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Cai Q, You S, Huang J, Gong C, Zhang W, Zhou A. Cost-effectiveness of trastuzumab deruxtecan as a second-line treatment for HER2-mutant advanced non-small cell lung cancer. Hum Vaccin Immunother 2025; 21:2468070. [PMID: 39989197 PMCID: PMC11853545 DOI: 10.1080/21645515.2025.2468070] [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: 12/11/2024] [Revised: 01/28/2025] [Accepted: 02/13/2025] [Indexed: 02/25/2025] Open
Abstract
The study of DESTINY-Lung01 and DESTINY-Lung02 demonstrated the favorable efficacy and optimal dosage of trastuzumab deruxtecan (T-DXd) in managing the human epidermal growth factor receptor 2 (HER2)-mutant non-small cell lung cancer (NSCLC) patients who had received previous treatment. The study sought to assess the cost-effectiveness of T-DXd in both the United States (US) and Chinese healthcare systems. Markov models were developed to evaluate the overall cost, incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALYs), and life years (LYs) of treatment with T-DXd compared with docetaxel, nivolumab, and pyrotinib for patients in the US and China. The level of willingness-to-pay (WTP) in the US and China is 150,000/QALYs and 32,517/QALYs, respectively. Sensitivity analyses were carried out to ensure the precision of the model. T-DXd yielded additional QALYs of 0.63 and 0.06 with an ICER of $338997.84 and $1437258.33 per QALY, respectively, in the US compared to the docetaxel and nivolumab regimens. And T-DXd yielded additional QALYs of 0.63, 0.06, and 0.13 with an ICER of $137959.45, $623805.93, and $515447.12 per QALY, respectively, in China compared to the docetaxel, nivolumab, and pyrotinib regimens. Sensitivity analysis showed that the cost of drugs is the most influential factor. T-DXd provides substantial therapeutic benefit for NSCLC patients with HER2 mutations who have had previous treatment but is not deemed cost-effective in either the US or China when compared to docetaxel, nivolumab, and pyrotinib. Price reduction is perhaps the main way to make T-DXd cost-effective.
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Affiliation(s)
- Qi Cai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuhui You
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinglong Huang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Caifeng Gong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Zhang Y, Fan W, Su F, Zhang X, Du Y, Li W, Gao Y, Hu W, Zhao J. Discussion on the mechanism of HER2 resistance in esophagogastric junction and gastric cancer in the era of immunotherapy. Hum Vaccin Immunother 2025; 21:2459458. [PMID: 39875210 PMCID: PMC11776468 DOI: 10.1080/21645515.2025.2459458] [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: 11/06/2024] [Revised: 01/11/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a critical biomarker and therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancers, despite the initial success of HER2-targeted therapies, such as trastuzumab, resistance to these drugs has emerged as a major impediment to effective long-term treatment. This review examines the mechanisms of drug resistance in HER2-positive G/GEJ cancer, the primary mechanisms of resistance explored include alterations in the HER2 receptor itself, such as mutations and changes in expression levels, as well as downstream signaling pathways, and interactions with the tumor microenvironment (TME). Furthermore, the review discusses the Novel therapeutic approaches, including the use of antibody-drug conjugates (ADCs) and combination therapies are assessed for their potential to enhance outcomes. By integrating recent research findings and clinical trials, this review aims to provide oncologists and researchers with insights into developing more effective treatments for patients with drug-resistant HER2-positive G/GEJ cancer.
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Affiliation(s)
- Yan Zhang
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, Shanxi, China
| | - Wenxuan Fan
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Fei Su
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoling Zhang
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Yunyi Du
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Weiling Li
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, Shanxi, China
| | - Yangjun Gao
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Wenqing Hu
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Jun Zhao
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
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Xu Q, Yin Z, Li Y, Zhu X, Lou H, Ni J. Prognostic value of HER2 expression in cervical adenocarcinoma: A retrospective cohort study. Oncol Lett 2025; 29:217. [PMID: 40093868 PMCID: PMC11907399 DOI: 10.3892/ol.2025.14963] [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: 10/15/2024] [Accepted: 01/30/2025] [Indexed: 03/19/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is an important therapeutic target in various types of cancer, although the prognostic value and therapeutic potential of HER2 in cervical adenocarcinoma are still underexplored. The present study aimed to examine the association between HER2 expression levels and prognosis in cervical adenocarcinoma, offering new insights into targeted therapies for HER2-expressing cervical adenocarcinoma. A total of 179 patients with cervical cancer who received surgery were included, and HER2 status in surgical specimens of the included patients were assessed using two classification methods: Immunohistochemistry (IHC) alone and traditional combined IHC/fluorescence in situ hybridization (FISH). IHC alone was used to categorize patients into the HER2 zero expression (IHC 0) and HER2 expression (IHC 1+, 2+ and 3+) groups, while traditional combined IHC/FISH classified the HER2 expression as negative (IHC 0 and 1+ or IHC 2+/FISH-) or positive (IHC 3+ or IHC 2+/FISH+). Kaplan-Meier survival analysis and log-rank tests were used to assess the patients' survival prognosis. A Cox proportional hazards regression model was used to identify independent prognostic factors. The HER2 expression rate was 44.1% (79/179) according to IHC alone, while 5.0% (9/179) were classified as HER2-positive according to the traditional method. HER2 expression was significantly associated with advanced International Federation of Gynecology and Obstetrics stages, higher rates of lymph node metastasis, vascular or perineural invasion, elevated cancer antigen 125 levels and increased recurrence rate (P<0.05). Moreover, HER2 expression was significantly associated with shorter progression-free survival (PFS) time [51.02±2.75 vs. 56.01±2.22 months; hazard ratio (HR), 0.559; 95% confidence interval (CI), 0.313-0.998; P=0.049]. Additionally, programmed death-ligand 1 expression levels were significantly higher in HER2-expressing patients who died (P=0.039). When HER2 status was assessed using the traditional combined IHC/FISH method, HER2 positivity was significantly associated with poorer PFS time (36.44±7.85 vs. 55.17±1.78 months; HR, 0.125; 95% CI, 0.03033-0.5156; P=0.004). In conclusion, classification of HER2 status in patients with cervical adenocarcinoma using IHC alone may provide a promising method for predicting patient outcomes and optimizing therapeutic strategies to improve treatment efficacy.
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Affiliation(s)
- Qing Xu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhuomin Yin
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yueqi Li
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Xiu Zhu
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Hanmei Lou
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Juan Ni
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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Zhang SH, Li W, Chen XY, Nie LL. Combining immune checkpoint inhibitors with standard treatment regimens in advanced human epidermal growth factor receptor-2 positive gastric cancer patients. World J Gastrointest Oncol 2025; 17:103855. [DOI: 10.4251/wjgo.v17.i4.103855] [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: 12/20/2024] [Revised: 01/12/2025] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide, with its incidence and mortality rates ranking among the highest in gastrointestinal cancers. The overexpression or gene amplification of human epidermal growth factor receptor 2 (HER-2) occurs in approximately 15%-20% of gastric cancers and serves as a critical molecular target influencing prognosis and treatment outcomes. For patients with HER-2-positive gastric cancer, trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment. However, despite the demonstrated clinical benefits in prolonging survival, the overall efficacy remains limited. In recent years, with the successful application of immune checkpoint inhibitors (ICIs) in various malignant tumors, combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer. Nevertheless, the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.
AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.
METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed. Patients were divided into a control group (n = 54, treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen) and an observation group (n = 50, treated with ICIs in addition to the standard regimen). The therapeutic efficacy, survival outcomes, and adverse reactions were compared between the two groups. Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.
RESULTS With a median follow-up time of 14.6 months, there were no significant differences between the two groups in terms of objective response rate or disease control rate (P > 0.05). The median progression-free survival (mPFS) and mPFS for patients with immunohistochemistry 3 + in the observation group were significantly higher than those in the control group (P < 0.05). Among patients in the observation group, those with positive programmed death-ligand 1 (PD-L1) expression had a significantly higher mPFS than those with negative PD-L1 expression (P < 0.05). Regarding adverse events, significant differences were observed between the two groups in hypothyroidism and neutropenia (P < 0.05). Cox multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) performance status, peritoneal metastasis, positive programmed death-1 expression, and treatment regimen were independent factors influencing PFS (hazard ratio > 1, P < 0.05).
CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy, significantly prolonging PFS with manageable safety. ECOG performance status, peritoneal metastasis, positive PD-L1 expression, and treatment regimen are independent factors influencing PFS, warranting increased clinical attention to patients exhibiting these factors.
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Affiliation(s)
- Sheng-Hu Zhang
- Department of Oncology, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze university, Jingzhou 434020, Hubei Province, China
| | - Wan Li
- Department of Ultrasound Medicine, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze university, Jingzhou 434020, Hubei Province, China
| | - Xi-Yan Chen
- Department of Medicine Imaging, The First People’s Hospital of Fuzhou City, Fuzhou 344000, Jiangxi Province, China
| | - Le-Le Nie
- Department of General Surgery, The First People’s Hospital of Fuzhou City, Fuzhou 344000, Jiangxi Province, China
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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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Xie X, Zhang J, Sun L, Xu S, Ma SS, Wang H, Li X, Xiang Q, Cui L, Liang X. Ultrasound-triggered topical oxygen delivery enhances synergistic sonodynamic and antibody therapies against hypoxic gastric cancer. J Control Release 2025; 380:736-750. [PMID: 39947405 DOI: 10.1016/j.jconrel.2025.02.019] [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: 12/12/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/21/2025]
Abstract
Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. In vitro experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. In vivo animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.
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Affiliation(s)
- Xinxin Xie
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory of Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China
| | - Jinxia Zhang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China
| | - Lihong Sun
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China
| | - Shuyu Xu
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China
| | - Shiti Sha Ma
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China
| | - Haonan Wang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China
| | - Xiaoda Li
- Peking University Health Science Center, Beijing 100191, China
| | - Qiong Xiang
- Institute of Medicine, Medical Research Center, Jishou University, Jishou, Hunan, China
| | - Ligang Cui
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China.
| | - Xiaolong Liang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory of Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Peking University Third Hospital, Beijing 100191, China.
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Ding Y, Yu Y. Therapeutic potential of flavonoids in gastrointestinal cancer: Focus on signaling pathways and improvement strategies (Review). Mol Med Rep 2025; 31:109. [PMID: 40017144 PMCID: PMC11884236 DOI: 10.3892/mmr.2025.13474] [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: 09/18/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025] Open
Abstract
Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.
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Affiliation(s)
- Ye Ding
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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8
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Tobias J, Heinl S, Dendinovic K, Ramić A, Schmid A, Daniel C, Wiedermann U. The benefits of Lactiplantibacillus plantarum: From immunomodulator to vaccine vector. Immunol Lett 2025; 272:106971. [PMID: 39765312 DOI: 10.1016/j.imlet.2025.106971] [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: 11/01/2024] [Revised: 12/23/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Probiotics have been increasingly recognized for positively influencing many aspects of human health. Lactiplantibacillus plantarum (L. plantarum), a non-pathogenic bacterium, previously known as Lactobacillus plantarum, is one of the lactic acid bacteria commonly used in fermentation. The probiotic properties of L. plantarum have highlighted its health benefits to humans when consumed in adequate amounts. L. plantarum strains primarily enter the body orally and alter intestinal microflora and modulate the immune responses in their host; thereby benefiting human health. Furthermore, the use of L. plantarum as vaccine vectors delivering mucosal antigens has been shown to be a promising strategy. These aspects, from Immunomodulation to vaccine delivery by L. plantarum in preclinical settings, are highlighted in this review. Along these lines, construction of a recombinant L. plantarum strain expressing a B cell multi-peptide, as a future vaccine to modulate immunity and confer anti-tumor effect by targeting Her-2/neu-overexpressing cancers in local and distal sites, is also presented and discussed.
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Affiliation(s)
- Joshua Tobias
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
| | - Stefan Heinl
- Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Kristina Dendinovic
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ajša Ramić
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Anna Schmid
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Catherine Daniel
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Ursula Wiedermann
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
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Heslin RT, Whitham ZA, Kim AC. Molecular and Genetic Markers of Peritoneal Metastasis. Surg Oncol Clin N Am 2025; 34:145-154. [PMID: 40015796 DOI: 10.1016/j.soc.2024.12.003] [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
Peritoneal surface malignancies (PSMs) represent a biologically diverse group of cancers that range from primary peritoneal mesothelioma to metastatic gastrointestinal cancers. Because of the heterogenous nature of PSM, there is a large gap in molecular characterization of these cancers. This article reviews the underlying molecular and genetic mechanisms for PSM.
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Affiliation(s)
- Ryan T Heslin
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Zachary A Whitham
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Alex C Kim
- Department of Surgical Oncology, UT Southwestern Medical Center, Dallas, TX, USA.
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Liu X, Fan X, Gao X, Hu W, Sun P. Leveraging HER2-targeted biparatopic antibodies in solid tumors. Pharmacol Res 2025; 214:107687. [PMID: 40054541 DOI: 10.1016/j.phrs.2025.107687] [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: 10/15/2024] [Revised: 01/14/2025] [Accepted: 03/04/2025] [Indexed: 03/23/2025]
Abstract
Biparatopic antibodies (bpAbs), which target non-overlapping epitopes on the same antigen, offer unique mechanisms of action and therapeutic applications that surpass those of conventional monospecific antibodies. These distinctive properties have positioned bpAbs as effective therapeutic agents in the treatment of cancer and infectious diseases, especially in cases where current treatments face limitations. Among these, HER2-targeted bpAbs have shown significant improvements in survival outcomes for patients with solid tumors that depend on HER2 signaling. However, a comprehensive understanding of their clinical impact, mechanisms of action, and limitations in therapeutic use remains lacking. Here, we review and contrast the clinical performance of the well-established HER2-targeted bpAbs in current use, with a focus on their mechanisms of action, associated limitations, and potential combination strategies. We also highlight emerging investigational bpAbs-based agents that have shown promise in the treatment of HER2-positive solid cancers. These advancements may lead to enhanced therapeutic options and potentially broaden the scope of bpAbs in cancer therapy.
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Affiliation(s)
- Xinlin Liu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Qingdao Cancer Institute, Qingdao 266071, China
| | - Xinyi Fan
- Department of Allergy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xiang Gao
- Department of Allergy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Weiyu Hu
- Department of Hepatobiliary and pancreatic surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
| | - Peng Sun
- Department of Hepatobiliary and pancreatic surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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11
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Ruff SM. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer Peritoneal Metastases. Surg Oncol Clin N Am 2025; 34:241-251. [PMID: 40015802 DOI: 10.1016/j.soc.2024.12.009] [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
Gastric cancer with peritoneal metastases (GC-PM) carries a poor prognosis and estimated survival is less than 6 to 12 months. One potential treatment of GC-PM is cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Success of this treatment largely relies on tumor biology and patient selection. These operations carry a high risk of morbidity and mortality and their efficacy in GC-PM remains controversial. This study will review the updated literature for CRS ± HIPEC in patients with GC-PM.
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Affiliation(s)
- Samantha M Ruff
- Department of Surgery, University of Virginia, 1215 Lee Street, Charlottesville, VA 22903, USA.
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12
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Tsutsumi C, Ohuchida K, Yamada Y, Shimada Y, Imamura M, Son K, Mochida Y, Katayama N, Iwamoto C, Torata N, Horioka K, Shindo K, Mizuuchi Y, Ikenaga N, Nakata K, Onishi H, Oda Y, Nakamura M. Claudin18.2-positive gastric cancer-specific changes in neoadjuvant chemotherapy-driven immunosuppressive tumor microenvironment. Br J Cancer 2025:10.1038/s41416-025-02981-y. [PMID: 40128286 DOI: 10.1038/s41416-025-02981-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/14/2025] [Accepted: 03/10/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Claudin 18 isoform 2 (CLDN18.2) is a potential therapeutic target in gastric cancer (GC). However, combining chemotherapy with anti-CLDN18.2 antibodies has shown limited efficacy in CLDN18.2-positive GC, and chemotherapy-induced changes in the tumor microenvironment (TME) remain unclear. METHODS This study analyzed 37 GC samples, including 11 CLDN18.2-positive cases, using single-cell RNA sequencing and multiplex immunofluorescence to assess chemotherapy-driven TME changes in CLDN18.2-positive GC. RESULTS In chemotherapy-treated CLDN18.2-positive GC, cytotoxic natural killer (NK) cells displayed antibody-dependent cytotoxicity (ADCC)-related genes at lower levels than in untreated CLDN18.2-positive GC, while regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) showed TGFB1 expression at higher levels. Additionally, NK cells, Tregs, and TAMs were more abundant in chemotherapy-treated than untreated CLDN18.2-positive GC. These chemotherapy-induced changes were absent in CLDN18.2-negative GC. Cell-cell interaction analysis identified unique interactions in chemotherapy-treated CLDN18.2-positive GC, including CCL5-CCR5 signaling between cytotoxic NK cells (Sender) and effector Tregs (Receptor) and TGFB1-TGFBR signaling between effector Tregs (Sender) and TAMs (Receptor). Cytotoxic NK cells expressed CCL5 at higher levels, CCR5-positive Tregs were more prevalent, and TAMs exhibited higher TGF-β receptor signature scores in chemotherapy-treated than untreated CLDN18.2-positive GC. CONCLUSIONS Our findings indicate that chemotherapy can drive immunosuppressive TME modifications specific to CLDN18.2-positive GC.
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Affiliation(s)
- Chikanori Tsutsumi
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan.
- Department of Advanced Medical Initiatives, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan.
| | - Yutaka Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Yuki Shimada
- Department of Anatomic Pathology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Masaki Imamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Kiwa Son
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Yuki Mochida
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Naoki Katayama
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Nobuhiro Torata
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Kohei Horioka
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Yusuke Mizuuchi
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Hideya Onishi
- Pancreatobiliary Surgery / Kidney & Pancreas Transplantation, Kyushu University Hospital, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan
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13
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Li R, Li J, Wang Y, Liu X, Xu W, Sun R, Xue B, Zhang X, Ai Y, Du Y, Jiang J. The artificial intelligence revolution in gastric cancer management: clinical applications. Cancer Cell Int 2025; 25:111. [PMID: 40119433 PMCID: PMC11929235 DOI: 10.1186/s12935-025-03756-4] [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: 08/27/2024] [Accepted: 03/18/2025] [Indexed: 03/24/2025] Open
Abstract
Nowadays, gastric cancer has become a significant issue in the global cancer burden, and its impact cannot be ignored. The rapid development of artificial intelligence technology is attempting to address this situation, aiming to change the clinical management landscape of gastric cancer fundamentally. In this transformative change, machine learning and deep learning, as two core technologies, play a pivotal role, bringing unprecedented innovations and breakthroughs in the diagnosis, treatment, and prognosis evaluation of gastric cancer. This article comprehensively reviews the latest research status and application of artificial intelligence algorithms in gastric cancer, covering multiple dimensions such as image recognition, pathological analysis, personalized treatment, and prognosis risk assessment. These applications not only significantly improve the sensitivity of gastric cancer risk monitoring, the accuracy of diagnosis, and the precision of survival prognosis but also provide robust data support and a scientific basis for clinical decision-making. The integration of artificial intelligence, from optimizing the diagnosis process and enhancing diagnostic efficiency to promoting the practice of precision medicine, demonstrates its promising prospects for reshaping the treatment model of gastric cancer. Although most of the current AI-based models have not been widely used in clinical practice, with the continuous deepening and expansion of precision medicine, we have reason to believe that a new era of AI-driven gastric cancer care is approaching.
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Affiliation(s)
- Runze Li
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
| | - Jingfan Li
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
| | - Yuman Wang
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
| | - Xiaoyu Liu
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
| | - Weichao Xu
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
- Hebei Hospital of Traditional Chinese Medicine, Hebei, 050011, China
| | - Runxue Sun
- Hebei Hospital of Traditional Chinese Medicine, Hebei, 050011, China
| | - Binqing Xue
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
| | - Xinqian Zhang
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China
| | - Yikun Ai
- North China University of Science and Technology, Tanshan 063000, China
| | - Yanru Du
- Hebei Hospital of Traditional Chinese Medicine, Hebei, 050011, China.
- Hebei Provincial Key Laboratory of Integrated Traditional and Western Medicine Research on Gastroenterology, Hebei, 050011, China.
- Hebei Key Laboratory of Turbidity and Toxicology, Hebei, 050011, China.
| | - Jianming Jiang
- Hebei University of Traditional Chinese Medicine, Hebei, 050011, China.
- Hebei Hospital of Traditional Chinese Medicine, Hebei, 050011, China.
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14
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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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15
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Chen Z, Ma Y, Chen J. Applications and challenges of immunotherapy in the management of gastric adenocarcinoma: current status and future perspectives. World J Surg Oncol 2025; 23:92. [PMID: 40108691 PMCID: PMC11921727 DOI: 10.1186/s12957-025-03752-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025] Open
Abstract
Gastric adenocarcinoma (GAC) remains a significant global public health challenge, characterized by high incidence and mortality rates. Progress in tumor immunology has introduced immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways, demonstrating substantial potential in GAC therapy. Clinical research indicates that ICIs, particularly when combined with chemotherapy or targeted therapies, significantly enhance treatment efficacy in advanced GAC and specific molecular subtypes, including microsatellite instability-high (MSI-H) and human epidermal growth factor receptor 2 (HER2)-positive patients. However, immunotherapy is also associated with a range of immune-related adverse events (irAEs), necessitating effective management strategies to ensure treatment safety and maintain patients' quality of life. Future studies should focus on identifying new therapeutic targets, optimizing patient selection, and developing personalized treatment approaches to further improve the efficacy and safety of immunotherapy in GAC.
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Affiliation(s)
- Zhiyao Chen
- Department of Gastrointestinal & Esophageal Surgery, The 2nd Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yunbin Ma
- Department of General surgery, Yiling Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jianan Chen
- Department of Clinical Sciences, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL, USA.
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16
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Liu D, Gong J, Li J, Qi C, Niu Z, Liu B, Peng Z, Luo S, Wang X, Wang Y, Zhao R, Chen L, Deng T, Li Z, Chen L, Fang M, Yang H, Lu L, Zhang Y, Kang F, Xu T, Zhang X, Shen L. Efficacy and safety of KN026, a bispecific anti-HER2 antibody, in combination with KN046, an anti-CTLA4/PD-L1 antibody, in patients with advanced HER2-positive nonbreast cancer: a combined analysis of a phase Ib and a phase II study. Signal Transduct Target Ther 2025; 10:104. [PMID: 40108113 PMCID: PMC11923254 DOI: 10.1038/s41392-025-02195-x] [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: 11/22/2024] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/22/2025] Open
Abstract
To evaluate the efficacy and safety of KN026, a novel bispecific HER2 (ECD2 and ECD4) antibody, plus KN046, a PD-L1, and CTLA4 bispecific antibody, in patients with advanced HER2-positive solid tumors. We conducted two sequentially designed phase Ib and II studies with similar target populations and evaluation schedules. The primary endpoints included safety, maximum tolerated dose (MTD), the recommended phase II dose (RP2D) for the phase Ib study, and the objective response rate (ORR) and duration of response (DoR) for the phase II study. Hereby, we solely report the results from 113 nonbreast cancer patients. In phase Ib, MTD was not reached. Dose 3 was confirmed to be acceptable for the phase II study. An objective response has been exclusively observed in HER2-positive patients. Any grade treatment-related adverse events (TRAEs) were reported in 108 (95.6%) patients. The most common TRAEs were infusion reactions (38.9%), anemia (37.2%), elevated AST (31.0%), and diarrhea (30.1%). Among the 108 patients evaluated for efficacy, the overall ORR was 55.6% (95%CI, 45.7%, 65.1%). In the HER2-positive GC subgroup, 38 patients received this regimen as the 1st-line treatment and 30 patients achieved an objective response, with an ORR of 78.9% (95%CI, 62.7%, 90.4%). Among 27 pretreated patients, the ORR was 44.4% (95%CI, 25.5%, 64.7%). In the other HER2-positive solid tumor subgroup (n = 34), the ORR was 52.9% (95%CI 35.1%,70.2%). Thus, KN026 plus KN04 exhibits promising efficacy and acceptable safety profiles in HER2-positive nonbreast cancer, as does the 1st-line treatment for GC.
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Affiliation(s)
- Dan Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Center, Peking University Cancer Hospital and 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 and 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 and 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 and Institute, Beijing, China
| | - Zuoxing Niu
- Department of Medical Oncology, Cancer Hospital of Shandong First Medical University (Shandong Cancer Hospital), Jinan, Shandong, China
| | - Bo Liu
- Department of Medical Oncology, Cancer Hospital of Shandong First Medical University (Shandong Cancer Hospital), Jinan, Shandong, 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 and Institute, Beijing, China
| | - Suxia Luo
- Department of Internal Medicine, Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Xicheng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - 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 and Institute, Beijing, China
| | - Rusen Zhao
- Department of Medical Oncology, Zibo Municipal Hospital, Zibo, Shandong, China
| | - Lilin Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Ting Deng
- Department of GI Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhen Li
- Department of Internal Medicine Ward 5, Linyi Cancer Hospital, Linyi, Shandong, China
| | - Lei Chen
- Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Meimei Fang
- Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Hongwei Yang
- Department of Breast and Thyroid Surgery, Suining Central Hospital, Suining, Sichuan, China
| | - Linzhi Lu
- Gastroenterology Department, Gansu Wuwei Tumour Hospital, Wuwei, Gansu, China
| | - Yanming Zhang
- Oncology Inpatient Area 2/3, Linfen Central Hospital, Linfen, Shanxi, China
| | - Fengling Kang
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, Jiang Su, China
| | - Ting Xu
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, Jiang Su, 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 and Institute, Beijing, 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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17
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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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18
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Leigh J, Ahmed A, Aubin F, Berry S, Boucher M, Campeau MP, Colwell B, Connors S, Corbett J, Dadwal S, Dudani S, Elimova E, Falkson C, Galvis L, Goel R, Gotfrit J, Hyde A, Febbraro M, Laidley DT, Locke G, Mahmud A, Baccili Cury Megid T, Michael J, Nair VJ, Quigley S, Ramjeesingh R, Samimi S, Seal M, Snow S, Spadafora S, Stuckless T, Wilson B, Asmis T, Goodwin R, Vickers M. Eastern Canadian Gastrointestinal Cancer Consensus Conference 2024. Curr Oncol 2025; 32:175. [PMID: 40136379 DOI: 10.3390/curroncol32030175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/27/2025] Open
Abstract
The Eastern Canadian Gastrointestinal Cancer Consensus Conference was an annual meeting that was held in St. John's, Newfoundland and Labrador, from 26 to 28 September 2024. This included experts in medical oncology, radiation oncology, surgical oncology, nuclear medicine, and general practitioners in oncology (GPO) from across the eastern Canadian provinces who are involved in the management of patients with gastrointestinal malignancies. This consensus statement generated by the conference addresses multiple topics, including the management of localized rectal cancer, liver-limited colorectal cancer, systemic therapy for advanced biliary tract cancers, radioligand therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), systemic therapy for pancreatic and midgut well-differentiated NETs, and systemic therapy for HER2-positive gastroesophageal cancers.
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Affiliation(s)
| | - Arwa Ahmed
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Francine Aubin
- Centre Hospitalier de l'Universite de Montreal, Montreal, QC H2X 3E4, Canada
| | - Scott Berry
- Trillium Health Partners, Mississauga, ON L5A 4G1, Canada
| | - Melanie Boucher
- Prince Edward Island Cancer Treatment Center, Charlottetown, PE C1A 8T5, Canada
| | | | - Bruce Colwell
- Queen Elizabeth II Health Sciences Center, Halifax, NS B3H 3A7, Canada
| | | | - Jessica Corbett
- Prince Edward Island Cancer Treatment Center, Charlottetown, PE C1A 8T5, Canada
| | | | - Shaan Dudani
- William Osler Health System, Brampton, ON L6R 3J7, Canada
| | - Elena Elimova
- Princess Margaret Cancer Center, Toronto, ON M5G 2M9, Canada
| | - Conrad Falkson
- Kingston Health Sciences Center, Kingston, ON K7L 2V7, Canada
| | - Luisa Galvis
- Horizon Health Network, Fredericton, NB E3B 4R3, Canada
| | - Rakesh Goel
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Joanna Gotfrit
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Angela Hyde
- Dr. H. Bliss Murphy Cancer Center, St. John's, NL A1B 3X5, Canada
| | - Michela Febbraro
- Algoma District Cancer Program, Sault Ste. Marie, ON P6B 0A8, Canada
| | | | - Gordon Locke
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Aamer Mahmud
- Kingston Health Sciences Center, Kingston, ON K7L 2V7, Canada
| | | | - James Michael
- Saint John Regional Hospital Oncology Center, Saint John, NB E2L 4L2, Canada
| | - Vimoj J Nair
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Stephen Quigley
- Health Sciences Center-Eastern Health, St. John's, NL A1B 3V6, Canada
| | - Ravi Ramjeesingh
- Queen Elizabeth II Health Sciences Center, Halifax, NS B3H 3A7, Canada
| | - Setareh Samimi
- Hopital du Sacre-Coeur de Montreal, Montreal, QC H4J 1C5, Canada
| | - Melanie Seal
- Dr. H. Bliss Murphy Cancer Center, St. John's, NL A1B 3X5, Canada
| | - Stephanie Snow
- Queen Elizabeth II Health Sciences Center, Halifax, NS B3H 3A7, Canada
| | - Silvana Spadafora
- Algoma District Cancer Program, Sault Ste. Marie, ON P6B 0A8, Canada
| | - Teri Stuckless
- Dr. H. Bliss Murphy Cancer Center, St. John's, NL A1B 3X5, Canada
| | - Brooke Wilson
- Kingston Health Sciences Center, Kingston, ON K7L 2V7, Canada
| | - Timothy Asmis
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Rachel Goodwin
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
| | - Michael Vickers
- The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada
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19
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Wang T, He M, Guan W. Pyrotinib monotherapy for advanced HER2-positive esophageal adenocarcinoma with trastuzumab resistance and chemotherapy intolerance: a case report and literature review. Discov Oncol 2025; 16:335. [PMID: 40095240 PMCID: PMC11914708 DOI: 10.1007/s12672-025-02049-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
HER2-positive advanced esophageal adenocarcinoma (EAC) cases demonstrate a poor prognosis because of drug resistance that develops after standard first-line trastuzumab therapy. The patient was initially diagnosed with stage cT2N1M0 III EAC. He underwent neoadjuvant chemotherapy, radical esophageal resection, and postoperative adjuvant radiotherapy. However, four months after treatment, the lesion relapsed and progressed to the right back, rendering the case inoperable. Pathological analysis revealed HER2 amplification. Given a poor tolerance to chemotherapy, the patient was administered cadonilimab and trastuzumab for three months. Subsequently, the second-line therapy was switched to pyrotinib monotherapy as a salvage treatment. Remarkably, after one month of treatment, the tumor showed significant reduction, with mild toxic side effects. Pyrotinib can be used for salvage later-line therapy in HER2-positive advanced EAC with trastuzumab resistance or poor chemotherapy tolerance, which deserves further promotion.
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Affiliation(s)
- Tao Wang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Mingyuan He
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Wei Guan
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
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20
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Li N, Zhang C, Li X, Liu S, Xu Y, Yang X. Targeting B7-H3 in solid tumors: Development and evaluation of novel CAR-T Cell therapy. Immunobiology 2025; 230:152888. [PMID: 40121824 DOI: 10.1016/j.imbio.2025.152888] [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: 12/01/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/25/2025]
Abstract
Ovarian and gastric cancers, representative of many solid tumors, remain among the most challenging malignancies to treat due to limited therapeutic options and poor outcomes at advanced stages. Although immunotherapies have revolutionized cancer treatment, their efficacy in solid tumors has been hindered by issues such as antigen heterogeneity and the immunosuppressive tumor microenvironment. This study presents the development and evaluation of third-generation chimeric antigen receptor T (CAR-T) cells targeting B7-H3, an immune checkpoint molecule widely overexpressed in solid tumors. The B7-H3 CAR-T cells exhibited robust and selective cytotoxicity against B7-H3-positive tumor cells, sparing normal tissues. In preclinical animal models, these cells significantly inhibited tumor growth, demonstrating higher targeting specificity and preferential accumulation in tumor sites. These results highlight B7-H3-targeted CAR-T cells as a potential breakthrough in immunotherapy for solid tumors, offering a foundation for future clinical trials to refine their safety and efficacy.
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Affiliation(s)
- Ning Li
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa 999078, Macao
| | - Chunhua Zhang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa 999078, Macao; The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
| | - Xiaoyu Li
- College of Mechanical and Vehicle Engineering, Chongqing University, Chongqing 400030, China
| | - Shufen Liu
- Surgical Intervention Departments, Hengshui People's Hospital, Hebei 053000, China
| | - Youhua Xu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa 999078, Macao.
| | - Xifei Yang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa 999078, Macao; Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen 518055, China..
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21
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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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22
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Grothey B, Lyu SI, Quaas A, Simon AG, Jung JO, Schröder W, Bruns CJ, Schiffmann LM, Popp FC, Schmidt T, Knipper K. Proteomic characterization of MET-amplified esophageal adenocarcinomas reveals enrichment of alternative splicing- and androgen signaling-related proteins. Cell Mol Life Sci 2025; 82:112. [PMID: 40074836 PMCID: PMC11904063 DOI: 10.1007/s00018-025-05635-7] [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: 09/10/2024] [Revised: 02/11/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs. METHODS In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified (n = 20) versus non-amplified tumors (n = 39) by mass spectrometry. RESULTS We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs. CONCLUSIONS Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.
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Affiliation(s)
- Bastian Grothey
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Su Ir Lyu
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Alexander Quaas
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Adrian Georg Simon
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Jin-On Jung
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Wolfgang Schröder
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Christiane J Bruns
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Lars M Schiffmann
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Felix C Popp
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Thomas Schmidt
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Karl Knipper
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany.
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23
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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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24
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Cabrit N, Cheugoua-Zanetsie M, Tierney J, Thirion P, Nankivell M, Winter K, Yang H, Wijnhoven B, Vernerey D, Smithers BM, Piessen G, Nilsson M, Boonstra J, Ychou M, Law S, Cunningham D, Vathaire FD, Stahl M, Urba S, Valmasoni M, Williaume D, Thomas J, Lordick F, Tepper J, Gebski V, Burmeister B, Paoletti X, Sandick JV, Fu J, Pignon JP, Ducreux M, Faron M, Michiels S. Disease-free survival as surrogate for overall survival in esophageal cancer: An individual patient data meta-analysis of neoadjuvant chemotherapy and chemoradiotherapy. Eur J Cancer 2025; 218:115292. [PMID: 39938127 DOI: 10.1016/j.ejca.2025.115292] [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: 12/13/2024] [Revised: 02/03/2025] [Accepted: 02/03/2025] [Indexed: 02/14/2025]
Abstract
BACKGROUND The use of surrogate endpoints may expedite the reporting of study outcomes of clinical trials. The validity of disease-free survival (DFS) as a surrogate for overall survival (OS) in the neoadjuvant treatment of esophageal (E) or gastroesophageal junctional (GEJ) carcinomas remains uncertain. OBJECTIVE To evaluate DFS as a surrogate end-point for OS in E/GEJ using the meta-analytical approach DESIGN, SETTING, AND PARTICIPANTS: individual patient data from an international meta-analysis on operable locally advanced E/GEJ, which including randomized trials comparing at least two of the neo-adjuvant treatment strategies: upfront surgery (S), chemotherapy followed by surgery (CS), and/or chemoradiotherapy followed by surgery (CRS). MAIN OUTCOMES AND MEASURES Individual (Kendall's tau) and trial-level (R2) correlations between DFS and OS were estimated using a Clayton copula. RESULTS DFS and OS data were available for a total of 4518 pts: 2222 pts included in CS vs S, 1908 pts in CRS vs S, and 388 in CS vs CRS comparisons. 3440 patients had a DFS event and 3303 patients died. Kendall's tau was 0.73 [95 % CI 0.71 - 0.75] and R2 trial-level correlation was 0.95 [0.84 - 0.99] for CS vs S, Kendall's tau was 0.76 [0.74 - 0.77] and R2 was 0.96 [0.87 - 0.99] for CRS vs S, Kendall's tau was 0.87 [0.78 - 0.92] and R2 was 0.93 [0.43 - 1] for CRS vs CS. In a multistate model, the median time in the recurrence state was shorter in older vs more recent trials: mean time of 10.8 [10.2 - 11.4] vs 16.5 months [15.4-17.6]. CONCLUSIONS AND RELEVANCE DFS is a validated surrogate endpoint for OS in trials evaluating neoadjuvant chemotherapy or chemoradiotherapy in E/GEJ. DFS may be more useful as an endpoint when delays between recurrences and death become larger.
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Affiliation(s)
- Nicolas Cabrit
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Maurice Cheugoua-Zanetsie
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; Biostatistics and Epidemiology Office, Gustave Roussy, Villejuif, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Jayne Tierney
- MRC Clinical trial Unit at UCL, London, United Kingdom; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Pierre Thirion
- St Luke's Radiation Oncology Network Dublin, Trinity College Dublin, Ireland; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Matthew Nankivell
- MRC Clinical trial Unit at UCL, London, United Kingdom; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Kathryn Winter
- NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Hong Yang
- Sun Yat-Sen University Cancer Center, Guangzhou, China; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Bas Wijnhoven
- Erasmus University Medical Center, Rotterdam, the Netherlands; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Dewi Vernerey
- CHRU Jean Minjoz, Besançon, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - B Mark Smithers
- University of Queensland, Princess Alexandra Hospital, Australia; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Guillaume Piessen
- Univ. Lille, CNRS, Inserm, Chu Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille F-59000, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Magnus Nilsson
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Jurjen Boonstra
- Leiden University Medical Center, Leiden, the Netherlands; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Marc Ychou
- Val d'Aurelles, Montpellier, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Simon Law
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - David Cunningham
- National Institute for Health Research, Biomedical Research Centres, Royal Marsden, London, UK; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Florent de Vathaire
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Michael Stahl
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Evang, Kliniken Essen-Mitte, Essen, Germany
| | - Susan Urba
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; University of Michigan, Ann Arbor, USA
| | - Michele Valmasoni
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Padova University Hospital, Center for Esophageal Diseases, Department of Surgery, Oncology and Gastroenterology, Padova, Italy
| | - Danièle Williaume
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Centre Eugène Marquis, Rennes, France
| | - Janine Thomas
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Princess Alexandra Hospital, Woolloongabba, Australia
| | - Florian Lordick
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Department of Oncology, University of Leipzig Medical Center, Leipzig, Germany
| | - Joel Tepper
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; University of North Carolina School of Medicine, Chapel Hill, USA
| | - Val Gebski
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; NHMRC, Sydney, Australia
| | - Bryan Burmeister
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Padova University Hospital, Center for Esophageal Diseases, Department of Surgery, Oncology and Gastroenterology, Padova, Italy
| | - Xavier Paoletti
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; Institut Curie, Paris, France
| | - Johanna van Sandick
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Jianhua Fu
- NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Jean-Pierre Pignon
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; Biostatistics and Epidemiology Office, Gustave Roussy, Villejuif, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Michel Ducreux
- CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France; University Paris-Saclay, Medical Oncology Department, Gustave Roussy, France
| | - Matthieu Faron
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France
| | - Stefan Michiels
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; Biostatistics and Epidemiology Office, Gustave Roussy, Villejuif, France; CESP U1018, Inserm, Université Paris-Saclay, Villejuif, France.
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25
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Kamp D, May AM, Adenis A, Capela A, Derks S, De Felice F, Dovnik NF, Hierro C, Ilhan-Mutlu A, Lordick F, Obermannova RL, Petrillo A, Puccini A, Raimundo A, Roviello G, Siebenhüner A, Slingerland M, Smyth EC, van Laarhoven HWM, Mohammad NH. Optimal timing for initiating first-line palliative systemic therapy in asymptomatic metastatic esophagogastric cancer: Insights from a European Delphi study. Eur J Cancer 2025; 218:115278. [PMID: 39919335 DOI: 10.1016/j.ejca.2025.115278] [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: 10/03/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 02/09/2025]
Abstract
BACKGROUND The enhanced application of imaging techniques is resulting in the diagnosis of more patients with asymptomatic metastatic esophagogastric cancer (mEGC). We conducted a Delphi study to gather insights from European experts on the optimal timing for initiating palliative systemic therapy for these patients. METHODS An online survey featured 14 scenarios where physicians chose their preferred timing for initiating systemic therapy: immediate(<3 weeks) or deferred. The standard scenario was a 65-year-old male, WHO/ECOG 0 with asymptomatic mEGC, 2 metastases in each lung, HER2 -, PDL1-CPS 2. In every subsequent case, one characteristic was modified. To investigate the fortitude of the physicians' preference for an immediate start, scenarios also included a patient who was motivated to start but preferred to defer if the physician deemed it judicious. Consensus was defined as ≥ 75 % agreement; scenarios without consensus were re-evaluated in Delphi round 2. RESULTS Thirty-nine physicians participated in the first round, and 33 in the second round. Consensus to start treatment immediately was reached in 12 (86 %) scenarios. When patients preferred to defer, the consensus was to still advise to start palliative systemic treatment immediately in half (n = 7) of the scenarios. Only 2 scenarios (pre-existent WHO/ECOG 2 or 78 years old) reached the consensus that treatment could be deferred. CONCLUSIONS In asymptomatic mEGC, immediate start of treatment is preferred by European experts. Consensus was established that treatment can be deferred for patients who prefer deferral and either have a pre-existent WHO/ECOG performance status of 2 or are of advanced age.
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Affiliation(s)
- Denice Kamp
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Anne M May
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Antoine Adenis
- Medical Oncology department, Institut du Cancer de Montpellier, Montpellier, France
| | - Andreia Capela
- Department of Medical Oncology, Unidade Local de Saúde de Gaia e Espinho, Villa Nova de Gaia, Portugal
| | - Sarah Derks
- Department of Medical Oncology, Amsterdam UMC, Free University, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands
| | - Francesca De Felice
- Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Nina Fokter Dovnik
- Department of Oncology, University Medical Centre Maribor, Maribor, Slovenia
| | - Cinta Hierro
- Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona, Badalona-Applied Research Group in Oncology (B-ARGO), Barcelona, Spain
| | - Aysegul Ilhan-Mutlu
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Florian Lordick
- University Cancer Center Leipzig, University of Leipzig, Leipzig, Germany
| | - Radka Lordick Obermannova
- Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk University, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Angelica Petrillo
- Medical Oncology unit, Ospedale del Mare, Via E. Russo, Naples, Italy
| | - Alberto Puccini
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20072, Italy; Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Rozzano, Milan, Italy
| | - Ana Raimundo
- Department of Medical Oncology, CUF Tejo Lisbon, Portugal
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | | | - Marije Slingerland
- Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Elizabeth C Smyth
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Hanneke W M van Laarhoven
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, the Netherlands; Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Nadia Haj Mohammad
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
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26
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Wu Y, Tian J, Zhou Y, Zhang R, Gao X, Luo L. Development and Characterization of 4A7: A High-Affinity Monoclonal Antibody Targeting Claudin18.2. Immunotargets Ther 2025; 14:189-203. [PMID: 40093351 PMCID: PMC11910048 DOI: 10.2147/itt.s494696] [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: 09/22/2024] [Accepted: 02/24/2025] [Indexed: 03/19/2025] Open
Abstract
Purpose Claudin18.2 has emerged as a promising therapeutic target due to its high expression in gastric (GC) and pancreatic cancers (PC). However, patients with advanced, unresectable, or metastatic GC or PC face poor prognoses, highlighting the urgent need for more effective Claudin18.2-targeted therapies. Methods and Results We developed 4A7, a fully human monoclonal antibody with superior affinity and specificity for Claudin18.2, using a rigorous positive and negative screening strategy to eliminate cross-reactivity with Claudin18.1. In vitro, 4A7 demonstrated significantly enhanced binding activity, as well as robust antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), outperforming IMAB362, a clinical investigational antibody. In vivo, 4A7 exhibited remarkable tumor growth inhibition both as a monotherapy and in combination with anti-mPD-1, achieving superior efficacy compared to IMAB362. Additionally, 4A7 demonstrated a higher degree of humanization and comparable stability, supporting its translational potential. Conclusion 4A7 shows great promise as a next-generation therapeutic for Claudin18.2-positive cancers, offering improved efficacy and reduced immunogenicity. This study not only highlights 4A7's potential to address unmet clinical needs but also provides a foundation for future innovations in monoclonal antibody-based cancer therapy.
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Affiliation(s)
- Yahui Wu
- Hunan Normal University Health Science Center, Changsha, Hunan Province, People's Republic of China
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China
| | - Juan Tian
- Hunan Normal University Health Science Center, Changsha, Hunan Province, People's Republic of China
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China
| | - Yangyihua Zhou
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China
| | - Ran Zhang
- Hunan Normal University Health Science Center, Changsha, Hunan Province, People's Republic of China
| | - Xiang Gao
- Hunan Normal University Health Science Center, Changsha, Hunan Province, People's Republic of China
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China
| | - Longlong Luo
- Hunan Normal University Health Science Center, Changsha, Hunan Province, People's Republic of China
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China
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27
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He L, Liu B, Wang Z, Han Q, Chen H. Evolving Landscape of HER2-Targeted Therapies for Gastric Cancer Patients. Curr Treat Options Oncol 2025:10.1007/s11864-025-01300-0. [PMID: 40056280 DOI: 10.1007/s11864-025-01300-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2025] [Indexed: 03/10/2025]
Abstract
OPINION STATEMENT Gastric cancer (GC) is a deadly disease worldwide, and trastuzumab in combination with chemotherapy has been the standard first-line treatment for HER2-positive GC following the TOGA trial. Besides adjuvant therapy, HER2-directed therapy is widely used as neoadjuvant or translational therapy, and survival benefit even surgical opportunities is seen in these patients. However, resistance is not rare in recent years, and the second-line treatment for trastuzumab beyond progression has received widespread attention in GC. Moreover, current evidence cannot recommend trastuzumab for patients with IHC1+ HER2 low expression GC yet. Researchers are currently investigating whether GC patients with low HER2 expression could also benefit from HER2-directed therapies. In addition to using HER2 as a target for targeted therapy, HER2-mediated targeted delivery of cytotoxic drugs and targeted immunity have made important contributions to overcoming trastuzumab resistance in recent trials. HER2/neu-derived peptide epitopes vaccination and HER2-specific chimeric antigen receptor (CAR) therapy focus on reestablishing anti-tumor immunity in different ways and show significant anti-tumor activity. Other antibodies that target different regions of the HER2 receptor or block key downstream pathways such as AKT or PI3K also offer potential anti-tumor activity against HER2. HER2 use in GC will not be hampered by resistance or low expression and will play a bigger role. We review the current efforts to enable GC patients with trastuzumab-resistant and HER2 low-expressing accessible to HER2 targeted therapy and present our consideration for future HER2 in GC.
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Affiliation(s)
- Lijuan He
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Ben Liu
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Zhuanfang Wang
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Qinying Han
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, 730030, China.
- Humanized animal model laboratory, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
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Rogers JE, Leung M, Ajani JA. Evaluating the pharmacokinetics of zolbetuximab in gastric adenocarcinoma. Expert Opin Drug Metab Toxicol 2025:1-6. [PMID: 40015974 DOI: 10.1080/17425255.2025.2474122] [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: 09/03/2024] [Revised: 01/29/2025] [Accepted: 02/26/2025] [Indexed: 03/01/2025]
Abstract
INTRODUCTION Gastric adenocarcinoma (GAC) represents a heterogeneous disease making treatment advancements difficult. Recently, claudin 18.2 (CLDN18.2) has emerged as an exciting new target in GAC. Zolbetuximab, an anti-CLDN18.2 monoclonal antibody, has now been FDA approved. AREAS COVERED Phase 1, 2, and 3 zolbetuximab trials have been completed in GAC. Phase 3 trials evaluating zolbetuximab in combination with front-line fluoropyrimidine plus platinum therapy improved survival endpoints compared to placebo plus chemotherapy in those with high CLDN18.2 positivity (>75% of tumor cells). This led to zolbetuximab's FDA approval in this population. Here, we review aspects of zolbetuximab's pharmacology known at this time. EXPERT OPINION Zolbetuximab is one of many agents targeting CLDN18.2 under development. Zolbetuximab in combination with chemotherapy has a slight impact on high CLDN18.2 expressed GAC to chemotherapy alone. Examining how to improve upon outcomes will be of benefit. Additionally, there are GAC subsets who may have benefit from zolbetuximab but need more close examination such as those with moderate CLDN18.2 expressed tumors, low CLDN18.2 expressed tumors, and CLD18-ARHGAP fusion patients.
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Affiliation(s)
- Jane E Rogers
- Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
| | - Michael Leung
- Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Anderson Cancer Center, Houston, TX, USA
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29
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Cai J, Wang W, Cong D, Bai Y, Zhang W. Development of treatment strategies for advanced HER2-positive gastric cancer: Insights from clinical trials. Crit Rev Oncol Hematol 2025; 207:104617. [PMID: 39805409 DOI: 10.1016/j.critrevonc.2025.104617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
HER2-positive gastric cancer (GC), a unique molecular subtype, has garnered significant interest in recent years. Here, we review clinical trial data on advanced HER2-positive GC from the past 15 years. Trastuzumab plus standard chemotherapy remain the first-line treatment. The initial survival benefits conferred by immune checkpoint inhibitors plus trastuzumab and standard chemotherapy are encouraging. The combination of ramucirumab and mono-chemotherapy, as well as the antibody conjugated drug trastuzumab deruxtecan, is the recommended second-line regimen. Treatment with immune checkpoint inhibitors plus ramucirumab and mono-chemotherapy shows promise. Despite the limited treatment options for third line and beyond, development of novel therapeutic strategies is expected. Although clinical cure of advanced HER2-positive GC is unlikely, current clinical studies offer valuable insight into regimens that prolong survival.
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Affiliation(s)
- Jing Cai
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wanning Wang
- Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China
| | - Dan Cong
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Yuansong Bai
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wenlong Zhang
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
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30
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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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31
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Baril JA, Ruedinger BM, Nguyen TK, Bilimoria KY, Ceppa EP, Maatman TK, Roch AM, Schmidt CM, Turk A, Yang AD, House MG, Ellis RJ. Staging accuracy in patients with clinical T2N0 gastric cancer: Implications for treatment sequencing. Surgery 2025; 179:108796. [PMID: 39358121 DOI: 10.1016/j.surg.2024.07.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/01/2024] [Accepted: 07/11/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Patients with clinical T2N0 (cT2N0) gastric adenocarcinoma are recommended to undergo either perioperative chemotherapy or upfront resection. If T2N0 disease is pathologically confirmed, patients may be observed without chemotherapy. These guidelines create the possibility of both systemic therapy overuse and underuse depending on clinical staging accuracy. Our objectives were to define factors associated with upstaging after upfront resection and describe the association between postoperative chemotherapy and survival. METHODS Patients with cT2N0 gastric adenocarcinoma were identified using the National Cancer Database. Factors associated with upstaging were assessed by logistic regression. Survival was assessed using Kaplan-Meier and Cox proportional hazard analyses. RESULTS Of 4,076 patients undergoing upfront resection for cT2N0 gastric cancer, 1,933 (47.4%) were pathologically upstaged. Patients were more likely to be upstaged if they had >3.0-cm (adjusted odds ratio [aOR] 2.31, 95% confidence interval [CI] 1.97-2.70; P < .001) or poorly differentiated tumors (aOR 2.22, 95% CI 1.89-2.60; P < .001). Patients were less likely to be upstaged if they had distal tumors (aOR 0.77, 95% CI 0.64-0.93; P = .006). Of those pathologically upstaged (n = 1,933), 1,111 (57.4%) received adjuvant chemotherapy that was associated with improved survival (HR 0.55, 95% CI 0.47-0.63; P < .001). Among those not upstaged (n = 2,143), 247 (11.5%) received adjuvant chemotherapy that was not associated with improved survival (HR 0.92, 95% CI 0.70-1.21; P = .54). CONCLUSIONS Pathologic upstaging after upfront resection in patients with cT2N0 gastric cancer is associated with patient and tumor characteristics. Adjuvant chemotherapy is associated with improved survival only in the patients upstaged at surgery. An upfront surgical approach may be preferred in select patients, especially if avoiding chemotherapy is desired.
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Affiliation(s)
- Jackson A Baril
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Brian M Ruedinger
- Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Trang K Nguyen
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Section of Surgical Oncology, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO
| | - Karl Y Bilimoria
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Eugene P Ceppa
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Thomas K Maatman
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Alexandra M Roch
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - C Max Schmidt
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Anita Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Anthony D Yang
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Michael G House
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Ryan J Ellis
- Division of Surgical Oncology, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
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32
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Sasagawa S, Honma Y, Peng X, Maejima K, Nagaoka K, Kobayashi Y, Oosawa A, Johnson TA, Okawa Y, Liang H, Kakimi K, Yamada Y, Nakagawa H. Predicting chemotherapy responsiveness in gastric cancer through machine learning analysis of genome, immune, and neutrophil signatures. Gastric Cancer 2025; 28:228-244. [PMID: 39621213 PMCID: PMC11842519 DOI: 10.1007/s10120-024-01569-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 11/11/2024] [Indexed: 02/21/2025]
Abstract
BACKGROUND Gastric cancer is a major oncological challenge, ranking highly among causes of cancer-related mortality worldwide. This study was initiated to address the variability in patient responses to combination chemotherapy, highlighting the need for personalized treatment strategies based on genomic data. METHODS We analyzed whole-genome and RNA sequences from biopsy specimens of 65 advanced gastric cancer patients before their chemotherapy treatment. Using machine learning techniques, we developed a model with 123 omics features, such as immune signatures and copy number variations, to predict their chemotherapy outcomes. RESULTS The model demonstrated a prediction accuracy of 70-80% in forecasting chemotherapy responses in both test and validation cohorts. Notably, tumor-associated neutrophils emerged as significant predictors of treatment efficacy. Further single-cell analyses from cancer tissues revealed different neutrophil subgroups with potential antitumor activities suggesting their usefulness as biomarkers for treatment decisions. CONCLUSIONS This study confirms the utility of machine learning in advancing personalized medicine for gastric cancer by identifying tumor-associated neutrophils and their subgroups as key indicators of chemotherapy response. These findings could lead to more tailored and effective treatment plans for patients.
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Affiliation(s)
- Shota Sasagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Yoshitaka Honma
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Xinxin Peng
- Precision Scientific (Beijing) Ltd, Beijing, 100085, China
| | - Kazuhiro Maejima
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Koji Nagaoka
- Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Immunology, Faculty of Medicine, Kindai University, Sayama, Osaka, 589-8511, Japan
| | - Yukari Kobayashi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Immunology, Faculty of Medicine, Kindai University, Sayama, Osaka, 589-8511, Japan
| | - Ayako Oosawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Todd A Johnson
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Yuki Okawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Han Liang
- Department of Bioinformatics and Computational Biology, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kazuhiro Kakimi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Immunology, Faculty of Medicine, Kindai University, Sayama, Osaka, 589-8511, Japan
| | - Yasuhide Yamada
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
- Department of Medical Research, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Hidewaki Nakagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
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Martínez-Ciarpaglini C, Barros R, Caballero C, Boggino H, Alarcón-Molero L, Peleteiro B, Ruiz-García E, Fernandez-Figueroa E, Herrera-Goepfert R, Díaz-Romero C, Ferreira R, Groen-van Schooten TS, Gauna C, Pereira R, Cantero D, Lezcano H, Esteso F, O Connor J, Riquelme A, Owen GI, Garrido M, Roa JC, Ruiz-Pace F, Vivancos A, Diez-García M, Alsina M, Matito J, Martin A, Gómez M, Castillo E, Vila M, Santos-Antunes J, Costa A, Lordick F, Farrés J, Palomar-De Lucas B, Cabeza-Segura M, Villagrasa R, Jimenez-Martí E, Miralles-Marco A, Dienstmann R, Derks S, Figueiredo C, Cervantes A, Carneiro F, Fleitas-Kanonnikoff T. Comprehensive histopathological analysis of gastric cancer in European and Latin America populations reveals differences in PDL1, HER2, p53 and MUC6 expression. Gastric Cancer 2025; 28:160-173. [PMID: 39755998 PMCID: PMC11842524 DOI: 10.1007/s10120-024-01578-3] [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: 08/24/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025]
Abstract
INTRODUCTION Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries. MATERIAL AND METHODS Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries. Formalin-fixed paraffin-embedded primary tumour endoscopic biopsy samples were collected and submitted for central morphological and immunohistochemical characterization and TP53 molecular assessment and Helicobacter pylori infection. RESULTS A total of 259 patients were included in the study: 137 (53%) from LATAM and 122 (47%) from Europe. Significant biological differences were detected between European and LATAM patients. Low representation of chromosomal instability (CIN) and HER2 positive cases were found in LATAM. MUC6 and PD-L1 were more frequently overexpressed in European cases, showing a significant correlation across the entire study population, with this association being especially pronounced in MMRdeficient cases. Both TP53 mutation by next-generation sequencing and p53 immunohistochemical aberrant pattern were linked with features associated with chromosomal instability. No regional differences were observed in H. pylori prevalence or abundance, indicating that the afore mentioned variations cannot be attributed to this factor. CONCLUSION Our findings underscore a need for region-specific approaches in gastroesophageal cancer diagnosis and treatment. MUC6 emerges as a putative immune regulator that needs further investigation. Research tailored to the unique biological profiles in different global regions is crucial to effectively address the observed disparities.
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Affiliation(s)
- Carolina Martínez-Ciarpaglini
- Department of Pathology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Rita Barros
- Ipatimup, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, 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
| | | | - Hugo Boggino
- Department of Pathology, GENPAT, Asunción, Paraguay
| | - Lorena Alarcón-Molero
- Department of Pathology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
- Department of Pathology, Hospital General de Valdepeñas, Valdepeñas, Spain
| | - Bárbara Peleteiro
- Hospital Epidemiology Center, University Hospital Center of São João, Porto, Portugal
- Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal
- EPIUnit-Institute of Public Health, University of Porto, Porto, Portugal
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, Porto, Portugal
| | - Erika Ruiz-García
- Departamento de Tumores de Tubo Digestivo, Instituto Nacional de Cancerología, Mexico City, México
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, México
| | - Edith Fernandez-Figueroa
- Núcleo B de Innovación en Medicina de Precisión, Instituto Nacional de Medicina Genómica, Mexico City, México
| | | | - Consuelo Díaz-Romero
- Departamento de Oncología Médica, Instituto Nacional de Cancerología, Mexico City, México
| | - Rui Ferreira
- Ipatimup, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Microbes & Cancer. i3S, Instituto de Investigação e Inovação em Saúde, , Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | - 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, The Netherlands
| | - Cinthia Gauna
- Medical Oncology Department, Instituto de Previsión Social, Asunción, Paraguay
| | - Rita Pereira
- Medical Oncology Department, Instituto de Previsión Social, Asunción, Paraguay
| | - Daniel Cantero
- Department of Gastroenterology, Instituto de Previsión Social, Asunción, Paraguay
| | - Horacio Lezcano
- Pathology Department, Instituto de Previsión Social, Asunción, Paraguay
| | - 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 MedicineCenter for Prevention and Control of Cancer (CECAN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Gareth I Owen
- Faculty of Biological Sciences & Faculty of Medicine, Millennium Institute for Immunology and ImmunotherapyCenter for Prevention and Control of Cancer (CECAN), Advance Center for Chronic Disease (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- Centro de Oncología de Precisión, Universidad Mayor, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology. Faculty of Medicine. Pontificia, Universidad Católica de Chile Santiago, Santiago, Chile
| | - Fiorella Ruiz-Pace
- Oncology Data Science, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Ana Vivancos
- Cancer Genomics Lab, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Marc Diez-García
- Medical Oncology Department, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Maria Alsina
- Medical Oncology Department, Valld`Hebron Institute of Oncology, Barcelona, Spain
- Hospital Universitario de Navarra, Navarrabiomed-IdiSNA, Pamplona, Spain
| | - Judit Matito
- Cancer Genomics Lab, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Agatha Martin
- Cancer Genomics Lab, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Marina Gómez
- Cancer Genomics Lab, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Ester Castillo
- Cancer Genomics Lab, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - Maria Vila
- Cancer Genomics Lab, Valld`Hebron Institute of Oncology, Barcelona, Spain
| | - 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
| | - Florian Lordick
- Department of Medicine (Oncology, Gastroenterology, Hepatology, and Pulmonology), Comprehensive Cancer Center Central Germany (CCCG), University of Leipzig Medical Center, Leipzig, Germany
| | | | - Brenda Palomar-De Lucas
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain
| | - Manuel Cabeza-Segura
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain
| | - Rosanna Villagrasa
- Department of Gastroenterology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Elena Jimenez-Martí
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain
| | - Ana Miralles-Marco
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain
| | - Rodrigo Dienstmann
- Oncology Data Science, Valld`Hebron Institute of Oncology, Barcelona, 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, The Netherlands
| | - Ceu Figueiredo
- Ipatimup, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, 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
| | - Andrés Cervantes
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain
- Department of Gastroenterology, Hospital Clínico Universitario de Valencia, Valencia, Spain
- CiberOnc. Carlos III Institute, Madrid, Spain
| | - Fátima Carneiro
- Ipatimup, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, 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
| | - Tania Fleitas-Kanonnikoff
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Avenida Menendez Pelayo nro 4 accesorio, Valencia, Spain.
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Gasparello J, Ceccon C, Angerilli V, Comunello T, Sabbadin M, D'Almeida Costa F, Antico A, Luchini C, Parente P, Bergamo F, Lonardi S, Fassan M. Liquid biopsy in gastric cancer: A snapshot of the current state of the art. THE JOURNAL OF LIQUID BIOPSY 2025; 7:100288. [PMID: 40027230 PMCID: PMC11863821 DOI: 10.1016/j.jlb.2025.100288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 03/05/2025]
Abstract
Circulating tumor DNA (ctDNA) is nowadays considered a robust source to search for druggable tumoral genetic alterations, and in some specific settings liquid biopsy (LB) is already part of the diagnostics scenario and it has successfully implemented in the everyday practice. Three strengths make LB an extraordinary tool: i) to represent the complex molecular mosaicism that characterizes spatially heterogeneous malignancies; ii) to monitor in real-time the tumoral molecular landscape (i.e. to depict the longitudinal/temporal tumor evolution); iii) to ensure molecular profiling even in those cases in which tissue sampling is not feasible or not adequate. This review provides a snapshot of the current state of the art concerning ctDNA assay utility in gastric cancer (GC), testing its robustness as marker and seeking to understand the reasons for the delay in its application in clinical practice.
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Affiliation(s)
| | - Carlotta Ceccon
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Valentina Angerilli
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Pathology, Nijmegen, the Netherlands
| | - Tatiane Comunello
- Department of Pathology, A.C. Camargo Cancer Center, Sao Paulo, Brazil
| | - Marianna Sabbadin
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Antonio Antico
- Department of Clinical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | | | - Sara Lonardi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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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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36
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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 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 Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, P. R. China
| | - Bo Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. 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, Beijing, P. R. 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, Beijing, P. R. China
| | - Luhua Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, P. R. China
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37
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Zhang H, Zheng M, Cai Y, Kamara S, Chen J, Zhu S, Zhang L. Novel affibody molecules targeting the AXL extracellular structural domain for molecular imaging and targeted therapy of gastric cancer. Gastric Cancer 2025; 28:174-186. [PMID: 39644434 PMCID: PMC11842530 DOI: 10.1007/s10120-024-01568-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 11/10/2024] [Indexed: 12/09/2024]
Abstract
Gastric cancer (GC) has a poor prognosis and high mortality because it is often diagnosed at an advanced stage. Targeted therapeutics are considered an important class for advanced GC treatment. However, the fewer effective therapeutic targets and the poor coverage of the GC population limit the use of GC targeted therapies. Recent research suggests that the AXL receptor tyrosine kinase (AXL) plays an vital role in the survival and proliferation of GC cells, and blocking AXL pathway may be an effective strategy for targeted therapies. On the other hand, the affibody molecule, with its small size and faster penetration of tissue, has great potential in tumor imaging and targeted therapy. In this study, we report the novel AXL-binding affibody molecules (ZAXL:239) screened by a phage-displayed peptide library. The ZAXL:239 could specifically bind and interact with AXL proteins in vitro and in vivo, as demonstrated by surface plasmon resonance, co-immunoprecipitation, immuno-fluorescence co-localization, and near infrared fluorescent imaging. In addition, ZAXL:239 affibody molecules could significantly inhibit the proliferative activity and induce apoptosis of AXL-positive GC cells by decreasing the phosphorylation levels of the PI3K/AKT1 and MEK/ERK pathway, leading to the suppression of the downstream nuclear protein c-myc. Moreover, ZAXL:239 was found to have significant anti-tumor effects in AXL-positive GC transplantation tumor nude mouse models. In brief, we provide strong evidence that the novel ZAXL:239 affibody molecules have great potential as a potent tumor-specific molecular imaging and targeted therapeutic agents for GC.
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Affiliation(s)
- HuiHui Zhang
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Maolin Zheng
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - YiQi Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Saidu Kamara
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Jun Chen
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Shanli Zhu
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China
| | - Lifang Zhang
- Institute of Molecular Virology and Immunology, Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
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Okines AFC, Curigliano G, Mizuno N, Oh DY, Rorive A, Soliman H, Takahashi S, Bekaii-Saab T, Burkard ME, Chung KY, Debruyne PR, Fox JR, Gambardella V, Gil-Martin M, Hamilton EP, Monk BJ, Nakamura Y, Nguyen D, O'Malley DM, Olawaiye AB, Pothuri B, Reck M, Sudo K, Sunakawa Y, Van Marcke C, Yu EY, Ramos J, Tan S, Bieda M, Stinchcombe TE, Pohlmann PR. Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial. Nat Med 2025; 31:909-916. [PMID: 39825152 PMCID: PMC11922774 DOI: 10.1038/s41591-024-03462-0] [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: 04/24/2024] [Accepted: 12/11/2024] [Indexed: 01/20/2025]
Abstract
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .
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Affiliation(s)
| | - Giuseppe Curigliano
- Istituto Europeo di Oncologia, IRCCS, Milan, Italy
- University of Milano, Milan, Italy
| | | | - Do-Youn Oh
- Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea
| | - Andree Rorive
- CHU Sart Tilman Liège, University of Liège, Liège, Belgium
| | - Hatem Soliman
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | | | | | - Mark E Burkard
- UW Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - Ki Y Chung
- Prisma Health Institute, Greenville, SC, USA
| | - Philip R Debruyne
- Kortrijk Cancer Centre, General Hospital AZ Groeninge, Kortrijk, Belgium
- Medical Technology Research Centre (MTRC), School of Life Sciences, Anglia Ruskin University, Cambridge, UK
- School of Nursing and Midwifery, University of Plymouth, Plymouth, UK
| | - Jenny R Fox
- Rocky Mountain Cancer Center, Boulder, CO, USA
| | | | - Marta Gil-Martin
- Institut Català d'Oncologia L'Hospitalet-IDIBELL, Hospitalet de Llobregat, Spain
| | | | - Bradley J Monk
- Florida Cancer Specialists and Research Institute, West Palm Beach, FL, USA
| | | | - Danny Nguyen
- City of Hope National Medical Center, Duarte, CA, USA
| | - David M O'Malley
- The Ohio State University and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Bhavana Pothuri
- Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Martin Reck
- Department of Thoracic Oncology, Airway Research Center North, Germany Center for Lung Disease, Grosshansdorf, Germany
| | | | - Yu Sunakawa
- St. Marianna University Hospital, Kawasaki, Japan
| | | | - Evan Y Yu
- Fred Hutchinson Cancer Center/University of Washington, Seattle, WA, USA
| | | | | | | | | | - Paula R Pohlmann
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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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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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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Kanwal W, Narjis K, Musani S, Nancy F, Qureshi L, Mudasir M, Naseem R, Tooba F, Yousuf J, Farhan K, Javed H, Eljack MMF. Exploring Zanidatamab's efficacy across HER2-positive Malignancies: a narrative review. BMC Cancer 2025; 25:382. [PMID: 40025472 PMCID: PMC11871714 DOI: 10.1186/s12885-025-13749-1] [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: 11/08/2024] [Accepted: 02/17/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND HER2-positive cancers involve amplification or overexpression of the HER2 gene, leading to aggressive tumor growth across several cancer types, including breast, gastric, ovarian, and pancreatic cancers. Detection methods such as immunohistochemistry, next-generation sequencing, and fluorescence in situ hybridization are used, with new advancements like biosensors and circulating tumor DNA offering improved diagnostic potential. Treatment strategies have evolved, including anti-HER2 drugs like trastuzumab and newer agents like zanidatamab, which show promise against HER2-positive malignancies. METHODS A comprehensive search of the following academic databases was performed including PubMed, Cochrane Library, and clinicaltrials.gov. A detailed search string was made. Studies were selected based on whether they contained the keywords and if they reported the details of treatment for zanidatamab. A total of 16 studies were selected. Abstracts were independently examined by one author and critically reviewed by another and if there were any conflicting viewpoints they were discussed until consensus was reached. DISCUSSION Zanidatamab has shown promising clinical outcomes in several HER2-positive cancers, including biliary tract, breast, gastric, and lung cancers, with high disease control rates and progression-free survival. Although it is not yet FDA-approved, it has received priority review for HER2-positive biliary tract cancer, with an FDA decision expected in November 2024. The safety profile of zanidatamab has been well-studied. The most common side effects include diarrhea, infusion reactions, and other mild to moderate treatment-related adverse events. In combination with Palbociclib for HER2-positive breast cancer, more severe side effects were observed, resulting in some patients discontinuing treatment. However, no treatment-related deaths have been reported across trials. While its anticancer efficacy and manageable safety profile are promising, long-term safety and efficacy data are still needed. Early clinical trials demonstrate strong efficacy, though some side effects, such as diarrhea and decreased ejection fraction, were noted. Future research should focus on understanding potential resistance mechanisms and establishing zanidatamab's broader role in the treatment landscape of HER2-positive cancers. CONCLUSION In summary, zanidatamab has shown significant tumor response, progression-free survival, disease control, and improved quality of life in early trials, however, the lack of long-term safety and efficacy data remains a key limitation, requiring further research.
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Affiliation(s)
| | - Kaneez Narjis
- Isra University of Medical Sciences, Hyderabad, Pakistan
| | - Sarah Musani
- Dow University of Health Sciences, Karachi, Pakistan
| | - Fnu Nancy
- Jinnah Sindh Medical University, Karachi, Pakistan
| | - Laiba Qureshi
- Isra University of Medical Sciences, Hyderabad, Pakistan
| | - Muhammad Mudasir
- Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Rohma Naseem
- Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Fnu Tooba
- Hamdard University, Karachi, Pakistan
| | | | - Kanza Farhan
- Jinnah Sindh Medical University, Karachi, Pakistan
| | - Hadiya Javed
- Dow University of Health Sciences, Karachi, Pakistan
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Camera S, Rossari F, Foti S, Vitiello F, Persano M, Prinzi FL, De Cobelli F, Aldrighetti L, Cascinu S, Rimini M, Casadei-Gardini A. HER2 Pathway in Biliary Tract Cancer: A Snapshot of the Current Understanding and Future Directions. Target Oncol 2025; 20:269-280. [PMID: 39985696 DOI: 10.1007/s11523-025-01132-w] [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: 02/05/2025] [Indexed: 02/24/2025]
Abstract
Biliary tract cancers (BTCs) are a wide class of malignancies with dismal prognosis. The therapeutic scenario of metastatic BTCs has profoundly changed during recent years. The combination of cisplatin-gemcitabine plus immunotherapy is currently the gold standard in the first line. The more extensive comprehension of the mechanisms at the basis of BTCs and the identification of several molecular alterations has led to the introduction of target-directed therapies in the second line and beyond that have expanded the therapeutic armamentarium alongside the standard FOLFOX regimen, and for the near future, the results of some trials with targeted therapies in first line are expected. HER2 represents a promising therapeutic target detected in BTCs, being overexpressed in approximately 15-20% of cases, with a strong predilection for gallbladder carcinoma and extrahepatic cholangiocarcinoma, although a small proportion of HER2 overexpression can be detected even in intrahepatic cholangiocarcinoma. The efficacy and safety of different HER2 inhibitors have been investigated in several studies in the second line and beyond with encouraging results. This comprehensive review is intended to provide a summary of existing evidence and future perspectives on HER2 altered BTCs.
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Affiliation(s)
- Silvia Camera
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy
| | - Federico Rossari
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Foti
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy
| | - Francesco Vitiello
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy
| | - Mara Persano
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Federica Lo Prinzi
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200-00128, Rome, Italy
| | - Francesco De Cobelli
- Radiology Department, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Stefano Cascinu
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, via Olgettina 60, 20132, Milan, Italy.
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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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Semenova Y, Kerimkulov A, Uskenbayev T, Zharlyganova D, Shatkovskaya O, Sarina T, Manatova A, Yessenbayeva G, Adylkhanov T. Chemotherapy Options for Locally Advanced Gastric Cancer: A Review. Cancers (Basel) 2025; 17:809. [PMID: 40075656 PMCID: PMC11899121 DOI: 10.3390/cancers17050809] [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: 01/24/2025] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Cancers represent a significant global health burden, affecting millions of individuals each year [...].
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Affiliation(s)
- Yuliya Semenova
- Department of Surgery, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan;
| | - Altay Kerimkulov
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
| | - Talgat Uskenbayev
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
| | - Dinara Zharlyganova
- Department of Scientific Management, National Research Oncology Center, Astana 020000, Kazakhstan; (D.Z.); (G.Y.)
| | - Oxana Shatkovskaya
- Board for Strategic Development, Scientific and Educational Activities, National Research Oncology Center, Astana 020000, Kazakhstan;
| | - Tomiris Sarina
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
| | - Almira Manatova
- Department of Scientific Management, National Research Oncology Center, Astana 020000, Kazakhstan; (D.Z.); (G.Y.)
| | - Gulfairus Yessenbayeva
- Department of Scientific Management, National Research Oncology Center, Astana 020000, Kazakhstan; (D.Z.); (G.Y.)
| | - Tasbolat Adylkhanov
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
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Mariani A, Triantafyllou E, Kepenekian V, Zaanan A, Glehen O, Karoui M. Management of peritoneal gastric metastasis: An update. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109731. [PMID: 40106892 DOI: 10.1016/j.ejso.2025.109731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/13/2025] [Accepted: 02/26/2025] [Indexed: 03/22/2025]
Abstract
IMPORTANCE Peritoneal metastases from gastric cancer (PMGC) are associated with poorer median survival and systemic chemotherapy remains the standard of care. This narrative review summarizes the current evidence for medical and surgical treatment of PMGC. OBSERVATIONS Treatment is moving to local ways of administering chemotherapy, either intraperitoneal normothermic chemotherapy, laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) or even pressurized intraperitoneal aerosol chemotherapy. Furthermore, cytoreductive surgery±HIPEC could also be an alternative in specific situations. CONCLUSIONS and relevance: This review provides an updated summary of existing strategies that can be discussed in the management of patients with PMGC.
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Affiliation(s)
- Antoine Mariani
- Department of Digestive Surgery, Université Paris Cité, Assistance Publique Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France.
| | - Evangelia Triantafyllou
- Department of Digestive Surgery, Université Paris Cité, Assistance Publique Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France
| | - Vahan Kepenekian
- Surgical Oncology Department, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France
| | - Aziz Zaanan
- Department of Digestive Oncology, Université Paris Cité, Assistance Publique Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France
| | - Olivier Glehen
- Surgical Oncology Department, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France
| | - Mehdi Karoui
- Department of Digestive Surgery, Université Paris Cité, Assistance Publique Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France
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Zhou C, Wu K, Gu M, Yang Y, Tu J, Huang X. Reversal of chemotherapy resistance in gastric cancer with traditional Chinese medicine as sensitizer: potential mechanism of action. Front Oncol 2025; 15:1524182. [PMID: 40052129 PMCID: PMC11882405 DOI: 10.3389/fonc.2025.1524182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025] Open
Abstract
Gastric cancer (GC) remains one of the most common types of cancer, ranking fifth among cancer-related deaths worldwide. Chemotherapy is an effective treatment for advanced GC. However, the development of chemotherapy resistance, which involves the malfunction of several signaling pathways and is the consequence of numerous variables interacting, seriously affects patient treatment and leads to poor clinical outcomes. Therefore, in order to treat GC, it is imperative to find novel medications that will increase chemotherapy sensitivity and reverse chemotherapy resistance. Traditional Chinese medicine (TCM) has been extensively researched as an adjuvant medication in recent years. It has been shown to have anticancer benefits and to be crucial in enhancing chemotherapy sensitivity and reducing chemotherapy resistance. Given this, the mechanism of treatment resistance in GC is summed up in this work. The theoretical foundation for TCM as a sensitizer in adjuvant treatment of GC is established by introducing the primary signal pathways and possible targets implicated in improving chemotherapy sensitivity and reversing chemotherapy resistance of GC by TCM and active ingredients.
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Affiliation(s)
| | | | | | | | | | - Xuan Huang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese
Medical University, Hangzhou, Zhejiang, China
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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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48
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He X, Guan XY, Li Y. Clinical significance of the tumor microenvironment on immune tolerance in gastric cancer. Front Immunol 2025; 16:1532605. [PMID: 40028336 PMCID: PMC11868122 DOI: 10.3389/fimmu.2025.1532605] [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: 11/22/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
In the realm of oncology, the tumor microenvironment (TME)-comprising extracellular matrix components, immune cells, fibroblasts, and endothelial cells-plays a pivotal role in tumorigenesis, progression, and response to therapeutic interventions. Initially, the TME exhibits tumor-suppressive properties that can inhibit malignant transformation. However, as the tumor progresses, various factors induce immune tolerance, resulting in TME behaving in a state that promotes tumor growth and metastasis in later stages. This state of immunosuppression is crucial as it enables TME to change from a role of killing tumor cells to a role of promoting tumor progression. Gastric cancer is a common malignant tumor of the gastrointestinal tract with an alarmingly high mortality rate. While chemotherapy has historically been the cornerstone of treatment, its efficacy in prolonging survival remains limited. The emergence of immunotherapy has opened new therapeutic pathways, yet the challenge of immune tolerance driven by the gastric cancer microenvironment complicates these efforts. This review aims to elucidate the intricate role of the TME in mediating immune tolerance in gastric cancer and to spotlight innovative strategies and clinical trials designed to enhance the efficacy of immunotherapeutic approaches. By providing a comprehensive theoretical framework, this review seeks to advance the understanding and application of immunotherapy in the treatment of gastric cancer, ultimately contributing to improved patient outcomes.
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Affiliation(s)
- Xiangyang He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Clinical Oncology, The University of Hongkong, Hong Kong, Hong Kong SAR, China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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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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Li H, Ren C, Cui D, Wu T, Nie Z. Case report: Patients with positive HER-2 amplification locally advanced gastroesophageal junction cancer achieved pathologic complete response with the addition of pembrolizumab to chemotherapy plus trastuzumab as neoadjuvant therapy. Front Immunol 2025; 16:1555074. [PMID: 40013139 PMCID: PMC11860954 DOI: 10.3389/fimmu.2025.1555074] [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: 01/03/2025] [Accepted: 01/20/2025] [Indexed: 02/28/2025] Open
Abstract
Background Human epidermal growth factor receptor 2(HER-2) is the most prominent therapeutic target for gastric (G)/gastroesophageal junction (GEJ) cancer. Guidelines recommend its use for treating G/GEJ cancers. However, targeted therapy did not significantly improve survival outcomes compared to those with neoadjuvant therapy. The KEYNOTE-811 trial revealed an improved objective response rate (74% vs. 52%; P=.0001) and median duration of response (10.6 vs 9.5 months) with the addition of pembrolizumab (PD-1) to chemotherapy plus trastuzumab compared to that with the addition of placebo in patients with HER-2 overexpression-positive advanced adenocarcinoma. Therefore, addition of PD-1 to chemotherapy plus trastuzumab may lead to a better response in patients with G/GEJ cancer. Case presentation A 66-year-old man was diagnosed with stage III GEJ adenocarcinoma with celiac lymph node metastasis. Immunohistochemical results indicated HER-2(3+) and PD-L1 CPS=5. The patient received three cycles of pembrolizumab plus trastuzumab and chemotherapy preoperatively and underwent radical surgery on November 22, 2022. Conclusion Patients with HER-2-positive locally advanced GEJ cancers received PD-1 immunotherapy combined with trastuzumab and neoadjuvant chemotherapy and achieved a complete pathological response. Hence, it is a novel, highly specific, and potent therapeutic option for HER-2-positive patients and should henceforth be considered as a new treatment approach.
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Affiliation(s)
| | | | | | | | - Zhiyong Nie
- Department of Oncology, Anyang Tumor Hospital, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang, China
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