survival and a more advanced tumor stage. Significantly, the joint use of SUSD2+ CAFs and CD8+ T cells demonstrated a remarkable ability to predict the efficacy of neoadjuvant immunotherapy superior to PD-L1 combined positive score. High SUSD2+ CAFs was correlated with resistance to immunotherapy as well as low CD8+ T infiltration and high exhausted T cell infiltration. CONCLUSIONS We have identified a novel subset of CAFs that could predict the survival and response to neoadjuvant immunotherapy of patients. The SUSD2+ CAFs have the potential to serve as a predictive biomarker and a promising target for immunotherapy.
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Affiliation(s)
- Rishun Su
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xuezeng Sun
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Yusheng Luo
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Liang Gu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Fulin Wang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Aoran Dong
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Masami Yamamoto
- Laboratory of Physiological Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Tetsuya Tsukamoto
- Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Sachiyo Nomura
- Department of Clinical Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
| | - Zhenzhen Zhao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Chen Dai
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Guofei Deng
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Baoding Zhuang
- Hepatic-Biliary-Pancreatic Surgery, The Second People's Hospital of Foshan, Foshan, Guangdong Province, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Songcheng Yin
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
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Abe H, Kuwata T, Kushima R, Ushiku T. Nationwide survey on HER2 and PD-L1 testing practices in gastric cancer across Japan. Gastric Cancer 2025; 28:294-300. [PMID: 39656340 PMCID: PMC11842516 DOI: 10.1007/s10120-024-01571-w] [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: 08/21/2024] [Accepted: 11/24/2024] [Indexed: 02/21/2025]
Abstract
BACKGROUND Since HER2 and PD-L1 testing are key to selecting drugs for first-line treatments in advanced gastric cancer, evaluating differences in these tests among institutions is necessary to standardize treatment. METHODS A questionnaire survey was conducted targeting institutions certified by the Japanese Gastric Cancer Association. RESULTS Responses were obtained from 155 institutions. Most institutions performed HER2 testing in-house, while PD-L1 tests were largely outsourced. HER2 scores and PD-L1 CPS rates showed greater variability across institutions than anticipated. In the pre-analytic phase, 10% neutral buffered formalin was commonly used, with fixation practices generally following guidelines. Overall, the impact of fixation-related factors was limited, but in surgical specimens, longer fixation was associated with a higher proportion of score 0/1+ and a lower proportion of score 3+. When examining HER2 scores by institution, if a particular score had a high (or low) frequency in biopsy, the same trend was also seen in surgical specimens. CONCLUSIONS These findings suggest that not only factors related to specimen preparation, but also biases in evaluation criteria among pathologists may contribute to the significant variability among institutions. Standardization of pre- and post-analytic phases, coupled with appropriate training, is essential to achieve consistent gastric cancer therapy.
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Affiliation(s)
- Hiroyuki Abe
- Japanese Gastric Cancer Association, Kyoto, Japan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takeshi Kuwata
- Japanese Gastric Cancer Association, Kyoto, Japan
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ryoji Kushima
- Japanese Gastric Cancer Association, Kyoto, Japan
- Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Tetsuo Ushiku
- Japanese Gastric Cancer Association, Kyoto, Japan.
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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28
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Dienstmann R, Ruiz-García E, Alsina M, Ruiz-Pace F, Groen-van Schooten TS, Martínez-Ciarpaglini C, Fernández-Figueroa EA, Herrera-Goepfert R, Díaz-Romero C, Lino-Silva L, Hernandez-Guerrero AI, Valdez-Reyes NM, León-Takahashi A, Falcón-Martínez JC, Pouw RE, Romero S, Villagrasa R, Cabeza-Segura M, Alarcón-Molero L, Jimenez-Martí E, Miralles A, Boggino H, Gauna C, Pereira R, Lezcano H, Cantero D, Vivancos A, Matito J, Martin A, Gómez M, Castillo E, Vila M, Ferreira RM, Barros R, Santos-Antunes J, Mendes-Rocha M, Costa A, Riquelme E, Roa JC, Latorre G, Freile B, Caro L, Esteso F, O'Connor J, Riquelme A, Owen G, Garrido M, Diez-García M, Figueiredo C, Caballero C, Lordick F, Farrés J, Derks S, Carneiro F, Cervantes A, Fleitas T. Integrated clinico-molecular analysis of gastric cancer in European and Latin American populations: LEGACY project. ESMO Open 2025; 10:104482. [PMID: 40036904 PMCID: PMC11926697 DOI: 10.1016/j.esmoop.2025.104482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is recognized for intrinsic heterogeneity, although it is similarly approached in Europe and Latin America (LATAM). The LEGACY project aimed to deepen GC molecular understanding through multi-omics analysis in Europe and LATAM GC samples. PATIENTS AND METHODS Tumor samples were centrally reviewed for histology, human epidermal growth factor receptor 2 (HER2) expression, and mismatch repair-deficient (dMMR)/microsatellite instability (MSI) status. In addition, we assessed Epstein-Barr virus (EBV) status, programmed death-ligand 1 (PD-L1) combined positive score (CPS), and carried out tissue genomic profiling including tumor mutation burden (TMB) quantification plus targeted transcriptomics for immune microenvironment and cancer cell signaling scores. RESULTS In total, 328 GC patients were enrolled. HER2-positive GC and high PD-L1 CPS were more frequent in Europe than in LATAM (9% versus 3% and 15% versus 3%, respectively), whereas EBV was mainly found in LATAM (7%, versus 3% in Europe), and dMMR/MSI tumors were equally distributed (16%). High TMB was enriched in dMMR/MSI and EBV tumors. Mutations in homologous recombination repair (HRR) genes were frequent in both cohorts (24.8% and 14.7% in Europe and LATAM, respectively), and mostly found in dMMR/MSI (63.6%) and intestinal HER2-negative (18.7%) tumors. The prognosis was poor in diffuse HER2-negative GC patients, whose tumors presented an immunosuppressive microenvironment and other distinct pathway activation signatures. CONCLUSIONS Our findings relate specific molecular alterations of GC tumors from Europe and LATAM to actionable biomarkers for precision cancer therapies. The proposed GC stratification can be implemented in routine care and guide drug development strategies.
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Affiliation(s)
- R Dienstmann
- Oncology Data Science, Vall d´Hebron Institute of Oncology, Barcelona, Spain; OC Precision Medicine, Oncoclínicas & Co, São Paulo, Brazil; University of Vic-Central University of Catalonia, Barcelona, Spain. https://twitter.com/rdienstmann
| | - E Ruiz-García
- Departamento de Tumores de Tubo Digestivo, Instituto Nacional de Cancerología, Mexico City, Mexico; Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Ruiz-García
| | - M Alsina
- Medical Oncology Department, Vall d`Hebron Institute of Oncology, Barcelona, Spain; Hospital Universitario de Navarra, Navarrabiomed-IdiSNA, Pamplona, Spain. https://twitter.com/Alsina
| | - F Ruiz-Pace
- Oncology Data Science, Vall d´Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Ruiz-Pace
| | - T S Groen-van Schooten
- Department of Medical Oncology, Amsterdam University Medical Center (UMC), location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - C Martínez-Ciarpaglini
- Department of Pathology, Hospital Clínico Universitario de Valencia, Valencia, Spain. https://twitter.com/Martínez-Ciarpaglini
| | - E A Fernández-Figueroa
- Núcleo B de Innovación en Medicina de Precisión, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - R Herrera-Goepfert
- Department of Pathology, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Herrera-Goepfert
| | - C Díaz-Romero
- Department of Medical Oncology, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Díaz-Romero
| | - L Lino-Silva
- Department of Head of Division, Surgical Pathology, National Cancer Institute (INCan), Mexico City, Mexico. https://twitter.com/Lino-Silva
| | - A I Hernandez-Guerrero
- Department of Gastrointestinal Endoscopy, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Hernandez-Guerrero
| | - N M Valdez-Reyes
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - A León-Takahashi
- Departamento de Gastroenterología, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/León-Takahashi
| | - J C Falcón-Martínez
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - R E Pouw
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center (UMC), location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - S Romero
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain. https://twitter.com/Romero
| | - R Villagrasa
- Department of Gastroenterology, Hospital Clínico Universitario de Valencia, Valencia, Spain. https://twitter.com/Villagrasa
| | - M Cabeza-Segura
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain. https://twitter.com/Cabeza-Segura
| | - L Alarcón-Molero
- Department of Pathology, Hospital Clínico Universitario de Valencia, Valencia, Spain; Department of Pathology, Hospital General de Valdepeñas, Valdepeñas, Spain. https://twitter.com/Alarcón-Molero
| | - E Jimenez-Martí
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain. https://twitter.com/Jimenez-Martí
| | - A Miralles
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - H Boggino
- Department of Pathology, GENPAT, Asunción, Paraguay
| | - C Gauna
- Department of Medical Oncology, Instituto de Previsión Social, Asunción, Paraguay
| | - R Pereira
- Department of Medical Oncology, Instituto de Previsión Social, Asunción, Paraguay
| | - H Lezcano
- Department of Pathology, Instituto de Previsión Social, Asunción, Paraguay
| | - D Cantero
- Department of Gastroenterology, Instituto de Previsión Social, Asunción, Paraguay
| | - A Vivancos
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Vivancos
| | - J Matito
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Matito
| | - A Martin
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Martin
| | - M Gómez
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Gómez
| | - E Castillo
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Castillo
| | - M Vila
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Vila
| | - R M Ferreira
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. https://twitter.com/Ferreira
| | - R Barros
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
| | - J Santos-Antunes
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Gastroenterology, Unidade Local de Saúde São João, Porto, Portugal. https://twitter.com/Santos-Antunes
| | - M Mendes-Rocha
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal. https://twitter.com/Mendes-Rocha
| | - A Costa
- Department of Oncology, Unidade Local de Saúde São João, Porto, Portugal
| | - E Riquelme
- Department of Respiratory Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - J C Roa
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - G Latorre
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - B Freile
- Department of Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina
| | - L Caro
- Department of Gastroenterology, Instituto Alexander Fleming, GEDYT (Gastroenterologia diagnostica y terapeutica), Buenos Aires, Argentina
| | - F Esteso
- Department of Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina. https://twitter.com/federico_esteso
| | - J O'Connor
- Department of Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina. https://twitter.com/juanmaoconnor
| | - A Riquelme
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Center for Prevention and Control of Cancer (CECAN), Santiago, Chile
| | - G Owen
- Faculty of Biological Sciences & Faculty of Medicine, Pontificia Universidad Católica de Chile, Millennium Institute for Immunology and Immunotherapy, Center for Prevention and Control of Cancer (CECAN), Advance Center for Chronic Disease (ACCDIS), Santiago, Chile
| | - M Garrido
- Facultad de Medicina y Ciencia de la Salud, Centro de Oncología de Precision, Universidad Mayor, Santiago, Chile. https://twitter.com/DrGarridoOncoGI
| | - M Diez-García
- Medical Oncology Department, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Diez-García
| | - C Figueiredo
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal. https://twitter.com/FigeuiredoCeu
| | - C Caballero
- Department of Pathology, GENPAT, Asunción, Paraguay
| | - F Lordick
- Department of Oncology and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany. https://twitter.com/FlorianLordick
| | - J Farrés
- Anaxomics Biotech S.L., Barcelona, Spain
| | - S Derks
- Department of Medical Oncology, Amsterdam University Medical Center (UMC), location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. https://twitter.com/derks_s
| | - F Carneiro
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal. https://twitter.com/Carneiro
| | - A Cervantes
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain; Ciberonc, Instituto Carlos III, Madrid, Spain.
| | - T Fleitas
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain; Ciberonc, Instituto Carlos III, Madrid, Spain.
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Ren S, Wei Y, Liu W, Zhang Y, Wang Y, Yang J, Liu B, Shi T, Wei J. Clinical Characteristics, Prognostic Factors and Therapeutic Strategies in Gastric Cancer Patients With Bone Metastasis: A Retrospective Analysis. Cancer Med 2025; 14:e70781. [PMID: 40105370 PMCID: PMC11921140 DOI: 10.1002/cam4.70781] [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: 11/06/2024] [Revised: 02/09/2025] [Accepted: 03/07/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Bone metastases are highly refractory and are associated with extremely poor survival. Despite the increasing incidence of bone metastasis in gastric cancer (GC), comprehensive analyses regarding the clinicopathological features, prognosis, and treatment of bone-metastatic GC remain limited. METHODS We obtained data from 120 bone-metastatic GC patients from Nanjing Drum Tower Hospital and 36,139 GC patients from the SEER database. Chi-square and Mann-Whitney U-tests evaluated clinicopathological features, while Cox models identified prognostic factors. Kaplan-Meier curves and forest plots assessed the effects of different treatment strategies on overall survival after bone metastasis (OS-BM). RESULTS Among 120 bone-metastatic GC patients, 55 (45.83%) were diagnosed with poorly cohesive gastric carcinoma (PCC). The higher incidence of bone metastasis was also observed in SRCC patients from the SEER database (p < 0.0001). PCC patients exhibited distinct pathological features compared to non-PCC patients, including lower PD-L1 (p = 0.042) and E-cadherin expression (p = 0.049). Multivariate analysis identified various negative prognostic factors such as metachronous bone metastasis (p < 0.001, HR = 2.35, 95% CI:1.47-3.74) and CA125 expression (p = 0.036, HR = 1.60, 95% CI:1.03-2.48), whereas immunotherapy was a positive prognostic factor (p < 0.001, HR = 0.44, 95% CI:0.29-0.66). Subgroup analysis also showed improved survival among different populations of bone-metastatic GC patients receiving immunotherapy. Moreover, combinational therapies including immunotherapy and other treatments (anti-angiogenic therapy and/or local radiotherapy) further improved patient OS-BM. CONCLUSION Our results suggest bone-metastatic GC patients exhibit distinct clinicopathological features, with a high incidence of bone metastasis in PCC. Immunotherapy-based combination therapies offer improved survival benefits, thus supporting the application of immunotherapy in GC patients at high risk of bone metastasis.
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Affiliation(s)
- Shiji Ren
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yutao Wei
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenqi Liu
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Yipeng Zhang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yue Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ju Yang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing Medical Key Laboratory of Oncology, Nanjing, China
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Yi XM, Cai HQ, Jiao Y. Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer. World J Gastrointest Surg 2025; 17:100257. [DOI: 10.4240/wjgs.v17.i2.100257] [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: 08/11/2024] [Revised: 12/18/2024] [Accepted: 12/25/2024] [Indexed: 01/22/2025] Open
Abstract
This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.
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Affiliation(s)
- Xue-Mei Yi
- Department of Second Operation Room, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Hong-Qiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Lewis KA, Diggs LP, Badgwell BD. Educational Review: Updates on Therapeutic Strategies for Gastric Cancer with Peritoneal Metastasis. Ann Surg Oncol 2025:10.1245/s10434-025-17069-3. [PMID: 40016614 DOI: 10.1245/s10434-025-17069-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 02/09/2025] [Indexed: 03/01/2025]
Abstract
Gastric cancer (GC) commonly presents in advanced stages with metastatic spread to the peritoneal cavity, and outcomes associated with gastric cancer with peritoneal metastasis (GCPM) continue to carry a dismal prognosis. Persistent challenges in the detection of peritoneal metastasis (PM) have resulted in a relative paucity of high-quality data to inform management decisions. Several consensus groups have published recommendations to guide management, including most recently the National Comprehensive Cancer Network guidelines, which now include cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a potential treatment modality in select patients with GCPM. Multiple clinical trials have investigated the use of CRS/HIPEC and other peritoneal-directed therapies, such as intraperitoneal chemotherapy (IPC) and pressurized intraperitoneal aerosolized chemotherapy (PIPAC). As high-volume centers work to incorporate such therapies into their practice, ongoing clinical trials are aimed at understanding their efficacy. Recent findings have improved understanding of the mechanisms and pathophysiology underlying GCPM while the discovery of novel targets offers potential for drug development and therapeutic strategies to overcome treatment resistance. This review highlights recent advancements and addresses the persistent challenges in managing GCPM while also offering a comprehensive summary of current guidelines and treatment strategies.
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Affiliation(s)
- Kever A Lewis
- Division of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Laurence P Diggs
- Division of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brian D Badgwell
- Division of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Wei J, Zhang P, Hu Q, Cheng X, Shen C, Chen Z, Zhuang W, Yin Y, Zhang B, Gou H, Yang K, Bi F, Liu M. Nab-paclitaxel combined with cadonilimab (AK104) as second-line treatment for advanced gastric cancer: protocol for a phase II prospective, multicenter, single-arm clinical trial. Front Immunol 2025; 16:1519545. [PMID: 40070819 PMCID: PMC11893503 DOI: 10.3389/fimmu.2025.1519545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/31/2025] [Indexed: 03/14/2025] Open
Abstract
Background Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide, often diagnosed at an advanced stage with a poor prognosis. Paclitaxel, nab-paclitaxel, and irinotecan, either as monotherapies or in combination with ramucirumab, are currently standard second-line treatments for GC. However, the efficacy of these therapies is limited, necessitating the development of new combination strategies to improve response rates. Immune checkpoint inhibitors (ICIs) have shown success in first-line treatment for advanced GC, leading to interest in immune rechallenge strategies for second-line treatment. Re-challenging patients with ICIs after progression on first-line treatment may restore immune responses and provide additional clinical benefit. Recently, cadonilimab (AK104), a bispecific antibody targeting PD-1 and CTLA-4, has demonstrated promising antitumor activity when combined with chemotherapy in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, the efficacy and safety of nab-paclitaxel combined with AK104 for the treatment of advanced GC remain unclear. Furthermore, identifying predictive biomarkers of efficacy is essential to developing personalized treatment strategies. This study aims to explore the safety and efficacy of nab-paclitaxel combined with AK104 as a second-line treatment for patients who have progressed after first-line chemoimmunotherapy, focusing on evaluating the therapeutic effect of ICIs rechallenge in gastric cancer. Methods This is a prospective, multicenter, open-label, single-arm Phase II clinical study. Eligible patients were histologically or cytologically diagnosed with unresectable recurrent or metastatic GC, failed first-line chemotherapy in combination with immune checkpoint inhibitor, aged between 18-75 years old, expected survival ≥3 months, and with a physical status of 0 or 1 in the Eastern Cooperative Cancer Group (ECOG). Enrolled patients will receive intravenous cadonilimab (AK104) 6 mg/kg on days 1, and 15, and intravenous nab-paclitaxel 100 mg/m2 every four weeks on days 1, 8, and 15. The primary endpoints were objective response rate (ORR), and secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The exploratory objective was to identify biomarkers associated with efficacy, mechanism of action, and safety. A total of 59 participants were planned to be recruited using Simon's two-stage design. The trial was initiated in June 2024 in China. Discussion This study is the first prospective trial to evaluate the combination of nab-paclitaxel and cadonilimab as second-line treatment after first-line chemoimmunotherapy failure. By investigating immune rechallenge, it aims to reactivate anti-tumor immune responses and improve clinical outcomes in GC patients. The exploration of predictive biomarkers, such as ctDNA, TMB, MSI, PD-L1 expression, TIL profiles, and gut microbiota, will help personalize treatment and identify patients most likely to benefit from immune rechallenge. This trial could provide valuable insights into overcoming immune resistance and contribute to developing a promising second-line therapeutic strategy for advanced GC. Clinical trial registration ClinicalTrials.Gov, identifier NCT06349967.
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Affiliation(s)
- Jing Wei
- Gastric Cancer Center, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Pengfei Zhang
- Gastric Cancer Center, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiancheng Hu
- Gastric Cancer Center, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaolong Cheng
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chaoyong Shen
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhixin Chen
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wen Zhuang
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuan Yin
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bo Zhang
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hongfeng Gou
- Gastric Cancer Center, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kun Yang
- Department of General Surgery/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Bi
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Liu
- Gastric Cancer Center, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Klempner SJ, Lee J, Sundar R. PD-1 or PD-L1-A Difference That Makes No Difference? JAMA 2025:2830743. [PMID: 39992673 DOI: 10.1001/jama.2025.0630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Affiliation(s)
- Samuel J Klempner
- Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Raghav Sundar
- Department of Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, Connecticut
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Zhang X, Wang J, Wang G, Zhang Y, Fan Q, Lu C, Hu C, Sun M, Wan Y, Sun S, Wang J, Zhang L, Shu Y, Luo J, Zhu D, Shen Z, Yao S, Shi Q, Yang J, Shen L. First-Line Sugemalimab Plus Chemotherapy for Advanced Gastric Cancer: The GEMSTONE-303 Randomized Clinical Trial. JAMA 2025:2830739. [PMID: 39992668 PMCID: PMC11851304 DOI: 10.1001/jama.2024.28463] [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: 05/29/2024] [Accepted: 12/20/2024] [Indexed: 02/26/2025]
Abstract
Importance Gastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti-programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising antitumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This combination was further evaluated in the GEMSTONE-303 phase 3 trial. Objective To evaluate the efficacy of sugemalimab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX as first-line treatment for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score (CPS) of 5 or greater. Design, Setting, and Participants GEMSTONE 303 is a phase 3, randomized, double-blind, placebo-controlled study conducted at 54 sites in China that enrolled patients from April 9, 2019, through December 29, 2021, with follow-up to July 9, 2023. A total of 479 eligible patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who did not receive any prior systemic therapy were randomized. Intervention Patients received sugemalimab (1200 mg intravenously) (n = 241) or placebo (n = 238) every 3 weeks for up to 24 months, plus CAPOX every 3 weeks for up to 6 cycles. Main outcomes and Measures Primary outcomes were overall survival and investigator-assessed progression-free survival. Results Baseline characteristics were well balanced between the 2 groups. Most patients were male (71.4% in sugemalimab group, 74.8% in placebo group). Median follow-up was 25.1 months in the sugemalimab group and 26.3 months in the placebo group. The sugemalimab group demonstrated significant improvements in overall survival (median, 15.6 months [95% CI, 13.3-17.8] vs 12.6 months [95% CI, 10.6-14.1]; hazard ratio, 0.75 [95% CI, 0.61-0.92]; P = .006) and progression-free survival (median, 7.6 months [95% CI, 6.4-7.9] vs 6.1 months [95% CI, 5.1-6.4]; hazard ratio, 0.66 [95% CI, 0.54-0.81]; P < .001). Grade 3 or higher treatment-related adverse events occurred in 53.9% of patients in the sugemalimab group and 50.6% in the placebo group. Conclusions and Relevance Sugemalimab plus chemotherapy significantly prolonged overall survival and progression-free survival with a manageable safety profile in previously untreated patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. Trial Registration ClinicalTrials.gov Identifier: NCT03802591.
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Affiliation(s)
- Xiaotian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jufeng Wang
- Gastroenterology Department, Henan Cancer Hospital, Zhengzhou, China
| | - Gang Wang
- Cancer Chemotherapy Department, Anhui Provincial Hospital, Hefei, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qingxia Fan
- Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chuangxin Lu
- Medical Oncology Department, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Changlu Hu
- Medical Oncology Department, Anhui Provincial Cancer Hospital, Hefei, China
| | - Meili Sun
- Oncology Department, Jinan Central Hospital, Jinan, China
| | - Yiye Wan
- Department of Gastroenterology and Medical Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Sanyuan Sun
- Oncology Department, Xuzhou Central Hospital, Xuzhou, China
| | - Junye Wang
- Oncology Department, Affiliated Hospital of Jining Medical University, Jining, China
| | - Li Zhang
- Oncology Department, Chongqing University Three Gorges Hospital, Chongqing, China
| | - Yongqian Shu
- Oncology Department, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Jie Luo
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Dan Zhu
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Zhenwei Shen
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Sheng Yao
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Qingmei Shi
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Jason Yang
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
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Shimozaki K, Ooki A, Yoshino K, Tamba M, Udagawa S, Osumi H, Fukuoka S, Nakayama I, Wakatsuki T, Ogura M, Takahari D, Shinozaki E, Chin K, Yamaguchi K. Investigating the role of immunotherapy for real-world patients with HER2-negative advanced gastric cancer between 2011 and 2023. Ther Adv Med Oncol 2025; 17:17588359251322670. [PMID: 40012706 PMCID: PMC11863253 DOI: 10.1177/17588359251322670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/04/2025] [Indexed: 02/28/2025] Open
Abstract
Background Although the emergence of immunotherapy has benefited patients with advanced gastric cancer (AGC), the magnitude of the benefit among real-world patients with HER2-negative AGC remains unclear. Objectives The current study aimed to evaluate the treatment features across various immunotherapy approval periods and investigate the utility of immunotherapy for patients with HER2-negative AGC in daily practice. Design Retrospective observational study. Methods We retrospectively evaluated the clinical outcomes of patients with HER2-negative AGC who received first-line platinum-based chemotherapy between 2011 and 2023 across different periods of immunotherapy approval in Japan: Group A (pre-immunotherapy approval): 2011-2017; Group B (approved for third-line treatment or later): 2018-2021; and Group C (approved for first-line treatment): 2022-2023. Results A total of 949 patients were enrolled (n = 477, 344, and 128 for Groups A, B, and C, respectively). Patient characteristics were comparable between the three groups, except for the proportion of those aged ⩾75 years (p = 0.002), prior gastrectomy (p = 0.03), and liver metastases (p = 0.0005). The median overall survival (OS) was 16.2, 15.2, and 21.3 months in Groups A, B, and C, respectively, with no significant difference between the groups (log-rank p = 0.50). Patients who received first-line immunotherapy plus chemotherapy (n = 173) showed significantly better OS than did those who did not receive any immunotherapy-containing treatment from 2011 to 2017 (n = 382; hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.61-0.99; p = 0.04). Multivariate analysis showed that the use of first-line immunotherapy was not significantly associated with worse OS, whereas the use of any-line immunotherapy was significantly associated with prognosis (HR, 0.54; 95% CI, 0.47-0.63; p < 0.0001). The proportion of patients receiving any second-line treatment was comparable between the groups: 76%, 80%, and 71%, respectively. Conclusion Our study suggests that immunotherapy has a moderate impact on improving the survival of real-world patients with HER2-negative AGC, highlighting the need for appropriate treatment strategies, including efforts to identify biomarkers and the development of other agents.
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Affiliation(s)
- Keitaro Shimozaki
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - Akira Ooki
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mikako Tamba
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shohei Udagawa
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shota Fukuoka
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mariko Ogura
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Daisuke Takahari
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Division of Medical Oncology, Department of Internal Medicine, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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Maubach G, Kanthasamy AK, Gogia S, Naumann M. The enigma of maladaptation in gastric pathophysiology. Trends Cancer 2025:S2405-8033(25)00040-8. [PMID: 39984410 DOI: 10.1016/j.trecan.2025.01.014] [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: 11/14/2024] [Revised: 01/24/2025] [Accepted: 01/29/2025] [Indexed: 02/23/2025]
Abstract
Despite a decline in global incidence, gastric cancer (GC) remains a major health concern. The development of GC is a sequential, multistage maladaptive process involving numerous different factors. Understanding the complexity of GC development is crucial for early detection, effective treatment, and, ultimately, prevention. In this respect, identifying the impact of risk factors contributing to the emergence or progression of GC, such as Helicobacter pylori infection, host and bacterial genetics, alcohol consumption, smoking, and preserved foods, will aid in combatting this disease. In this review, we focus on recent developments in understanding the role of the microbiome, dysfunctional molecular pathways, and immune evasion in gastric pathophysiology. We also highlight challenges and advances in treatment of GC.
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Affiliation(s)
- Gunter Maubach
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Arun K Kanthasamy
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Sandro Gogia
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.
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Antonella C, Kroopa J, Farah A, Rachel W, Rafael G, Anja W, Catherine SE, Elisa F. Outcomes of patients with refractory upper GI cancers enrolled in phase I trials: a 10-year analysis from the Sarah Cannon Research Institute UK Drug Development Unit. Ther Adv Med Oncol 2025; 17:17588359251318864. [PMID: 39975511 PMCID: PMC11837055 DOI: 10.1177/17588359251318864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/22/2025] [Indexed: 02/21/2025] Open
Abstract
Background Patients with unresectable upper gastrointestinal (UGI) cancers have limited treatment options and poor prognosis. Although phase I trials provide access to novel therapies, their benefits in this population are unclear. Objectives We aimed to assess efficacy and survival outcomes of patients with refractory UGI cancers within phase I trials. Design We conducted a retrospective pooled analysis of phase I trials enrolling patients with advanced UGI cancers who received at least one dose of the study drug at SCRI UK between 2011 and 2023. Methods Efficacy and survival outcomes, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS), were assessed. Analyses were conducted for the entire cohort and stratified by trial agent class, molecularly matched therapy allocation and receipt of the recommended phase II dose (RP2D). Patients participating in multiple trials were analysed separately for each study. Results From 1796 screened patients, 124 with UGI cancers were included in 37 phase I trials. Most were male (75%), with liver or peritoneal metastases (73%), treated with a median of 2 prior therapy lines. Of these, 60% received immunotherapy, 30% small molecules and 10% antibody-drug conjugates. Molecularly matched therapy was given to 22% and 86% received treatment at RP2D. In response-evaluable patients, ORR was 15%, CBR 40%, DCR 86% and median OS was 9.7 months. Treatment at RP2D was significantly associated with higher CBR (odds ratio 4.75, p = 0.04) and prolonged PFS (p = 0.04). Depth of response and treatment at RP2D were independent prognostic factors. Conclusions Participation in phase I trials offers benefits in refractory upper gastrointestinal cancers with compelling results in late-line settings and potential early access to new therapies.
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Affiliation(s)
- Cammarota Antonella
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Joshi Kroopa
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK
| | - Aghayeva Farah
- UCL Cancer Institute, University College London, London, UK
| | - Woodford Rachel
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK
- HRMC Clinical Trials Centre, University of Sydney, Parramatta, NSW, Australia
| | - Grochot Rafael
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK
| | - Williams Anja
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK
| | | | - Fontana Elisa
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK
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Zhang W, Guo K, Zheng S. Immunotherapy Combined with Chemotherapy in the First-Line Treatment of Advanced Gastric Cancer: Systematic Review and Bayesian Network Meta-Analysis Based on Specific PD-L1 CPS. Curr Oncol 2025; 32:112. [PMID: 39996912 PMCID: PMC11854702 DOI: 10.3390/curroncol32020112] [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: 12/23/2024] [Revised: 02/05/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
Objective: To compare the efficacy and safety of immunotherapy combined with chemotherapy as the first-line treatment for advanced gastric cancer. Data Sources: Phase III randomised controlled trials were searched from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials databases, and several international conference databases, from inception to 15 November 2024. Results: A total of eight eligible trials involved 7898 patients and eight treatments. The network meta-analysis showed that cadonilimab plus chemotherapy was the most superior treatment in improving overall survival (versus conventional chemotherapy, hazard ratio 0.62, 95% credible interval 0.50 to 0.78) and progression-free survival (0.53, 0.43 to 0.65), and consistency of results were observed in specific PD-L1 combined positive score groups. All immune checkpoint inhibitors combined with chemotherapy improved patient prognosis, but nivolumab plus chemotherapy may lead to an increase in grade 3 or higher adverse events (odds ratio 1.68, 95% credible interval 1.04 to 2.54), and the toxicity of cadonilimab plus chemotherapy was more likely to force patients to discontinue treatment. Conclusions: These results showed that cadonilimab plus chemotherapy had the best overall survival and progression-free survival benefits for advanced gastric cancer patients with HER-2 negative, and was preferentially recommended to patients with positive PD-L1 CPS.
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Affiliation(s)
- Wenwei Zhang
- Department of Oncology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China;
- Department of Oncology, Hangzhou First People’s Hospital, Hangzhou 310006, China;
| | - Kaibo Guo
- Department of Oncology, Hangzhou First People’s Hospital, Hangzhou 310006, China;
| | - Song Zheng
- Department of Oncology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China;
- Department of Oncology, Hangzhou First People’s Hospital, Hangzhou 310006, China;
- Zhejiang University School of Medicine, Hangzhou 310006, China
- Key Laboratory of Clinical Cancer Pharmacology & Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou 310006, China
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Zheng B, Lou F, He Y, Fu M, Huang X, Tan W, Chen Q, Xie X, Hu T, Xiao L. Deeper Analysis to Identify the True Benefit of ICIs Immunotherapy in First-Line Treatment for Non-HER2-Positive/HER2-Negative Advanced or Metastatic Advanced or Metastatic Gastric Cancer (GC) or Gastroesophageal Junction Cancer (GEJC). Cancers (Basel) 2025; 17:657. [PMID: 40002252 PMCID: PMC11852535 DOI: 10.3390/cancers17040657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/07/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Gastric cancer (GC) has a high global incidence and mortality rate [...].
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Affiliation(s)
- Bowen Zheng
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, China
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (M.F.); (X.X.)
| | - Fanzhuoran Lou
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
| | - Yuting He
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
| | - Miao Fu
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (M.F.); (X.X.)
| | - Xintian Huang
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
| | - Weijuan Tan
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
| | - Quan Chen
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
| | - Xiaowen Xie
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (M.F.); (X.X.)
| | - Tianhui Hu
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, China
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (M.F.); (X.X.)
- Shenzhen Research Institute of Xiamen University, Shenzhen 518057, China
| | - Li Xiao
- Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; (B.Z.); (F.L.); (Y.H.); (X.H.); (W.T.); (Q.C.)
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (M.F.); (X.X.)
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Liu Z, Liu A, Li M, Xiang J, Yu G, Sun P. Efficacy and safety of sintilimab combined with trastuzumab and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction cancer. Front Immunol 2025; 16:1545304. [PMID: 40028325 PMCID: PMC11867958 DOI: 10.3389/fimmu.2025.1545304] [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: 12/14/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Background To evaluate the efficacy and safety of sintilimab in combination with trastuzumab and chemotherapy for HER2-positive advanced gastric/gastroesophageal junction cancer (GC/GEJC). Methods HER2-positive advanced GC/GEJC patients admitted to our department between January 2018 and October 2024 were included in this study. Patients who received sintilimab in combination with trastuzumab and chemotherapy were assigned to cohort A, while patients who received trastuzumab and chemotherapy alone were assigned to cohort B. The primary endpoints were progression-free survival (PFS) and overall survival (OS), while the secondary endpoints included disease control rate (DCR), objective response rate (ORR), and safety. Results A total of 103 patients were analyzed, with 46 in cohort A and 57 in cohort B. The ORR was 65.2% in cohort A compared to 40.4% in cohort B, while the DCR was 87.0% in cohort A and 70.2% in cohort B. The median follow-up duration was 14.0 months. Median PFS (mPFS) was 9.4 months (95% CI: 5.6-13.2) for cohort A and 7.4 months (95% CI: 6.1-8.7) for cohort B (p = 0.089). Median OS (mOS) was 16.4 months (95% CI: 11.5-21.3) in cohort A versus 14.2 months (95% CI: 11.2-17.2) in cohort B (p = 0.069). Adverse events were predominantly mild, and no treatment-related deaths occurred. Conclusion Sintilimab combined with trastuzumab and chemotherapy showed promising efficacy and acceptable safety in HER2-positive advanced GC/GEJC. However, no statistically significant improvement in survival outcomes was observed compared to trastuzumab and chemotherapy alone.
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Affiliation(s)
- Zeyu Liu
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Aina Liu
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Ming Li
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinyu Xiang
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Guohua Yu
- Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Ping Sun
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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Rogers JE, Ajani JA. Contemporary management of advanced gastric and gastroesophageal adenocarcinomas. Expert Rev Anticancer Ther 2025:1-7. [PMID: 39918299 DOI: 10.1080/14737140.2025.2463493] [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: 12/04/2024] [Accepted: 02/03/2025] [Indexed: 02/09/2025]
Abstract
INTRODUCTION Gastric and gastroesophageal adenocarcinomas (GEACs) continue to carry a poor prognosis in most patients. New and exciting therapies have entered the treatment landscape in recent years. Prior to these recent approvals, treatment advances had been limited. AREAS COVERED Important treatment decision biomarkers for metastatic GEAC are microsatellite instability-high/deficient mismatch repair, human epidermal growth factor receptor-2, programmed-death ligand 1, and claudin 18.2 expression among others (such as Epstein Barr Virus (EBV) and agnostic biomarkers). Results of these biomarkers drive therapy decisions. Second-line treatment in most cases is less biomarker driven and needs further progress. EXPERT OPINION Studies of molecular subsets in GEAC has led to the understanding that these are heterogenous diseases that need to be treated differently. Other biomarkers with targeted therapies are being studied including fibroblast growth factor receptor, trophoblast cell surface antigen-2, and epidermal growth factor receptor. Additionally, epidemiological distinctions are starting to drive therapy such as in EBV in GAC.
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Affiliation(s)
- Jane E Rogers
- Department of Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center Pharmacy Clinical Programs, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, U.T. M.D. Anderson Cancer Center Department of Gastrointestinal Medical Oncology, Houston, TX, USA
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Luo D, Zhou J, Ruan S, Zhang B, Zhu H, Que Y, Ying S, Li X, Hu Y, Song Z. Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies. Cell Death Dis 2025; 16:75. [PMID: 39915459 PMCID: PMC11803115 DOI: 10.1038/s41419-025-07385-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 02/09/2025]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.
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Affiliation(s)
- Dingtian Luo
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jing Zhou
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shuiliang Ruan
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Binzhong Zhang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Huali Zhu
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yangming Que
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shijie Ying
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaowen Li
- Pathology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yuanmin Hu
- Intensive Care Unit, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
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Zhang F, Ding Z, Lian Y, Yang X, Hu P, Liu Y, Xu L, Li Z, Qiu H. Prophylactic antibiotic use is associated with better clinical outcomes in gastric cancer patients receiving immunotherapy. Oncologist 2025; 30:oyae362. [PMID: 40036772 PMCID: PMC11879193 DOI: 10.1093/oncolo/oyae362] [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: 04/26/2024] [Accepted: 11/03/2024] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND The relationship between antibiotic treatment and immunotherapy efficacy is complex. METHODS This study was a single-center study. History of antibiotic use in gastric cancer (GC) patients within 1 or 3 months prior to immunotherapy was collected. Patients were categorized into 3 groups according to whether they had used antibiotics prior to immunotherapy: none, prophylactic use, and infection. RESULTS A total of 252 GC patients received immunotherapy, of which 38.5% (97/252) received antibiotic treatment within 1 month before immunotherapy (prophylactic use in 72.2% of patients) and 48.8% (123/252) received antibiotic treatment within 3 months before immunotherapy (prophylactic use in 74.8% of patients). The prophylactic use of antibiotic within 1 month prior to immunotherapy significantly improved overall survival (OS) compared with patients who received anti-infective therapy and had no history of antibiotic use (prophylactic vs infection: OS, 22.6 vs 9.7 m, HR, 0.53, 95% CI, 0.27-1.07; prophylactic vs none: OS, 22.6 vs 14.7 m, HR, 0.57; 95% CI, 0.39-0.83). The use of antibiotics in infected patients did not increase the risk of death in patients compared with those who did not use antibiotics. Prophylactic antibiotic use within 1 month before immunotherapy is an independent prognostic factor for OS. CONCLUSIONS Prophylactic use of antibiotics is associated with better prognosis in GC patients receiving immunotherapy. Therefore, there is no necessity to delay the use of immune checkpoint inhibitors in this group of patients.
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Affiliation(s)
- Fangyuan Zhang
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Zixuan Ding
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yongping Lian
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Xiao Yang
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Pengbo Hu
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Yongqing Liu
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Liang Xu
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Zhou Li
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong, University of Science and Technology, Wuhan 430000, Hubei, China
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Nie RC, Yuan SQ, Ding Y, Chen YM, Li YF, Liang CC, Cai MY, Chen GM, Wang W, Sun XW, Weng DS, Li DD, Zhao JJ, Chen XJ, Guan YX, Liu ZM, Liang Y, Luo M, Chi J, Qiu HB, Zhou ZW, Zhang XS, Chen YB. Perioperative tislelizumab plus chemotherapy for locally advanced gastroesophageal junction adenocarcinoma (NEOSUMMIT-03): a prospective, nonrandomized, open-label, phase 2 trial. Signal Transduct Target Ther 2025; 10:60. [PMID: 39910052 PMCID: PMC11799164 DOI: 10.1038/s41392-025-02160-8] [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: 07/30/2024] [Revised: 01/20/2025] [Accepted: 01/23/2025] [Indexed: 02/07/2025] Open
Abstract
This prospective, nonrandomized, open-label phase 2 trial (Chinese Clinical Trial Registry, ChiCTR2200061906) aimed to evaluate the effectiveness of adding the PD-1 antibody tislelizumab to perioperative chemotherapy in patients with locally advanced gastroesophageal junction adenocarcinoma (GEJA). This study enrolled patients with GEJA clinically staged as cT3-4aNanyM0 or cT1-2N+M0 from October 2022 to June 2023. Eligible patients were administered three preoperative and five postoperative 3-week cycles of treatment with PD-1 antibody tislelizumab plus SOX (S-1 and oxaliplatin) regimen. The primary endpoint was major pathological response (MPR) rate. Thirty-two patients were enrolled. The median age was 60 years (range: 28-74 years), and 53.1% (17/32) patients were Siewert III type. All patients received at least one cycle of assigned preoperative treatment, and 93.8% (30/32) patients completed three cycles of assigned preoperative tislelizumab and SOX. The R0 resection rate was 96.9% (31/32). MPR, pathological complete response (pCR) of primary tumors and ypT0N0 rates were 50.0% (16/32, 95% CI: 31.9-68.1%), 28.1% (9/32, 95% CI: 13.7-46.7%) and 25.0% (8/32, 95% CI: 11.5-43.4%), respectively. The surgical morbidity rate was 15.6% (5/32), and no 30-day mortality was observed. In the preoperative and postoperative treatment periods, the rate of treatment-related grade 3-4 adverse events was 31.2% (10/32). At the date of 7th Jan 2025, 8 (25.0%) patients occurred recurrence. Therefore, perioperative tislelizumab plus chemotherapy demonstrated significantly improved pathological regression and might be a promising option for patients with locally advanced resectable GEJA.
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Affiliation(s)
- Run-Cong Nie
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
| | - Shu-Qiang Yuan
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Ya Ding
- Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Yong-Ming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Yuan-Fang Li
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Cheng-Cai Liang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Mu-Yan Cai
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Guo-Ming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Wei Wang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Xiao-Wei Sun
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - De-Sheng Weng
- Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Dan-Dan Li
- Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Jing-Jing Zhao
- Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Xiao-Jiang Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Yuan-Xiang Guan
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Zhi-Min Liu
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Yao Liang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Ma Luo
- Department of Medical Imaging, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Jun Chi
- Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Hai-Bo Qiu
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Xiao-Shi Zhang
- Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
| | - Ying-Bo Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
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Hirano H, Takahashi N, Amanuma Y, Suzuki N, Takahari D, Kawakami T, Kudo-Saito C, Nagashima K, Boku N, Kato K, Shoji H. Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE). BMC Cancer 2025; 25:201. [PMID: 39905373 PMCID: PMC11795988 DOI: 10.1186/s12885-025-13591-5] [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: 03/09/2024] [Accepted: 01/23/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between immune checkpoint inhibitors and angiogenesis inhibitors, and a preferable combination of steroid-free chemotherapy with immunotherapy. These rationales imply that nanoparticle albumin-bound (nab)-paclitaxel plus ramucirumab in combination with nivolumab (anti-PD-1 antibody) may enhance anti-tumor effects as second-line treatment. Therefore, we hypothesized that this triplet regimen may improve clinical outcomes in patients with AGC who experienced disease progression on first-line treatment including anti-PD-1/PD-L1 antibody. METHODS The PADDLE trial, which is sponsored by Ono Pharmaceutical, is an investigator-initiated, multicenter, open-label, single-arm, prospective phase II trial conducted at six institutions in Japan. Key eligibility criteria are as follows: (1) advanced gastric or esophagogastric junction cancer, (2) histologically confirmed diagnosis of adenocarcinoma, (3) refractory to first-line treatment including fluoropyrimidines, platinum, and an anti-PD-1/PD-L1 antibody, (4) performance status of 0-1, and (5) at least one measurable lesion. Patients are to receive nab-paclitaxel (100 mg/m2 weekly, with a 1-week rest after 3 consecutive weeks), ramucirumab (8 mg/kg every 2 weeks), and nivolumab (240 mg/body every 2 weeks). The primary endpoint is 6-month progression-free survival (PFS) rate. The target number of patients was set at 45 based on threshold and expected 6-month PFS rates of 35% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.95. Secondary endpoints include objective response rate, disease control rate, PFS, overall survival, duration of response, time to response, and safety. Biomarker analyses of serial blood and tumor samples are planned to clarify predictive markers and molecular mechanisms underlying treatment resistance by multifaceted analytical methods (e.g., flow cytometry, DNA sequencing [DNAseq]/RNA sequencing [RNAseq]). Recruitment started in November 2022. DISCUSSION The PADDLE trial is expected to clarify the efficacy of nab-paclitaxel plus ramucirumab in combination with nivolumab as second-line treatment in patients with AGC refractory to first-line treatment including an anti-PD-1/PD-L1 antibody and to identify potential biomarkers for predicting clinical responses in patients with AGC undergoing this triplet regimen. TRIAL REGISTRATION jRCT2031220448.
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Affiliation(s)
- Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Yusuke Amanuma
- Department of Clinical Trial Promotion, Chiba Cancer Center, Chiba, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeshi Kawakami
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Chie Kudo-Saito
- Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Kengo Nagashima
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Narikazu Boku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Oncology and General Medicine, Institute of Medical Science, IMSUT Hospital, University of Tokyo, Tokyo, Japan
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hirokazu Shoji
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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46
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Zhan Z, Chen B, Xu S, Lin R, Chen H, Ma X, Lin X, Huang W, Zhuo C, Chen Y, Guo Z. Neoadjuvant chemotherapy combined with antiangiogenic therapy and immune checkpoint inhibitors for the treatment of locally advanced gastric cancer: a real - world retrospective cohort study. Front Immunol 2025; 16:1518217. [PMID: 39967656 PMCID: PMC11832677 DOI: 10.3389/fimmu.2025.1518217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/20/2025] [Indexed: 02/20/2025] Open
Abstract
Background Although immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs have demonstrated effectiveness in treating advanced gastric cancer (GC), their role in neoadjuvant or conversion therapy remains uncertain. This study aimed to evaluate the efficacy and safety of combining neoadjuvant chemotherapy with anti-angiogenesis and ICIs in patients with locally advanced GC (LAGC). Methods In this cohort study, we reviewed our prospectively maintained GC database and included individuals diagnosed with clinical stage II-III GC who received neoadjuvant therapy followed by surgery between January 2022 and August 2023. The treatment protocol combined ICIs, anti-angiogenic therapy (specifically apatinib), and chemotherapy (S-1 with oxaliplatin). A systematic approach was used to document patients' clinical and pathological characteristics, pathological findings, and survival outcomes, which were subsequently analyzed in detail. Results A total of 38 individuals met the study's inclusion criteria, with the majority (32 patients, 84.2%) having clinical stage III GC. All participants underwent surgery, resulting in a notable R0 resection rate of 97.4%. The rates of major pathological response (MPR) and pathological complete response (pCR) were 47.4% and 23.7%, respectively. Post-surgery, 36 patients (92.1%) received adjuvant chemotherapy. With a median follow-up of 22 months, ten patients experienced disease recurrence, including three who died from tumor relapse. The 1-year overall survival (OS) rate stood at 100%, and the disease-free survival (DFS) rate was 94.7%, with median OS and DFS yet to be reached. The neoadjuvant therapy regimen was generally well-tolerated, with no grade 5 treatment-related adverse events (TRAEs) reported. Only one patient experienced a grade 4 TRAE (immune-related hepatitis), while the most common grade 3 TRAEs included thrombocytopenia, elevated aminotransferase levels, and neutropenia. Conclusions The combination of neoadjuvant chemotherapy, anti-angiogenic therapy, and ICIs has proven effective in treating LAGC patients, achieving high pCR rates and favorable survival outcomes while maintaining an acceptable safety profile.
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Affiliation(s)
- Zhouwei Zhan
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Bijuan Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Shaohua Xu
- Department of Hepatobiliary and Pancreatic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Ruyu Lin
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Haiting Chen
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xiaohuan Ma
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xuanping Lin
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Wanting Huang
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Changhua Zhuo
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Yu Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Zengqing Guo
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
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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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Cheng N, Wang B, Xu J, Xue L, Ying J. Tumor stroma ratio, tumor stroma maturity, tumor-infiltrating immune cells in relation to prognosis, and neoadjuvant therapy response in esophagogastric junction adenocarcinoma. Virchows Arch 2025; 486:257-266. [PMID: 38383941 DOI: 10.1007/s00428-024-03755-2] [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: 10/31/2023] [Revised: 01/14/2024] [Accepted: 01/27/2024] [Indexed: 02/23/2024]
Abstract
Accurate predictions on prognosis and neoadjuvant therapy response are crucial for esophagogastric junction adenocarcinoma (EGJA) patients. Therefore, we aimed to investigate the predictive abilities of several indicators, including tumor stroma ratio (TSR), tumor stroma maturity (TSM), and the density and spatial distribution of tumor-infiltrating immune cells (TIICs), such as T cells, B cells, and tumor-associated macrophages (TAMs). Resection and biopsy specimens of a total of 695 patients were included, obtained from the National Cancer Center (NCC) and The Cancer Genome Atlas (TCGA) cohorts. TSR and TSM were evaluated based on histological assessment. TIICs were quantified by QuPath following immunohistochemical (IHC) staining in resection specimens, while the Klintrup-Mäkinen (KM) grade was employed for evaluating TIIC in biopsy specimens. Patients with high stromal levels or immature stroma had relatively worse prognoses. Furthermore, high CD8+T cell count in the tumor periphery, as well as low CD68+ TAM count either in the tumor center or in the tumor periphery, was an independent favorable prognostic factor. Significantly, the combination model incorporating TSM and CD163+TAMs emerged as an independent prognostic factor in both two independent cohorts (HR 3.644, 95% CI 1.341-9.900, p = 0.011 and HR 1.891, 95% CI 1.195-2.99, p = 0.006, respectively). Additionally, high stromal levels in preoperative biopsies correlated with poor neoadjuvant therapy response (p < 0.05). In conclusion, our findings suggest that TSR, TSM, CD8+T cell, CD68+TAMs, and CD163+TAMs predict the prognosis to some extent in patients with EGJA. Notably, the combined model incorporating TSM and CD163+TAM can contribute significantly to prognostic stratification. Additionally, high stromal levels evaluated in preoperative biopsy specimens correlated with poor neoadjuvant therapy response.
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Affiliation(s)
- Na Cheng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Chaoyang District, Beijing, 100021, China
| | - Bingzhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Chaoyang District, Beijing, 100021, China
| | - Jiaqi Xu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Chaoyang District, Beijing, 100021, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Chaoyang District, Beijing, 100021, China.
| | - Jianming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Chaoyang District, Beijing, 100021, China.
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Baehr F, Teloh-Benger J, Damanakis A, Gebauer F, Schlößer H, Schroeder W, Bruns CJ, Quaas A, Zander T. Impact of structured surveillance of patients with esophageal cancer following surgical resection with curative intent. Surg Oncol 2025; 58:102184. [PMID: 39756157 DOI: 10.1016/j.suronc.2024.102184] [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: 06/18/2024] [Revised: 12/06/2024] [Accepted: 12/24/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Esophageal cancer (EC) is a disease with a poor prognosis. While treatment options have been improved, there is no consensus for surveillance strategies following therapy with curative intent. As the incidence of EC is rising and a large fraction of patients will experience disease recurrence, the need for evidence-based treatment and optimal surveillance is evident. STUDY DESIGN Included were 1128 patients with esophageal and gastroesophageal junction cancer (squamous cell/adenocarcinoma) that underwent surgical resection at the University Hospital Cologne (UHC) between 2012 and 2021. Patients were retrospectively split into two groups: monitored structured surveillance at the center (n = 635) (MSS) and not monitored surveillance (n = 493) (NMS). RESULTS In the MSS group, we identified 292 (45.98 %) cases of recurrence while 66 (13.39 %) cases of recurrence were identified in the NMS group. Overall survival (OS) was not significantly longer in MSS than in NMS, yet a positive trend can be seen (p = 0.108). Progression free survival (PFS) was significantly different between groups (p ≤ 0.05). Almost a third of recurrences diagnosed in MSS were limited to a singular location. About 35 % of recurrences in MSS were treated or were intended to be treated with local treatment options like surgery or curative intended radiotherapy, by times in combination with sensitizing chemotherapy. The correlation of time of recurrence and time of death was stronger within NMS than in MSS. CONCLUSIONS Structured surveillance leads to detection of more patients with singular recurrence but no clear sign of prolonged survival. Further prospective trials are warranted to define the clinical benefit of structured surveillance.
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Affiliation(s)
- Friederike Baehr
- Department of Internal Medicine, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany; CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany.
| | - Johanna Teloh-Benger
- CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany.
| | - Alexander Damanakis
- CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany; Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Florian Gebauer
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany; Department of General, Visceral and Oncological Surgery, University Hospital Wuppertal, University of Witten-Herdecke, Heusnerstraße 40, 42283, Wuppertal, Germany.
| | - Hans Schlößer
- CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany; Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany; Center for Molecular Medicine Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Wolfgang Schroeder
- CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany; Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Christiane J Bruns
- CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany; Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Alexander Quaas
- CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany; Department of Pathology, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Thomas Zander
- Department of Internal Medicine, University Hospital Cologne, Faculty of Medicine of University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany; CIO Cologne, University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Kerpener Str. 62, 50937, Cologne, Germany.
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50
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Lordick F, Mauer ME, Stocker G, Cella CA, Ben-Aharon I, Piessen G, Wyrwicz L, Al-Haidari G, Fleitas-Kanonnikoff T, Boige V, Lordick Obermannová R, Martens UM, Gomez-Martin C, Thuss-Patience P, Arrazubi V, Avallone A, Shiu KK, Artru P, Brenner B, Buges Sanchez C, Chau I, Lorenzen S, Daum S, Sinn M, Merelli B, van Grieken NCT, Nilsson M, Collienne M, Giraut A, Smyth E. Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIGE study. Ann Oncol 2025; 36:197-207. [PMID: 39542422 DOI: 10.1016/j.annonc.2024.10.829] [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: 09/29/2024] [Revised: 10/31/2024] [Accepted: 10/31/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.
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Affiliation(s)
- F Lordick
- Department of Medicine (Oncology, Gastroenterology, Hepatology, Pulmonology), University of Leipzig Medical Center, Comprehensive Cancer Center Central Germany (CCCG), Leipzig, Germany.
| | - M E Mauer
- European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - G Stocker
- Department of Medicine (Oncology, Gastroenterology, Hepatology, Pulmonology), University of Leipzig Medical Center, Comprehensive Cancer Center Central Germany (CCCG), Leipzig, Germany
| | - C A Cella
- Istituto Europeo di Oncologia, IRCCS, Milan, Italy
| | - I Ben-Aharon
- Department of Oncology, Rambam Health Care Campus, Haifa, Israel
| | - G Piessen
- CHRU de Lille-Hôpital Huriez, Lille, France
| | - L Wyrwicz
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - G Al-Haidari
- Oslo University Hospital-Ullevaal Hospital, Oslo, Norway
| | - T Fleitas-Kanonnikoff
- Hospital Clinico Universitario De Valencia, Incliva Biomedical Research Institute, Valencia, Spain
| | - V Boige
- Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France
| | - R Lordick Obermannová
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - U M Martens
- Department of Oncology, SLK-Kliniken Heilbronn, Heilbronn, Germany
| | | | - P Thuss-Patience
- Charité-Universitäetsmedizin Berlin-Charité Campus Virchow-Klinikum, Berlin, Germany
| | - V Arrazubi
- Hospital Universitario de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - A Avallone
- Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - K K Shiu
- University College Hospital, London, UK
| | - P Artru
- Hôpital Privé Jean Mermoz, Lyon, France
| | - B Brenner
- Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
| | - C Buges Sanchez
- Department of Medical Oncology, ICO-Badalona (Catalan Institute of Oncology-Badalona), Barcelona, Spain
| | - I Chau
- Royal Marsden Hospital, London, UK
| | - S Lorenzen
- Department of Haematology and Oncology, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany
| | - S Daum
- Charité-Universitäetsmedizin Berlin-Charité Campus Benjamin-Franklin, Berlin, Germany
| | - M Sinn
- University Medical Center Hamburg-Eppendorf, Center of Oncology, Hamburg, Germany
| | - B Merelli
- Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - N C T van Grieken
- Department of Pathology, Amsterdam UMC, location VUmc, Cancer Center Amsterdam, VU University, Amsterdam, The Netherlands
| | - M Nilsson
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Solna, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - M Collienne
- European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - A Giraut
- European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - E Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
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