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Phillips MJ, Alese OB, Horvat NK, Greene E, Gbolahan OB, Coleman K, Doxie DB, Parihar V, Mahdi ZK, McCook-Veal A, Switchenko JM, Diab M, Herting CJ, Paulos CM, El-Rayes BF, Lesinski GB. XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial. Oncoimmunology 2025; 14:2475620. [PMID: 40079916 PMCID: PMC11913390 DOI: 10.1080/2162402x.2025.2475620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 02/17/2025] [Accepted: 03/02/2025] [Indexed: 03/15/2025] Open
Abstract
We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients. Comprehensive analyses of plasma cytokines, peripheral blood mononuclear cells (PBMCs), and spatial immune cell patterns in liver biopsies were performed to identify unique immune signatures resulting from the combined therapy. The combination of pembrolizumab and XL888 proved to be safe and feasible, with a subset of patients achieving stable disease, although no objective responses were observed in this heavily pre-treated population. Correlative studies revealed immunomodulatory effects in tumors and circulation, including a reduction in IL6+ cells and macrophages (CD68+) within metastatic liver tissue, alterations in blood CD3+ cells, and upregulation of numerous inflammatory plasma cytokines. These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation.
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Affiliation(s)
- Maggie J. Phillips
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Olatunji B. Alese
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Natalie K. Horvat
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Emily Greene
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Olumide B. Gbolahan
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | | | - Deon B. Doxie
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Vaunita Parihar
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Zaid K. Mahdi
- Department of Pathology, Emory University, Atlanta, GA, USA
| | - Ashley McCook-Veal
- Department of Biostatistics & Bioinformatics, Emory University, Atlanta, GA, USA
| | | | - Maria Diab
- Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Cameron J. Herting
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Chrystal M. Paulos
- Department of Surgery, Emory University, Atlanta, GA, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Bassel F. El-Rayes
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gregory B. Lesinski
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
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Bahrami P, Al Zein M, Eid AH, Sahebkar A. Liver Transplantation for Non-hepatocellular Carcinoma: The Role of Immune Checkpoint Inhibitors. J Clin Exp Hepatol 2025; 15:102558. [PMID: 40303874 PMCID: PMC12036051 DOI: 10.1016/j.jceh.2025.102558] [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: 09/28/2024] [Accepted: 03/22/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC), gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), and cholangiocarcinoma (CCA) exhibit high rates of morbidity and mortality once metastasized to the liver. Liver transplantation (LT) is a viable therapeutic approach for these cancers in highly selected patients; however, their invasive nature at late stages causes many patients to be delisted from transplantation or to require further downstaging. Immunotherapy with immune checkpoint modulators has revolutionized cancer research. Immune checkpoint inhibitors (ICI) leverage the chronic inflammatory state and the overexpression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) by malignant cells and regulatory T cells, to block immune checkpoints and counteract tumor's ability to evade the immune system. However, the interaction between allograft PD-L1 and PD-1 on infiltrating T cells functions as a means of graft tolerance in cases of LT. Therefore, the application of ICIs might block this protective effect and induce graft rejection, a phenomenon particularly observed in PD-1/PD-L1 inhibiting ICIs. The risk of post-LT graft rejection can be mitigated by applying advanced biomarkers and specifying certain mutations that enhance patient selection criteria for pre-LT ICI use. Furthermore, the determination of optimal intervals of ICI administration pre- and post-LT, identification of ICI indications in de novo malignancies occurring after LT, and investigation of biomarkers for early rejection detection, pave the way for more promising LT outcomes in patients with CRC, GEP-NEN, or CCA. Therefore, this review aims to illustrate a comprehensive overview of the role of ICI therapy in the management of non-hepatocellular carcinoma transplant oncology cancers by demonstrating the potential for its application in both pre-and post-LT states, and pathways to reduce or timely detect ICI-associated graft rejection.
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Affiliation(s)
- Pegah Bahrami
- Applied Biomedical Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Al Zein
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Hu G, Shen S, Zhu M. CXCL9 is a dual‑role biomarker in colorectal cancer linked to mitophagy and modulated by ALKBH5. Mol Med Rep 2025; 32:188. [PMID: 40341964 PMCID: PMC12076282 DOI: 10.3892/mmr.2025.13553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 03/18/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC), the third most prevalent cancer globally, shows a diminished 5‑year survival rate compared with patients at early stages of the disease, underscoring the urgency for early diagnostic biomarker identification. The C‑X‑C motif chemokine ligand (CXCL) family plays a significant role in immune modulation and cancer progression. the present study constructed a prognostic model for CXCL family in CRC and conducted an in‑depth investigation of the hub gene CXCL9 within the model. CXCL9 is highly expressed in CRC while high expression levels of CXCL9 in patients with CRC often indicates an improved prognosis. Through Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis enrichment analysis, it was discovered that CXCL9 is not only associated with immune modulation but also closely related to pathways that affect the occurrence and development of cancer. CXCL9 is closely related to mitophagy and blocks autophagy flow by altering the expression of autophagy‑related genes. Additionally, it was found that CXCL9 is a downstream gene modified by ALKBH5 and can partially restore the tumor‑suppressive effects induced by the knockdown of ALKBH5. These studies indicated that CXCL9 is a prognostic marker in CRC and plays a dual role in cancer progression: It activates immune responses on one hand and promotes the malignant characteristics of cancer on the other hand.
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Affiliation(s)
- Geng Hu
- Department of Laboratory, Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, P.R. China
| | - Shijun Shen
- Department of Hepatobiliary and Pancreatic Minimally Invasive Surgery, Lincang People's Hospital, Lincang, Yunnan 677099, P.R. China
| | - Mingchao Zhu
- Department of Laboratory, Tianmen First People's Hospital, Tianmen, Hubei 431700, P.R. China
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Qi GX, Zhao RX, Gao C, Ma ZY, Wang S, Xu J. Recent advances and challenges in colorectal cancer: From molecular research to treatment. World J Gastroenterol 2025; 31:106964. [DOI: 10.3748/wjg.v31.i21.106964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/22/2025] [Accepted: 05/26/2025] [Indexed: 06/06/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the top causes of cancer-related fatalities globally. Recent progress in genomics, proteomics, and bioinformatics has greatly improved our comprehension of the molecular underpinnings of CRC, paving the way for targeted therapies and immunotherapies. Nonetheless, obstacles such as tumor heterogeneity and drug resistance persist, hindering advancements in treatment efficacy. In this context, the integration of artificial intelligence (AI) and organoid technology presents promising new avenues. AI can analyze genetic and clinical data to forecast disease risk, prognosis, and treatment responses, thereby expediting drug development and tailoring treatment plans. Organoids replicate the genetic traits and biological behaviors of tumors, acting as platforms for drug testing and the formulation of personalized treatment approaches. Despite notable strides in CRC research and treatment - from genetic insights to therapeutic innovations - numerous challenges endure, including the intricate tumor microenvironment, tumor heterogeneity, adverse effects of immunotherapies, issues related to AI data quality and privacy, and the need for standardization in organoid culture. Future initiatives should concentrate on clarifying the pathogenesis of CRC, refining AI algorithms and organoid models, and creating more effective therapeutic strategies to alleviate the global impact of CRC.
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Affiliation(s)
- Gao-Xiu Qi
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Rui-Xia Zhao
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Chen Gao
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Zeng-Yan Ma
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Shang Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Jing Xu
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
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Wang Y, Tang C, Wang K, Zhang X, Zhang L, Xiao X, Lin H, Xiong L. The role of ferroptosis in breast cancer: Tumor progression, immune microenvironment interactions and therapeutic interventions. Eur J Pharmacol 2025; 996:177561. [PMID: 40154567 DOI: 10.1016/j.ejphar.2025.177561] [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: 12/29/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.
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Affiliation(s)
- Yi Wang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Chuanyun Tang
- First Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Keqin Wang
- First Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Xiaoan Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Lifang Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Xinghua Xiao
- Department of Pathology, The First Affiliated Hospital, Nanchang University, 17 Yongwaizheng Road, Nanschang, 330066, China
| | - Hui Lin
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Lixia Xiong
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
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Cannarozzi AL, Biscaglia G, Parente P, Latiano TP, Gentile A, Ciardiello D, Massimino L, Di Brina ALP, Guerra M, Tavano F, Ungaro F, Bossa F, Perri F, Latiano A, Palmieri O. Artificial intelligence and whole slide imaging, a new tool for the microsatellite instability prediction in colorectal cancer: Friend or foe? Crit Rev Oncol Hematol 2025; 210:104694. [PMID: 40064251 DOI: 10.1016/j.critrevonc.2025.104694] [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: 12/20/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/18/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common and second most deadly cancer worldwide. Despite advances in screening and treatment, CRC is heterogeneous and the response to therapy varies significantly, limiting personalized treatment options. Certain molecular biomarkers, including microsatellite instability (MSI), are critical in planning personalized treatment, although only a subset of patients may benefit. Currently, the primary methods for assessing MSI status include immunohistochemistry (IHC) for DNA mismatch repair proteins (MMRs), polymerase chain reaction (PCR)-based molecular testing, or next-generation sequencing (NGS). However, these techniques have limitations, are expensive and time-consuming, and often result in inter-method inconsistencies. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) are critical predictive biomarkers of response to immune checkpoint inhibitor (ICI) therapy and MSI testing is recommended to identify patients who may benefit. There is a pressing need for a more robust, reliable, and cost-effective approach that accurately assesses MSI status. Recent advances in computational pathology, in particular the development of technologies that digitally scan whole slide images (WSI) at high resolution, as well as new approaches to artificial intelligence (AI) in medicine, are increasingly gaining ground. This review aims to provide an overview of the latest findings on WSI and advances in AI methods for predicting MSI status, summarize their applications in CRC, and discuss their strengths and limitations in daily clinical practice.
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Affiliation(s)
- Anna Lucia Cannarozzi
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Giuseppe Biscaglia
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo 71013, Italy.
| | - Tiziana Pia Latiano
- Oncology Unit, Fondazione Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo 71013, Italy.
| | - Annamaria Gentile
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Davide Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan.
| | - Luca Massimino
- Gastroenterology and Digestive Endoscopy Department, IRCCS Ospedale San Raffaele, Milan, Italy.
| | - Anna Laura Pia Di Brina
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Maria Guerra
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Francesca Tavano
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Federica Ungaro
- Gastroenterology and Digestive Endoscopy Department, IRCCS Ospedale San Raffaele, Milan, Italy.
| | - Fabrizio Bossa
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Francesco Perri
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Anna Latiano
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
| | - Orazio Palmieri
- Division of Gastroenterology, Fondazione IRCCS - Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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Richard M, Koch C, Trojan J. [Chemotherapy, targeted therapy and immunotherapy of metastatic colorectal cancer : What is new?]. RADIOLOGIE (HEIDELBERG, GERMANY) 2025; 65:443-449. [PMID: 40274654 DOI: 10.1007/s00117-025-01455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
In recent years the treatment options for metastatic colorectal cancer have significantly improved. This progress has particularly benefited specific subgroups of patients identified by certain biomarkers, such as those with a microsatellite instability, patients with B‑Raf (BRAF) V600E mutation, Kirsten rat sarcoma (KRAS) G12C mutation or v‑erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2) amplification. Additionally, targeted anti-epidermal growth factor (EGF) receptor therapy can be more effectively utilized through further patient selection. For patients who no longer respond to treatment, the new standard trifluridine/tipiracil in combination with bevacizumab has become established as the new third-line option. Furthermore, the selectively anti-angiogenic tyrosine kinase inhibitor fruquintinib has recently been approved as a last-line treatment. This article provides an overview of current standards and future developments in therapy.
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Affiliation(s)
- Mirjam Richard
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland
| | - Christine Koch
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland
| | - Jörg Trojan
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland.
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Cercek A, Bachet JB, Capdevila J, Starling N, Chen E, Salvatore L, Bando H, O'Donnell S, Harfst L, Szijgyarto Z, Heinemann V. A Phase Two, Single-Arm, Open-Label Study With Dostarlimab Monotherapy in Participants With Untreated Stage II/III dMMR/MSI-H Locally Advanced Rectal Cancer (AZUR-1). Clin Colorectal Cancer 2025; 24:325-330. [PMID: 40107952 DOI: 10.1016/j.clcc.2025.02.003] [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] [Received: 12/11/2024] [Revised: 02/17/2025] [Accepted: 02/18/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) had the second highest cancer mortality worldwide in 2020; nearly a third of CRCs were rectal cancers (RC). A recent study demonstrated that dostarlimab, an immune-checkpoint inhibitor, was highly effective in treating mismatch repair deficient (dMMR) locally advanced RC as all included patients had a clinical complete response (cCR) without radiation or chemotherapy. This study's objective is to evaluate the efficacy and safety of dostarlimab monotherapy in patients with previously untreated locally advanced dMMR RC. PATIENTS/METHODS AZUR-1 (NCT05723562) is a multicenter, open-label, nonrandomized, single-arm phase 2 study enrolling approximately 150 patients across 10 countries. Key eligibility criteria include dMMR status or microsatellite instability-high (MSI-H) phenotype. Dostarlimab 500 mg will be administered intravenously every 3 weeks for 9 cycles. The primary endpoint is cCR by independent central review (ICR) at 12 months. Key secondary endpoints include cCR by ICR at 24 and 36 months, and 3-year event-free survival by investigator assessment. Additional secondary endpoints include organ preservation rate at 3 years and disease-specific survival and overall survival at 5 years. Efficacy and safety will be assessed in all patients who receive ≥1 dose of dostarlimab. All patients will be followed for 5 years (unless consent is withdrawn). CONCLUSIONS AZUR-1 will evaluate the efficacy of dostarlimab immunotherapy in dMMR/MSI-H RC. Utilizing novel aspects including long follow-up of all patients and standardization of clinical response assessment, this study will provide international multicentric data to evaluate tumor response in an immunotherapy setting and new evidence on long-term outcomes.
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Affiliation(s)
- Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
| | - Jean-Baptiste Bachet
- Sorbonne University, Department of Hepato-Gastroenterology and Digestive Oncology, Pitié Salpêtrière Hospital, Paris, France
| | - Jaume Capdevila
- Gastrointestinal Cancer Unit, Medical Oncology Department, Vall Hebron University Hospital and Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, United Kingdom
| | - Eric Chen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - Lisa Salvatore
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Rome, Italy
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | | | | | - Volker Heinemann
- Department of Medical Hematology/Oncology, Comprehensive Cancer Center, LMU University Hospital, Klinikum der Universität München-Großhadern, Munich, Germany
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Arabi S, Fadaee M, Kazemi T, Rahmani M. Advancements in colorectal cancer immunotherapy: from CAR-T cells to exosome-based therapies. J Drug Target 2025; 33:749-760. [PMID: 39754507 DOI: 10.1080/1061186x.2024.2449482] [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: 09/27/2024] [Revised: 12/03/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.
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Affiliation(s)
- Sepideh Arabi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Manouchehr Fadaee
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammadreza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Yap J, Pattison S. Deficient Mismatch Repair and BRAF Mutations in Metastatic Colorectal Cancer in the South Island of New Zealand. Asia Pac J Clin Oncol 2025; 21:311-318. [PMID: 39807600 DOI: 10.1111/ajco.14151] [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: 10/08/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025]
Abstract
AIM Manatū Hauora, the Ministry of Health of New Zealand (NZ), published minimum standards for molecular testing of colorectal cancers (CRCs) in June 2018. These included mismatch repair (MMR) testing at diagnosis and BRAFV600E mutation analysis on newly diagnosed stage IV CRCs. This study aimed to determine the proportion of patients with CRC in the South Island of NZ with metastatic deficient mismatch repair (dMMR) CRC, the proportion of metastatic CRCs and dMMR CRCs that have a BRAFV600E mutation, and audit testing for BRAF mutations and appropriate referral to genetics services. METHODS People from the South Island with histologically diagnosed colorectal adenocarcinoma between July 1, 2018, and June 30, 2019, were identified by the National Cancer Registry. Data points extracted from the electronic medical record included staging, MMR status, BRAF mutation testing, and genetics referral. RESULTS A total of 845 patients met the inclusion criteria; 166 of 845 (19.6%) had dMMR CRC, and of these 130 (78%) had BRAF mutation, 256 patients developed metastatic disease by data cut-off, 20 (7.8%) had dMMR, and 41 (22.2%) had BRAF mutation. When indicated, 275 of 330 (83.3%) were tested for BRAF mutation and 32 of 45 (71.1%) referred to genetics. Compared with other populations, South Island CRC patients had higher rates of dMMR and BRAF mutation. CONCLUSION Less than 10% of patients (n = 20) had metastatic dMMR CRC. These patients could be considered candidates for immune checkpoint inhibitor therapy, a small number that would not significantly burden the NZ health system if funded. The vast majority of dMMR CRC was sporadic. Rates of testing could be improved.
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Affiliation(s)
- Jeremy Yap
- Southern Blood and Cancer Service, Health New Zealand/Te Whatu Ora - Southern, Dunedin, New Zealand
| | - Sharon Pattison
- Wellington Blood and Cancer Centre, Health New Zealand/Te Whatu Ora - Capital, Coast and Hutt Valley, Wellington, New Zealand
- Department of Pathology, Otago Medical School - Dunedin Campus, University of Otago, Dunedin, New Zealand
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Burge ME, Espinoza D, Sjoquist KM, Siu DH, Mercieca-Bebber R, Chantrill LA, Karapetis CS, Steer CB, Yip S, Cuff J, Winata S, Tie J, Thaker DA, Srivastav R, Abdi E, Strickland A, Segelov E, Francesconi A, Price T, Ladwa R, Joubert W, Tebbutt NC. AGITG MONARCC: A Randomized Phase 2 Study of Panitumumab Monotherapy and Panitumumab Plus 5-Fluorouracil as First-Line Therapy for Older Patients With RAS and BRAF Wild Type Metastatic Colorectal Cancer. A Study by the Australasian Gastro-Intestinal Trials Group (AGITG). Clin Colorectal Cancer 2025; 24:120-128. [PMID: 39779412 DOI: 10.1016/j.clcc.2024.11.003] [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] [Received: 10/14/2024] [Revised: 11/21/2024] [Accepted: 11/24/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Panitumumab (pan) plus chemotherapy is a preferred first-line therapy for unresectable RAS and BRAF wild type metastatic colorectal cancer (mCRC). Older patients may not be suitable for combination regimens. We investigated 2 lower intensity pan-containing regimens. METHODS Prospective, noncomparative, randomized (1:1) phase 2 study of pan alone (Arm A) or pan plus FU (Arm B). Previously untreated mCRC were ≥70 years; RAS/BRAF wild type. PRIMARY ENDPOINT 6-month progression-free survival (PFS). Secondary endpoints included: overall survival (OS), response rate (RR), feasibility of geriatric assessments and overall treatment utility (OTU)-a composite measure based on radiological response, clinical progress, toxicity and patient-reported treatment worth. Planned sample size was 40 patients per arm. RESULTS 36 patients (Arm A n = 19, Arm B n = 17) were randomized between June 2018 and June 2021. Median age was 79 and 80 years respectively. 6-month PFS 63% (95% CI 38%-80%) arm A 82% (95%CI 55%-94%) Arm B. Median OS 21 months Arm A (95%CI 13-31) 28 (95%CI 14-39) months Arm B. RR 47% and 65% Arms A and B respectively. Baseline comprehensive geriatric assessments were completed in >80% of patients. At week 16, OTU was categorized as good in 92% (Arm A) and 90% (Arm B). No unexpected adverse events were seen. CONCLUSIONS Six-month PFS in both arms was consistent with that achieved with FU/bev, whilst the rate was numerically higher for Arm B. Baseline comprehensive geriatric assessments were feasible and OTU was high. Both treatment arms might be suitable in appropriately selected patients.
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Affiliation(s)
- Matthew E Burge
- Royal Brisbane and Women's Hospital, Brisbane, Australia; The University of Queensland, Brisbane, Australia.
| | - David Espinoza
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | | | - Derrick Ho Siu
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | | | | | | | - Christopher B Steer
- Border Medical Oncology, Albury Wodonga Regional Cancer Centre, Victoria, Australia
| | - Sonia Yip
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | - Jeff Cuff
- Australasian Gastro-Intestinal Trials Group-Community Advisory Panel. Level 6, Camperdown, New South Wales, Australia
| | - Stephanie Winata
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | | | | | | | - Ehtesham Abdi
- The Tweed Hospital, Tweed Heads, New South Wales, Australia; Griffith University, Southport, Queensland, Australia
| | - Andrew Strickland
- Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia; Monash University, Clayton, Australia
| | - Eva Segelov
- Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia
| | | | - Timothy Price
- The Queen Elizabeth Hospital, Woodville South, South Australia
| | - Rahul Ladwa
- Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Warren Joubert
- Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
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12
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Maguire B, Kisakol B, Prehn JHM, Burke JP. SATB2 Expression Affects Chemotherapy Metabolism and Immune Checkpoint Gene Expression in Colorectal Cancer. Clin Colorectal Cancer 2025; 24:129-134.e7. [PMID: 39794188 DOI: 10.1016/j.clcc.2024.12.004] [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: 03/10/2024] [Revised: 12/04/2024] [Accepted: 12/08/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Special AT-rich binding protein-2 (SATB2) is a nuclear matrix associated protein regulating gene expression which is normally expressed in colonic tissue. Loss of SATB2 expression in colorectal cancer (CRC) has negative implications for prognosis and has been associated with chemotherapy resistance. Furthermore, recent evidence suggests SATB2 may influence immune checkpoint (IC) expression. We hypothesized that SATB2 expression may be associated with altered expression of chemotherapy resistance associated and IC genes. METHODS Clinicopathologic and gene expression data were extracted from The Cancer Genome Atlas PanCancer Atlas. SATB2 expression was compared by clinicopathologic characteristic and by using multivariate regression analysis to explore associations with chemotherapy and IC gene expression. RESULTS About 553 patients were included for analysis. Lower quartile SATB2 expression was associated with worse disease specific survival (P = .04). MSI (P < .001) and mucinous (P < .001) tumors were associated with reduced SATB2 expression independently. SATB2 varied by consensus molecular subtype (P < .001) and was lowest in CMS1. On multivariate analysis, SATB2 was negatively associated with 5-FU related metabolism genes, while more complex but significant relationships were seen with oxaliplatin and irinotecan related genes. Low SATB2 expression was associated with increased expression of PD-1, PD-L1, TIM-3 and CTLA-4 IC genes. CONCLUSION The positive prognostic influence of SATB2 expression is reaffirmed in this study. This effect may be explained by the negative association between SATB2 and 5-FU-resistance related gene expression. Enhanced IC gene expression in SATB2 low cases suggests a potential role for IC inhibition in this setting, but further study is required.
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Affiliation(s)
- Barry Maguire
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland; Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Batuhan Kisakol
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland.
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13
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Jing Z, Yinhang W, Jian C, Zhanbo Q, Xinyue W, Shuwen H. Interaction between gut microbiota and T cell immunity in colorectal cancer. Autoimmun Rev 2025; 24:103807. [PMID: 40139455 DOI: 10.1016/j.autrev.2025.103807] [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: 07/02/2024] [Revised: 02/26/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025]
Abstract
This review delves into the complex and multi-layered mechanisms that govern the interaction between gut microbiota and T cells in the context of colorectal cancer (CRC), revealing a novel "microbiota-immune regulatory landscape" within the tumor microenvironment. As CRC progresses, the gut microbiota experiences a significant transformation in both its composition and metabolic patterns. On one hand, specific microbial entities within the gut microbiota can directly engage with T cells, functioning as "immunological triggers" that shape T-cell behavior. Simultaneously, microbial metabolites, such as short-chain fatty acids and bile acids, serve as "molecular regulators" that intricately govern T-cell function and differentiation, fine-tuning the immune response. On the other hand, the quorum-sensing mechanism, a recently recognized communication network among bacteria, also plays a pivotal role in orchestrating T-cell immunity. Additionally, the gut microbiota forms an intriguing connection with the neuro-immune regulatory axis, a largely unexplored "territory" in CRC research. Regarding treatment strategies, a diverse array of intervention approaches-including dietary modifications, the utilization of probiotics, bacteriophages, and targeted antibiotic therapies-offer promising prospects for restoring the equilibrium of the gut microbiota, thereby acting as "ecosystem renovators" that impede tumor initiation and progression. Nevertheless, the current research landscape in this field is fraught with challenges. These include significant variations in microbial composition, dietary preferences, and tumor microenvironments among individuals, a lack of large-scale cohort studies, and insufficient research that integrates tumor mutation analysis, gut microbiota investigations, and immune microenvironment evaluations. This review emphasizes the necessity for future research efforts to seamlessly incorporate multiple factors and utilize bioinformatics analysis to construct a more comprehensive "interactive map" of the gut microbiota-T cell relationship in CRC. The aim is to establish a solid theoretical basis for the development of highly effective and personalized treatment regimens, ultimately transforming the therapeutic approach to CRC.
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Affiliation(s)
- Zhuang Jing
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Wu Yinhang
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Chu Jian
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Qu Zhanbo
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Wu Xinyue
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Han Shuwen
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; ASIR (Institute - Association of intelligent systems and robotics), 14B rue Henri Sainte Claire Deville, 92500 Rueil-Malmaison, France.
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14
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Zhang Y, Fan J, Zhao J, Zhu H, Xia Y, Xu H. A telomere-associated molecular landscape reveals immunological, microbial, and therapeutic heterogeneity in colorectal cancer. Front Mol Biosci 2025; 12:1615533. [PMID: 40492114 PMCID: PMC12146184 DOI: 10.3389/fmolb.2025.1615533] [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: 04/21/2025] [Accepted: 05/12/2025] [Indexed: 06/11/2025] Open
Abstract
Background Colorectal cancer (CRC) ranks among the most prevalent malignancies of the gastrointestinal tract and remains a leading cause of cancer-related mortality worldwide. Although telomere biology has been increasingly implicated in immune modulation and tumor progression, its clinical significance in CRC remains poorly understood. Methods We developed a telomere score, termed TELscore, by integrating transcriptomic and intratumoral microbiome profiles from publicly available colorectal cancer (CRC) cohorts. To comprehensively characterize TELscore subgroups, we performed pathway enrichment analysis, tumor immune microenvironment (TIME) profiling, and microbiome niche assessment. Whole-slide histopathological images (WSIs) and immunohistochemical (IHC) staining were utilized to visualize immune features, including tertiary lymphoid structures (TLSs), across subgroups. Patients were stratified into high and low TELscore categories, and the predictive robustness was validated across multiple independent training and validation cohorts. Chemotherapeutic drug sensitivity was evaluated using pharmacogenomic data from the Genomics of Drug Sensitivity in Cancer (GDSC) database. Furthermore, the predictive capacity of TELscore for immunotherapy response was independently assessed in an external cohort. Finally, single-cell RNA sequencing (scRNA-seq) analysis was conducted to further dissect the cellular landscape and immunological heterogeneity within the TME. Results TELscore stratified patients into two biologically and clinically distinct subgroups. The high TELscore group, which exhibited significantly shorter DFS, showed marked enrichment of tumorigenic pathways such as EMT, along with a distinctly immunosuppressive TME. This was reflected by elevated ESTIMATE/TIDE scores and corroborated by CIBERSORT, which revealed increased infiltration of M0 macrophages and upregulation of immunosuppressive signatures. In contrast, the low TELscore group was enriched for cell cycle related pathways, including E2F targets and the G2/M checkpoint, and demonstrated higher infiltration of pro-inflammatory M1 macrophages. 16S rRNA sequencing further revealed a divergent intratumoral microbiome between subgroups, the high TELscore group harbored significantly greater relative abundance of Selenomonas and Lachnoclostridium, two pathogenic genera previously associated with colorectal tumorigenesis. Complementary histopathological assessment via WSI demonstrated a marked absence of intraTLSs in high TELscore tumors. From a therapeutic standpoint, high TELscore tumors exhibited reduced sensitivity to standard chemotherapeutic agents-including Fluorouracil, Irinotecan, Oxaliplatin, and Docetaxel-as reflected by elevated IC50 values. Conversely, these tumors demonstrated increased susceptibility to MAPK pathway inhibitors, such as Selumetinib and Trametinib. Notably, TELscore also served as a robust predictor of immunotherapy response, which was validated in the IMvigor210 cohort. Finally, scRNA analysis highlighted profound cellular and functional divergence between TELscore subgroups. We identified intensified intercellular communication between inflammatory macrophages and fibroblasts, reinforcing the presence of an immunosuppressive niche. Conclusion TELscore is a robust stratification tool that captures the interplay between tumor biology, immune characteristics, and microbial ecology in colorectal cancer. By identifying clinically relevant subtypes with distinct therapeutic vulnerabilities, TELscore offers a powerful framework to advance personalized treatment and precision oncology.
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Affiliation(s)
| | | | | | | | | | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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15
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Cheng F, Shao F, Tian Y, Chen S. Genomic and clinical insights into ovarian cancer: subtype-specific alterations and predictors of metastasis and relapse. Discov Oncol 2025; 16:907. [PMID: 40411628 PMCID: PMC12103430 DOI: 10.1007/s12672-025-02725-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 05/16/2025] [Indexed: 05/26/2025] Open
Abstract
Ovarian cancer exhibits marked molecular heterogeneity and variable clinical outcomes. Understanding genomic alterations associated with metastasis and relapses may guide personalized management, particularly in high-grade serous carcinoma (HGSC). We performed targeted sequencing of 1021 cancer-related genes in tumor-normal pairs from 99 treatment-naïve ovarian cancer patients. Associations between copy number variations (CNVs), metastatic patterns, tumor mutation burden (TMB), and relapses were assessed. Analyses of relapse predictors were restricted to HGSC patients. Statistical significance was determined with Bonferroni correction for multiple comparisons. TP53 mutations were frequent in HGSC (96.6%), whereas PIK3CA, ARID1A, and ATRX mutations were enriched in non-HGSC tumors. FLT3, CDH23, and EPAS1 mutations were associated with metastasis. TMB-high tumors (≥ 9 mutations/Mb) showed distinct profiles, including SMARCA4 and FUBP1 mutations and CNV gains in CEBPA. Among HGSC patients, TBX3 mutations were exclusively observed in those relapsing within six months (p = 0.028), while ARID1B, MAP2K1, and FLT4 were enriched in relapse groups. After neoadjuvant chemotherapy and FIGO stage IV were also associated with relapses. This study reveals subtype-specific and metastasis-related genomic alterations in ovarian cancer and identifies potential relapse-associated mutations in HGSC. While exploring, these findings support further investigation into individualized risk stratification and biomarker-driven therapeutic strategies.
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Affiliation(s)
- Feng Cheng
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Feng Shao
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Yiping Tian
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Shujun Chen
- Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
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16
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Zhou D, Tang E, Wang W, Xiao Y, Huang J, Liu J, Zheng C, Zhang K, Hu R, Wang F, Xiong P, Chu X, Li W, Liu D, Zeng X, Zheng D, Wang L, Zheng Y, Zhang S. Combined therapy with DR5-targeting antibody-drug conjugate and CDK inhibitors as a strategy for advanced colorectal cancer. Cell Rep Med 2025:102158. [PMID: 40449480 DOI: 10.1016/j.xcrm.2025.102158] [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: 08/25/2023] [Revised: 02/21/2025] [Accepted: 05/06/2025] [Indexed: 06/03/2025]
Abstract
Targeted therapies for advanced microsatellite stable (MSS) subtype colorectal cancer (MSS-CRC) remain a clinical challenge. Here, we show that death receptor 5 (DR5) is elevated in both MSS and microsatellite instability-high (MSI-H) colorectal cancer (CRC) cohorts, highlighting its potential as a clinical target. Oba01, a clinical-stage DR5-targeting antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE), shows superior efficacy in CRC cell lines, patient-derived xenografts and their corresponding organoids, irrespective of MSS or MSI-H status. Importantly, our functional multi-omics analysis reveals that the cell cycle pathway and cyclin-dependent kinases (CDKs) are key synergistic targets of Oba01's tumor-killing activity. We further show that Oba01 synergizes with the Food and Drug Administration (FDA)-approved CDK inhibitor abemaciclib in clinically relevant in vivo models. This synergy is also observed with other CDK inhibitors, underscoring the potential of combining Oba01 with CDK inhibition as a therapeutic strategy for advanced CRC, particularly the refractory MSS subtype.
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Affiliation(s)
- Dongdong Zhou
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Er'jiang Tang
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
| | - Wenjun Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Youban Xiao
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Jianming Huang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Jie Liu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Chao Zheng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Kai Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Ruxia Hu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Feiqi Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Peng Xiong
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China
| | - Xin Chu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; Department of Pathology, First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, China
| | - Weisong Li
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; Department of Pathology, First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, China
| | - Dongqin Liu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; Department of General Surgery, First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, China
| | - Xiangfu Zeng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; Department of General Surgery, First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, China
| | - Dexian Zheng
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Yantai Obioadc Biomedical Technology Ltd., Yantai 264000, China
| | - Liefeng Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China; School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, China.
| | - Yong Zheng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
| | - Shuyong Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China; School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, China; Yantai Obioadc Biomedical Technology Ltd., Yantai 264000, China.
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17
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Flanagan M, Kelly M, McCormick P. Autoamputation in Mismatch Repair-Deficient Colon Cancer. JAMA Oncol 2025:2834391. [PMID: 40402493 DOI: 10.1001/jamaoncol.2025.1323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
A woman in her 50s with a history of hemochromatosis, psoriasis, and type 2 diabetes presented with a 3-month history of abdominal pain, weight loss, and a large palpable fixed abdominal mass. What is your diagnosis?
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Affiliation(s)
- Michael Flanagan
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - Michael Kelly
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - Paul McCormick
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
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18
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Aldera AP, Cifci D, Veldhuizen GP, Tsai WJ, Pillay K, Boutall A, Brenner H, Hoffmeister M, Kather JN, Ramesar R. Deep learning predicts microsatellite instability status in colorectal carcinoma in an ethnically heterogeneous population in South Africa. J Clin Pathol 2025:jcp-2025-210053. [PMID: 40393786 DOI: 10.1136/jcp-2025-210053] [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: 01/09/2025] [Accepted: 05/09/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Deep learning (DL) models are effective pre-screening tools for detecting mismatch repair deficiency (dMMR) in colorectal carcinoma (CRC). These models have been trained and validated on large cohorts from the Northern Hemisphere, without representation of African samples. We sought to determine the performance of a DL model in an ethnically heterogeneous cohort of patients from South Africa. METHODS Our cohort comprised 197 CRC resection specimens, with scanned whole slide images tessellated and inputted into a transformer-based DL model trained on large international cohorts. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC), sensitivity and specificity. The maximal Youden's J index was calculated to determine the optimal cut-off threshold for the model prediction score. RESULTS Our model yielded an AUROC of 0.91 (±0.05). Using a prediction score threshold of 0.620 produced an overall sensitivity of 85.7% (95% CI 73.3% to 92.9%) and a specificity of 82.4% (95% CI 75.5% to 87.7%). The false negative cases were predominantly left-sided (71.4%) and did not show the typical dMMR/microsatellite instability-high histological phenotype. Sensitivity was lower (50%-75%) in cases showing isolated PMS2 or MSH6 loss of staining. Calibrating the classification threshold to 0.470, the sensitivity was optimised to 95.6% (95% CI 86.3% to 98.9%) with a specificity of 69.6% (95% CI 61.8% to 76.4%). This would have resulted in excluding 103 cases (52.3%) from downstream immunohistochemical (IHC) or molecular testing. CONCLUSIONS Following appropriate region-specific calibration, we have shown that this model could be employed to accurately prescreen for dMMR in CRC, thereby reducing the burden of downstream IHC and molecular testing in a resource-limited setting.
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Affiliation(s)
- Alessandro Pietro Aldera
- Division of Anatomical Pathology, University of Cape Town, Observatory, South Africa
- JDW Pathology Inc, Cape Town, South Africa
- UCT MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences and University of Cape Town, Cape Town, South Africa
| | - Didem Cifci
- Else Kroener Fresenius Center for Digital Health, Dresden University of Technology, Dresden, Germany
| | - Gregory Patrick Veldhuizen
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA
| | - Wan-Jung Tsai
- Division of Anatomical Pathology, University of Cape Town, Observatory, South Africa
- National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa
| | - Komala Pillay
- Division of Anatomical Pathology, University of Cape Town, Observatory, South Africa
- National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa
| | - Adam Boutall
- Division of General Surgery, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
| | - Hermann Brenner
- German Cancer Research Centre Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- German Cancer Research Centre Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
| | - Jakob Nikolas Kather
- Else Kroener Fresenius Center for Digital Health, Dresden University of Technology, Dresden, Germany
- Department of Medicine I, University Hospital Dresden, Dresden, Germany
- Medical Oncology, National Center for Tumour Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Raj Ramesar
- UCT MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences and University of Cape Town, Cape Town, South Africa
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19
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ALKhemeiri N, Eljack S, Saber-Ayad MM. Perspectives of Targeting Autophagy as an Adjuvant to Anti-PD-1/PD-L1 Therapy for Colorectal Cancer Treatment. Cells 2025; 14:745. [PMID: 40422248 DOI: 10.3390/cells14100745] [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: 02/13/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/28/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, with increasing incidence and mortality rates. Standard conventional treatments for CRC are surgery, chemotherapy, and radiotherapy. Recently, immunotherapy has been introduced as a promising alternative to CRC treatment that utilizes patients' immune system to combat cancer cells. The beneficial effect of immune checkpoint inhibitors, specifically anti-PD-1/ PD-L1, has been ascribed to the abundance of DNA replication errors that result in the formation of neoantigens. Such neoantigens serve as distinct flags that amplify the immune response when checkpoint inhibitors (ICIs) are administered. DNA replication errors in CRC patients are expressed as two statuses: the first is the deficient mismatch repair (MSI-H/dMMR) with a higher overall immune response and survival rate than the second status of patients with proficient mismatch repair (MSS/pMMR). There is a limitation to using anti-PD-1/PD-L1 as it is only confined to MSI-H/dMMR, where there is an abundance of T-cell inhibitory ligands (PD-L1). This calls for investigating new therapeutic interventions to widen the scope of ICIs' role in the treatment of CRC. Autophagy modulation provides a good example. Autophagy is a cellular process that plays a crucial role in maintaining cellular homeostasis and has been studied for its impact on tumor development, progression, and response to treatment. In this review, we aim to highlight autophagy as a potential determinant in tumor immune response and to study the impact of autophagy on the tumor immune microenvironment. Moreover, we aim to investigate the value of a combination of anti-PD-1/PD-L1 agents with autophagy modulators as an adjuvant therapeutic approach for CRC treatment.
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Affiliation(s)
- Nasrah ALKhemeiri
- College of Graduate Studies, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Sahar Eljack
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Pharmaceutics, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan
| | - Maha Mohamed Saber-Ayad
- College of Graduate Studies, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Pharmacology, Faculty of Medicine, Cairo University, Cairo 12211, Egypt
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20
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Lin Z, Rasinski P, Nilsson T, Holstensson M, Song Y, Blomgren A, Jutidamrongphan W, Pandya K, Hong J, Rominger A, Shi K, Axelsson R, Lan X, Seifert R. FAPI PET Versus FDG PET/CT in Gastrointestinal Cancers: An Overview. Semin Nucl Med 2025:S0001-2998(25)00056-X. [PMID: 40399164 DOI: 10.1053/j.semnuclmed.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 05/23/2025]
Abstract
Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is highly expressed in cancer-associated fibroblasts (CAFs) but absent in quiescent fibroblasts. Its overexpression is associated with poor prognosis in various cancers and contributes to treatment resistance. In recent years, radiolabeled FAP inhibitors (FAPI) for PET imaging have shown promising clinical value across a range of cancers. Gastrointestinal (GI) malignancies, which often exhibit a desmoplastic reaction with a high density of FAP-expressing CAFs, are particularly well-suited for FAPI PET. Given the limitations of [18F]FDG PET in GI cancers, such as low sensitivity in certain histological subtypes and high physiological background uptake, FAPI PET is expected to serve as a complementary method, potentially enhancing both diagnostic accuracy and treatment guidance. This review provides a comprehensive comparison of the clinical applications of FAPI PET and [18F]FDG PET in various GI cancers, including their value in diagnosis, staging, and treatment guidance. Additionally, this review summarizes studies on the expanding role of FAPI PET, including its use in assessing treatment response and predicting prognosis, aiming to provide insights into its potential contribution to the improved management of GI malignancies.
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Affiliation(s)
- Zhaoguo Lin
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Pawel Rasinski
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Ted Nilsson
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Maria Holstensson
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Yangmeihui Song
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Hubei Key Laboratory of Molecular Imaging, Wuhan, China; Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, China
| | - August Blomgren
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Warissara Jutidamrongphan
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Kalyani Pandya
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Jimin Hong
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Axel Rominger
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Kuangyu Shi
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Rimma Axelsson
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Hubei Key Laboratory of Molecular Imaging, Wuhan, China; Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, China
| | - Robert Seifert
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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21
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Aoki D, Yamauchi M, Izawa M, Ito Y, Hamada M, Ozaki M, Maekawa S, Muro K. Effectiveness and safety of pembrolizumab for the treatment of Japanese patients with microsatellite instability-high tumors excluding colorectal cancer: a post-marketing surveillance. Jpn J Clin Oncol 2025:hyaf064. [PMID: 40382714 DOI: 10.1093/jjco/hyaf064] [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: 12/20/2024] [Accepted: 04/08/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND We aimed to assess the real-world effectiveness and safety of pembrolizumab monotherapy in Japanese patients with high-frequency microsatellite instability (MSI-H) solid tumors except colorectal cancer. METHODS This multicenter, observational, post-marketing surveillance had a 12-month observation period. We included all patients with locally advanced or metastatic MSI-H solid tumors, except colorectal cancer, in whom standard treatment was difficult or who had shown tumor progression after conventional chemotherapies and had started treatment with pembrolizumab by 31 December 2019. RESULTS In total, 403 patients were enrolled, and 396 and 376 patients were included in the safety and effectiveness analysis sets, respectively. The numbers of patients and frequencies of tumor types occurring in ≥20 cases were: endometrial, 162/403 (40.2%); gastric, 61/403 (15.1%); biliary tract, 42/403 (10.4%); pancreatic, 29/403 (7.2%); and ovarian, 20/403 (5.0%). The objective response rate was 50.3% (189/376) and the disease control rate was 71.5% (269/376). The 12-month progression-free survival (PFS) rate was 42.1% and the median PFS was 8.8 months (95% confidence interval, 6.4-11.5). The 12-month overall survival (OS) rate was 75.1%, and median OS was not reached. Treatment-related adverse events (AEs) of special interest of any grade occurred in 128/396 (32.3%) patients, and those of Grade ≥ 3, in 54/396 (13.6%) patients. One patient with esophageal cancer experienced a Grade 5 AE. No new safety signals were observed. CONCLUSIONS This study confirmed the real-world effectiveness and safety of pembrolizumab monotherapy in patients with MSI-H solid tumors except colorectal cancer in Japan.
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Affiliation(s)
- Daisuke Aoki
- International University of Health and Welfare Graduate School, W 4-1-26 Akasaka, Minato-ku, Tokyo 107-8402, Japan
- Akasaka Sanno Medical Center, W 4-1-26 Akasaka, Minato-ku, Tokyo 107-8402, Japan
| | - Mai Yamauchi
- Medical Affairs Oncology, MSD K.K., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan
| | - Makiko Izawa
- Medical Affairs Oncology, MSD K.K., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan
| | - Yuichiro Ito
- Medical Affairs Oncology, MSD K.K., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan
| | - Masahiro Hamada
- Pharmacovigilance, MSD K.K., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan
| | - Masahiko Ozaki
- Pharmacovigilance, MSD K.K., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan
| | - Shinichiroh Maekawa
- Pharmacovigilance, MSD K.K., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo 102-8667, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
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22
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Huang W, Liu Y. Targeted Therapy and Immunotherapy in Elderly Patients with Metastatic Colorectal Cancer. Curr Treat Options Oncol 2025:10.1007/s11864-025-01326-4. [PMID: 40381062 DOI: 10.1007/s11864-025-01326-4] [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: 04/15/2025] [Indexed: 05/19/2025]
Abstract
OPINION STATEMENT At initial diagnosis, over half of the patients with metastatic colorectal cancer (mCRC) are aged 65 years or older. In this population, age-related declines in organ reserve and the presence of comorbidities can significantly weaken drug tolerance and affect treatment outcomes. However, existing clinical guidelines, largely based on clinical trials involving younger, fitter adults, may not be fully applicable to older patients, particularly those are vulnerable. Moreover, chronologic age and commonly used performance assessment tools, such as the Eastern Cooperative Oncology Group and Karnofsky Performance Status scores, are insufficient for accurate evaluation of physiological fitness in older adults. To provide evidence-based references for clinicians, this review summarizes advances in targeted therapy and immunotherapy for elderly patients with mCRC over the past five years, with a focus on vascular endothelial growth factor (VEGF) targeting agents, epidermal growth factor receptor (EGFR) inhibitors, multi-targeted tyrosine kinase inhibitors (TKIs) and single-agent immunotherapy. Overall, for elderly patients assessed as fit, first-line treatment may include dose-reduced doublet chemotherapy combined with VEGF targeting agents, or alternatively, single-agent chemotherapy plus VEGF targeting agents. For vulnerable elderly patients with mCRC, single-agent chemotherapy with VEGF targeting agents remains the preferred first-line strategy, while RAS wild-type left-sided tumors may benefit from single-agent chemotherapy plus EGFR inhibitors. Although multi-targeted TKIs have shown positive outcomes in elderly patients who are intolerant to other therapies. There is currently no evidence supporting their use in first-line treatment or combination therapy. In terms of immunotherapy, similar to the general mCRC population, single-agent immunotherapy is recommended as a first-line option for elderly microsatellite instability-high/mismatch repair-deficient patients. Notably, integrating comprehensive geriatric assessment into clinical practice can facilitate personalized treatment strategies, particularly for vulnerable and frail patients.
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Affiliation(s)
- Wenjie Huang
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang City, China
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang City, China.
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23
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Goto N, Agudo J, Yilmaz ÖH. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment. Trends Cancer 2025:S2405-8033(25)00112-8. [PMID: 40382216 DOI: 10.1016/j.trecan.2025.04.016] [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: 01/27/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/20/2025]
Abstract
Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
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Affiliation(s)
- Norihiro Goto
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02215, USA; New York Stem Cell Foundation, New York, NY 10019, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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24
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Liu J, Su Y, Zhang C, Dong H, Yu R, Yang X, Tian Y, Feng Y, Zhang J, Shi M, Wang C, Li W, Liu J, He L, Yang X, Liu H. NCOA3 impairs the efficacy of anti-PD-L1 therapy via HSP90α/EZH2/CXCL9 axis in colon cancer. Int Immunopharmacol 2025; 155:114579. [PMID: 40215778 DOI: 10.1016/j.intimp.2025.114579] [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: 12/05/2024] [Revised: 03/19/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized colon cancer treatment, but their efficacy is largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs). However, the specific genetic alterations that impact the CD8+ CTL infiltration in colon cancer remain poorly understood. Here, we analyzed clinical and multi-omics data from the Memorial Sloan-Kettering Cancer Center (MSKCC) ICIs-treated and The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) cohorts to screen the key mutations that may influence the efficacy of immunotherapy. We found that patients with NCOA3 mutations exhibit better response to immunotherapy and higher CD8+ CTL infiltration. In vitro and in vivo experiments revealed that mutant NCOA3 increases the efficacy of anti-PD-L1 and CD8+ CTL recruitment by upregulating C-X-C motif chemokine ligand 9 (CXCL9), which is dependent on its impaired intrinsic histone acetyltransferase activity. Mechanistically, wild-type NCOA3 as histone acetyltransferase upregulates Heat shock protein 90 alpha (HSP90α) by enhancing histone H3 lysine 27 acetylation (H3K27ac) at its promoter region. Increased HSP90α stabilizes Enhancer of zeste homolog 2 (EZH2), which then increase the histone H3 lysine 27 trimethylation (H3K27me3) at the CXCL9 promoter region, thereby suppressing the expression of CXCL9. Targeted inhibition of NCOA3 by small molecular inhibitor SI-2 improves the efficacy of PD-L1 blockade therapy. NCOA3 could serve as a novel biomarker and potential target to improve the efficacy of immunotherapy.
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Affiliation(s)
- Jiaqi Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yixi Su
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chi Zhang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Haiyan Dong
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Runfeng Yu
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xin Yang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yu Tian
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yanchun Feng
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jingdan Zhang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Mengchen Shi
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chen Wang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Weiqian Li
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jun Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Lingyuan He
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiangling Yang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
| | - Huanliang Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
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25
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Meng X, Lu Z, Mi F, Sha S, Li T. Research hotspots and emerging trends in targeted therapy for colorectal cancer: a bibliometric analysis (2000-2023). Discov Oncol 2025; 16:789. [PMID: 40380023 PMCID: PMC12084209 DOI: 10.1007/s12672-025-02632-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 05/08/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Targeted therapy has significantly transformed the treatment landscape of colorectal cancer (CRC), enabling personalized treatment approaches and improving patient prognosis. This study employs bibliometric analysis to explore the research hotspots and development trends in the field of CRC-targeted therapy from 2000 to 2023. METHODS Based on the Web of Science Core Collection, this study collected literature related to CRC-targeted therapy published between 2000 and 2023. CiteSpace and VOSviewer were used for data analysis, with a focus on publication trends, key contributors, and keyword co-occurrence patterns. RESULTS A total of 2252 relevant articles were included, demonstrating a steady growth trend in research output. China ranked first in terms of the number of publications, while the University of Texas MD Anderson Cancer Center was identified as the institution with the highest research output. Josep Tabernero was the most prolific author in this field. Among journals, Cancers had the highest impact, while Clinical Cancer Research held a significant advantage in citation frequency. Keyword co-occurrence and clustering analysis indicated that research primarily focused on treatment strategies and precision medicine, with emerging technologies such as cell therapy and liquid biopsy garnering increasing attention. CONCLUSION This study reveals the research trends, core hotspots, and emerging directions in the field of CRC-targeted therapy, providing valuable insights for future research.
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Affiliation(s)
- Xiangnv Meng
- General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Second Department of Medical Oncology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Zhongting Lu
- General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Fu Mi
- Second Department of Medical Oncology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Sha Sha
- Second Department of Medical Oncology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Tao Li
- Department of Surgical Oncology, Tumor Hospital, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
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Zhang Y, Zhu H, Fan J, Zhao J, Xia Y, Zhang N, Xu H. A glutamine metabolism gene signature with prognostic and predictive value for colorectal cancer survival and immunotherapy response. Front Mol Biosci 2025; 12:1599141. [PMID: 40443528 PMCID: PMC12119274 DOI: 10.3389/fmolb.2025.1599141] [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: 04/02/2025] [Accepted: 04/23/2025] [Indexed: 06/02/2025] Open
Abstract
Background Colorectal cancer (CRC) remains a major cause of cancer mortality, and dysregulated glutamine metabolism has emerged as a potential therapeutic target. However, the precise role of glutamine in CRC progression and treatment response remains debated. Methods The authors collected transcriptome and microbiome information, from multiple sources to construct the GLMscore, a prognostic signature in CRC. To comprehensively characterize the biological features of GLMscore groups, the integration of transcriptomic profiling, KEGG pathway enrichment analysis, immune infiltration analysis, tumor immune microenvironment characterization, microbiome analysis, and tissue imaging were applied. Furthermore, CRC patients were stratified into GLMscore high and GLMscore low groups. The robustness of GLMscore was validated in both training and validation cohorts, and the predictive value for immunotherapy response was assessed. Finally, single-cell RNA sequencing (scRNA-seq) analysis was conducted to delineate the differences between GLMscore high and GLMscore low groups. Results High GLMscore was associated with elevated expression of pathways related to tumorigenesis, epithelial-mesenchymal transition (EMT), and angiogenesis. Furthermore, high GLMscore patients exhibited an immunosuppressive TME characterized by increased infiltration of M0 and M2 macrophages, reduced overall immune infiltration (supported by ESTIMATE and TIDE scores), and increased expression of immune exclusion and suppression pathways. Analysis of pathological whole-slide images (WSIs) revealed a lack of intratumoral tertiary lymphoid structures (TLSs) in high GLMscore patients. The GLMscore also predicted resistance to common chemotherapeutic agents (using GDSC data) and, importantly, predicted poor response to immunotherapy in the IMvigor210 cohort. Analysis of 16S rRNA gene sequencing data revealed an enrichment of potentially oncogenic microbiota, including Hungatella and Selenomonas, in high GLMscore group. Single-cell analysis further confirmed the immunosuppressive TME and identified increased cell-cell communication between inflammatory macrophages and tumor cells in high GLMscore group. Conclusion The authors innovatively constructed GLMscore, a robust scoring system in quantifying CRC patients, exploring the distinct biological features, tumor immune microenvironment and microbiome ecology, exhibiting high validity in predicting survival prognosis and clinical treatment efficacy.
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Affiliation(s)
| | | | | | | | | | | | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Xu C, Cao K, Ma A, Zheng M, Xu Y, Tang L. KLRG1 expression induces functional exhaustion of NK cells in colorectal cancer patients. Cancer Immunol Immunother 2025; 74:203. [PMID: 40372495 PMCID: PMC12081801 DOI: 10.1007/s00262-025-04059-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/14/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Natural killer (NK) cells are a subset of innate lymphoid cells that possess cytotoxic properties, playing a pivotal role in immune surveillance against tumor cells. However, it remains unclear whether there are any alterations in the quantity and functional status of NK cells in colorectal cancer (CRC). METHODS In this study, we collected peripheral blood samples from both CRC patients and age- and sex-matched healthy controls (HCs). The distribution characteristics, phenotypic changes, functional status, apoptosis susceptibility, and proliferative capacity of circulating NK cells were detected and analyzed by flow cytometry. An in vitro study was performed to investigate the blocking effect of KLRG1 antibody on peripheral blood NK cells in CRC patients. RESULTS The frequency and absolute number of circulating NK cells were significantly decreased in CRC patients compared to those in HCs. Meanwhile, the function of NK cells from CRC patients was compromised, as shown by the reduced production of IFN-γ, TNF-α, and CD107a, with this impairment becoming increasingly significant as neural invasion progressed and tumor invasion advanced. We further found that the expression of activating receptors NKp30 and NKp46 were reduced, while the expression of inhibitory receptor KLRG1 was remarkably increased. The increased proportion of KLRG1 on NK cells was associated with CRC progression, and KLRG1+ NK cells showed impaired production of IFN-γ, TNF-α, and CD107a and were more susceptible to apoptosis. Importantly, blockade of the KLRG1 pathway could restore the cytokine production and degranulation ability of NK cells from CRC patients. CONCLUSIONS The present study demonstrates that NK cells in CRC patients exhibit functional exhaustion, and KLRG1 blockade restores the effector function of NK cells, indicating that targeting KLRG1 represents a promising strategy for immunotherapy in patients with CRC.
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Affiliation(s)
- Cairui Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Kangli Cao
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Along Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Meijuan Zheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Yuanhong Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Ling Tang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China.
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Feng H, Zhao LY, Xu Z, Xie QF, Deng HJ, Yu J, Liu H. Homologous recombination deficiency and immunotherapy response in microsatellite-stable colorectal cancer: Evidence from a cohort study in China. World J Gastrointest Oncol 2025; 17:102767. [DOI: 10.4251/wjgo.v17.i5.102767] [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: 11/02/2024] [Revised: 02/14/2025] [Accepted: 03/07/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Patients with colorectal cancer (CRC) exhibiting microsatellite instability (MSI)-high generally demonstrate a favorable response to immunotherapy. In contrast, the efficacy of immunotherapy in microsatellite-stable (MSS) CRC patients is considerably restricted. This study sought to evaluate the effectiveness of immunotherapy in MSS patients characterized by homologous recombination deficiency (HRD) as opposed to those with homologous recombination proficiency (HRP).
AIM To investigate and compare the clinicopathological characteristics, treatment modalities, and outcomes between the HRD and HRP groups in CRC.
METHODS Next-generation sequencing was performed on 268 CRC patients to identify tumor-associated genetic alterations and assess their HRD scores and MSI status. Patients with HRD-related gene alterations or an HRD score ≥ 30 were classified into the HRD group, while the remaining patients were assigned to the HRP group. Clinical data, including staging and treatment regimens, were collected for analysis. Cox regression and Kaplan-Meier survival curves were employed to evaluate whether the HRD group demonstrated improved survival outcomes following immunotherapy treatment.
RESULTS Among the 268 patients, 64 were classified into the HRD group, which had a higher proportion of early-stage CRC diagnoses compared to the HRP group. Kaplan-Meier survival curves indicated significantly better survival rates in the HRD group compared to the HRP group across all cohorts, as well as among MSS patients treated with immunotherapy (P < 0.05).
CONCLUSION This study demonstrates that CRC patients with HRD have a more favorable prognosis and suggests that HRD status could serve as a predictive marker for immunotherapy response in MSS patients.
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Affiliation(s)
- Hao Feng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Ying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhou Xu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Qing-Feng Xie
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hai-Jun Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Lakbir S, de Wit R, de Bruijn I, Kundra R, Madupuri R, Gao J, Schultz N, Meijer GA, Heringa J, Fijneman RJA, Abeln S. Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers. NPJ Precis Oncol 2025; 9:140. [PMID: 40369102 PMCID: PMC12078582 DOI: 10.1038/s41698-025-00922-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/24/2025] [Indexed: 05/16/2025] Open
Abstract
While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.
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Affiliation(s)
- Soufyan Lakbir
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Renske de Wit
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Ino de Bruijn
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Ritika Kundra
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | - Jianjiong Gao
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | - Gerrit A Meijer
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jaap Heringa
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Remond J A Fijneman
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Sanne Abeln
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands.
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Zou D, Xin X, Xu H, Xu Y, Xu T. Development and validation of a cancer-associated fibroblast gene signature-based model for predicting immunotherapy response in colon cancer. Sci Rep 2025; 15:16550. [PMID: 40360558 PMCID: PMC12075585 DOI: 10.1038/s41598-025-01185-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
The efficacy of immune checkpoint inhibitors in colon cancer has been established, and there is an urgent need to identify new molecular markers for colon cancer immunotherapy to guide clinical decisions. Using the "EPIC" and "MCPcounter" R packages to conduct cancer-associated fibroblast (CAF) infiltration scoring on colon cancer samples from the TCGA database and the GEO database, the WGCNA analysis was performed on the two databases' samples based on the CAF infiltration scores to screen for CAF-related genes. LASSO regression analysis was used to construct a risk model with these genes. Comprehensive bioinformatics analysis was conducted on the constructed model to evaluate the stability of its prediction of CAF infiltration abundance and the stability of its prediction of immunotherapy efficacy. The newly constructed risk model could well reflect the abundance of CAF infiltration in colon cancer, with a correlation coefficient of 0.91 in the training cohort TCGA-COAD and 0.88 in the validation cohort GSE39582. GSEA analysis revealed that CAF is closely related to functions associated with extracellular matrix remodeling. The constructed risk model can predict the efficacy of immunotherapy in colon cancer well, with the high-risk group showing significantly poorer immunotherapy response than the low-risk group, with an expected effective rate of immunotherapy of 68 vs. 24% in the training group (P < 0.001) and 64 vs. 26% in the validation group (P < 0.001). The AUC value for predicting immunotherapy response by the risk model in the training group was 0.780 (95% CI 0.736-0.820), and in the validation group, the AUC value was 0.774 (95% CI 0.735-0.810). Drug sensitivity analysis showed that the expected chemotherapeutic effect in the low-risk group was superior to that in the high-risk group. CAF is associated with immunosuppression and drug resistance. Predicting the efficacy of immunotherapy in colon cancer based on the abundance of CAF infiltration is a feasible approach. For the high-risk population identified by our model, clinical consideration should be given to prioritizing non-immunotherapy approaches to avoid potential risks associated with immunotherapy.
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Affiliation(s)
- Daoyang Zou
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xi Xin
- Ganzhou People's Hospital, Ganzhou, China
| | - Huangzhen Xu
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yunxian Xu
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Tianwen Xu
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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Huang R, Jin X, Liu Q, Bai X, Karako K, Tang W, Wang L, Zhu W. Artificial intelligence in colorectal cancer liver metastases: From classification to precision medicine. Biosci Trends 2025; 19:150-164. [PMID: 40240167 DOI: 10.5582/bst.2025.01045] [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: 04/18/2025]
Abstract
Colorectal cancer liver metastasis (CRLM) remains the leading cause of mortality among colorectal cancer (CRC) patients, with more than half eventually developing hepatic metastases. Achieving long-term survival in CRLM necessitates early detection, robust stratification, and precision treatment tailored to individual classifications. These processes encompass critical aspects such as tumor staging, predictive modeling of therapeutic responses, and risk stratification for survival outcomes. The rapid evolution of artificial intelligence (AI) has ushered in unprecedented opportunities to address these challenges, offering transformative potential for clinical oncology. This review summarizes the current methodologies for CRLM grading and classification, alongside a detailed discussion of the machine learning models commonly used in oncology and AI-driven applications. It also highlights recent advances in using AI to refine CRLM subtyping and precision medicine approaches, underscoring the indispensable role of interdisciplinary collaboration between clinical oncology and the computational sciences in driving innovation and improving patient outcomes in metastatic colorectal cancer.
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Affiliation(s)
- Runze Huang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Xin Jin
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Qinyu Liu
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Xuanci Bai
- Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Kenji Karako
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Wei Tang
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- National Center for Global Health and Medicine, Japan Institute for Health Security, Tokyo, Japan
| | - Lu Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Weiping Zhu
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
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Reitsam NG, Offermans K, Simons CCJM, Grosser B, Zimmermann J, Grabsch HI, Märkl B, van den Brandt PA. Prognostic and Predictive Value of SARIFA-status Within Molecular Subgroups of Colorectal Cancer: Insights From the Netherlands Cohort Study. Am J Surg Pathol 2025:00000478-990000000-00520. [PMID: 40340947 DOI: 10.1097/pas.0000000000002408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
We recently proposed Stroma AReactive Invasion Front Areas (SARIFA), defined as direct tumor-adipocyte interaction at the invasion front, as a novel hematoxylin-and-eosin (H&E)-based histopathological prognostic biomarker in various cancers. Given that microsatellite instability, BRAF, and RAS mutation status are routinely tested for colorectal cancers (CRC), studying SARIFA's additional prognostic value within these molecular subgroups is crucial. In addition, exploring whether the survival benefit from adjuvant therapy differs according to SARIFA-status may enhance patient treatment and outcome. SARIFA-status, BRAF, RAS, and DNA mismatch repair (MMR) status were available for 1726 CRC patients from the prospective Netherlands Cohort Study (NLCS, 1986-2006). In this study, we investigated (1) the relationship between SARIFA-status and CRC molecular characteristics, (2) the prognostic value of SARIFA-status within these molecular subgroups, and (3) whether SARIFA-status was associated with survival benefit from adjuvant therapy. SARIFA-positive CRCs more frequently showed a BRAF mutation compared to SARIFA-negative CRCs (P<0.001). BRAF-mutant/MMR-proficient CRCs were enriched in SARIFA-positive cases. SARIFA-positivity was associated with poor CRC-specific (HRrange: 1.47 to 1.78) and overall survival (HRrange: 1.35 to 1.70) within all molecular subgroups except MMR-deficient CRCs. Patients with SARIFA-positive CRC showed a CRC-specific survival benefit from adjuvant therapy compared to surgery alone (HRCRC-specific: 0.59; 95% CI: 0.44-0.79), while no CRC-specific survival benefit was observed for patients with SARIFA-negative CRC. To conclude, our results indicate that SARIFA-positivity is more common in the aggressive subset of BRAF-mutant and BRAF-mutant/MMR-proficient CRCs. Moreover, SARIFA-positivity provides additional prognostic value within molecular subgroups based on BRAF, RAS, and MMR status, suggesting that it may enhance prognostic stratification of CRC patients.
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Affiliation(s)
- Nic G Reitsam
- Pathology, Medical Faculty, University of Augsburg
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | - Kelly Offermans
- Department of Epidemiology, GROW Research Institute for Oncology and Reproduction
| | - Colinda C J M Simons
- Department of Epidemiology, GROW Research Institute for Oncology and Reproduction
| | - Bianca Grosser
- Pathology, Medical Faculty, University of Augsburg
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | | | - Heike I Grabsch
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Bruno Märkl
- Pathology, Medical Faculty, University of Augsburg
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | - Piet A van den Brandt
- Department of Epidemiology, GROW Research Institute for Oncology and Reproduction
- Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands
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Zhao K, Muralidharan V, Brown S, Upton A, Alshimirti M, Cooray PD. Neoadjuvant Pembrolizumab Enables Successful Downstaging and Resection of Borderline Resectable MSI-H/dMMR Pancreatic Ductal Adenocarcinoma: A Case Report and Literature Review. J Gastrointest Cancer 2025; 56:112. [PMID: 40341577 PMCID: PMC12062155 DOI: 10.1007/s12029-025-01237-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis. While immunotherapy has shown limited efficacy in most PDAC cases due to an immunosuppressive tumour microenvironment, tumours with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status exhibit increased responsiveness to immune checkpoint inhibitors. CASE PRESENTATION We report the case of a 45-year-old woman with Lynch syndrome who was diagnosed with MSI-H/dMMR PDAC during routine surveillance. Given the borderline resectable nature of her tumour and previous chemotherapy-related neurotoxicity, she was treated with neoadjuvant pembrolizumab instead of conventional chemotherapy. Following four cycles of pembrolizumab, imaging revealed a marked metabolic response, allowing for successful R0 pancreatoduodenectomy. Postoperative histology confirmed a significant reduction in tumour size, and immunohistochemical analysis demonstrated increased CD8 + T cell infiltration, supporting an enhanced anti-tumour immune response. The patient continues adjuvant pembrolizumab therapy without complications. CONCLUSION This case highlights the potential role of neoadjuvant pembrolizumab in MSI-H/dMMR PDAC, demonstrating successful tumour downstaging and facilitating surgical resection. Our findings support further investigation into the integration of immunotherapy as a neoadjuvant strategy for select PDAC patients.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacology
- Female
- Middle Aged
- Neoadjuvant Therapy/methods
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/surgery
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/surgery
- Pancreatic Neoplasms/genetics
- Microsatellite Instability
- DNA Mismatch Repair
- Antineoplastic Agents, Immunological/therapeutic use
- Pancreaticoduodenectomy
- Colorectal Neoplasms, Hereditary Nonpolyposis
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Affiliation(s)
- Kevin Zhao
- University of Melbourne School of Medicine, Melbourne, Australia
| | - Vijayaragavan Muralidharan
- Prometheus Research Collaborative, Department of Surgery, Austin Precinct, The University of Melbourne, Austin Health, Melbourne, Australia
| | | | | | | | - Prasad D Cooray
- Department of Surgery, The University of Melbourne, Austin Health, Melbourne, Australia.
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Saad A, Taylor A, Felder S, Helpman L, Bauer S, Shapira R, Levanon K, Korach J, Atamneh R, Breslauer S, Goldstein J, Peleg Hasson S. De-escalating first-line treatment in stage IVB or recurrent cervical cancer: outcomes of immunotherapy alone and systemic review. Oncologist 2025; 30:oyaf096. [PMID: 40421960 PMCID: PMC12107546 DOI: 10.1093/oncolo/oyaf096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 03/23/2025] [Indexed: 05/28/2025] Open
Abstract
INTRODUCTION Chemo-immunotherapy (IO) is the preferred first-line treatment for stage IVB or recurrent cervical cancer. However, limited data exist on the efficacy and safety of using IO-alone as a de-escalation strategy. We report outcomes from a case series of selected patients treated with IO-alone and review the feasibility of de-escalating first-line treatment. METHODS The authors conducted a literature review using Google Scholar and PubMed to identify reports using IO-alone as a de-escalation strategy across malignancies published between 1999 and December 2024 and also reviewed a cervical cancer database from a tertiary academic to identify patients with stage IVB or recurrent disease treated with IO-alone. The authors used the Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS). RESULTS Among 582 patients treated between 2015 and 2021, 18 met the inclusion criteria. The median age was 43 years (range 28-84); 67% had squamous cell carcinoma, 11% adenocarcinoma, and 80% expressed PD-L1. CPS scores were <1 in 20%, 1--10 in 33%, and >10 in 47%. Most patients had oligo-metastatic disease (83%). Treatment with IO-alone began a median of 7 months after platinum-based chemotherapy. Indications included prior adjuvant (44%) or neoadjuvant (22%) chemotherapy, clinical trial participation (11%), or patient preference (22%). Median PFS and OS were 27 months and 82 months, respectively. CONCLUSIONS These findings support the need for clinical trials evaluating IO-alone as a first-line treatment option for de-escalation in stage IVB or recurrent cervical cancer. Biomarker development is needed to better identify candidates for personalized therapy.
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Affiliation(s)
- Akram Saad
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Sheba Cancer Center and Institute of Oncology, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Alexandra Taylor
- The Royal Marsden, Department of Clinical Oncology, 203 Fulham Rd., London SW3 6JJ, United Kingdom
| | - Shira Felder
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Sheba Cancer Center and Institute of Oncology, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Limor Helpman
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Gynecologic Oncology, Sheba Medical Center, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Smadar Bauer
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Sheba Cancer Center and Institute of Oncology, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Ronnie Shapira
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Sheba Cancer Center and Institute of Oncology, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Keren Levanon
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Sheba Cancer Center and Institute of Oncology, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Jacob Korach
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Gynecologic Oncology, Sheba Medical Center, Tel-Hashomer, Derech Sheba 2, Ramat Gan, Israel
| | - Ronza Atamneh
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
| | - Samantha Breslauer
- Rappaport Faculty of Medicine, Technion Israel Institute of Technology, 1 Efron St. Bat Galim, Haifa 3525433, Israel
| | - Jeffrey Goldstein
- Tel Aviv Sourasky Medical Center, Department of Radiation Oncology, Weizmann St 6, Tel Aviv-Yafo, Israel
| | - Shira Peleg Hasson
- Faculty of Medicine, Tel Aviv University, P.O.B 39040 Ramat Aviv, Tel Aviv 69978, Israel
- Tel Aviv Sourasky Medical Center, Department of Medical Oncology, Weizmann St 6, Tel Aviv-Yafo, Israel
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Han L, Huang B, Li L, Xu B, Yang Y, Zhao L, Wang Z, Zhang C, Gao Q. Utility of the neutrophil-to-lymphocyte ratio and the ratio of neutrophil-to-lymphocyte ratio after and before adverse events for differential diagnosis of immune-related adverse events and bacterial infections in cancer patients treated with PD-(L)1 inhibitors. J Leukoc Biol 2025; 117:qiaf029. [PMID: 40083232 DOI: 10.1093/jleuko/qiaf029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/25/2024] [Accepted: 03/13/2025] [Indexed: 03/16/2025] Open
Abstract
Differential diagnosis of immune-related adverse events (irAEs) or bacterial infections is sometimes very difficult in cancer patients undergoing treatment with PD-(L)1 inhibitors. This study aimed to assess the effectiveness of the neutrophil-to-lymphocyte ratio (NLR) in distinguishing between irAEs and bacterial infections in cancer patients receiving PD-(L)1 inhibitors. We conducted a retrospective analysis of cancer patients who received at least 1 dose of PD-(L)1 inhibitors at Affiliated Cancer Hospital of Zhengzhou University from 2018 to 2023. We compared the changes in peripheral blood cell counts before and after the occurrence of adverse events, as well as the ratios of the NLR that were closest after the occurrence of adverse events (post-NLR) to the NLR that were closest before the occurrence of adverse events (pre-NLR). Among the 4173 patients who were administered PD-(L)1 inhibitors, 217 individuals experienced a total of 249 irAEs, while 256 patients were diagnosed with 257 bacterial infections. The post-NLR increased significantly compared with pre-NLR in patients with bacterial infection (P < 0.001), while the post-NLR had smaller increase compared with pre-NLR in patients sufffering irAEs (P < 0.001). Notably, the NLR was significantly higher in patients with bacterial infection compared with those with irAEs (P < 0.001). Furthermore, the post-NLR/pre-NLR ratio was higher in the bacterial infection group than in the irAEs group (P < 0.001). The NLR along with the post-NLR/pre-NLR ratio could serve as valuable diagnostic indicators for irAEs and bacterial infections in cancer patients undergoing treatment with PD-(L)1 inhibitors.
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Affiliation(s)
- Lu Han
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Beibei Huang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Linlin Li
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Benling Xu
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yonghao Yang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Lingdi Zhao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Zibing Wang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Chaoji Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Quanli Gao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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Shi Y, Ba Y, Wang J, Xiong J, Gu K, Chen Y, Zheng Z, Wang Z, Guo W, Cheng Y, Yin X, Liu Y, Bai Y, Li E, Li Q, Zhu L, Li W, Jiang D, He J, Chen J, Sun J, Hou S. First-line treatment of anti-EGFR monoclonal antibody cetuximab β plus FOLFIRI versus FOLFIRI alone in Chinese patients with RAS/BRAF wild-type metastatic colorectal cancer: a randomized, phase 3 trial. Signal Transduct Target Ther 2025; 10:147. [PMID: 40328753 PMCID: PMC12056184 DOI: 10.1038/s41392-025-02229-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 03/20/2025] [Accepted: 03/31/2025] [Indexed: 05/08/2025] Open
Abstract
Cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) represents a first-line therapeutic standard for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Despite this established approach, cetuximab β (CMAB009), as a modified antibody of cetuximab, prospectively selected for dual RAS/BRAF wild-type patients, has not yet been validated in the Chinese mCRC patients through phase 3 trial. In this study (ClinicalTrials.gov identifier: NCT03206151), patients with RAS/BRAF wild-type mCRC who were not suitable for radical resection were randomly assigned in a 1:1 ratio to receive cetuximab β plus FOLFIRI or FOLFIRI alone. The primary endpoint was blinded independent review committee-assessed progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), surgery rate for metastasis and R0 resection rate, and safety. From January 4, 2018 to September 2, 2021, a total of 505 eligible patients were enrolled and received study treatment; the median follow-up duration was 8.7 months (95% confidence interval [CI], 7.77 to 9.29) and 5.9 months (95% CI, 5.63 to 6.65) in cetuximab β plus FOLFIRI group and FOLFIRI group, respectively. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI demonstrated statistically significant improvements in median PFS (13.1 vs. 9.6 months, hazard ratio [HR], 0.639; 95% CI, 0.468 to 0.872; P = 0.004), median OS (28.3 vs. 23.1 months, HR, 0.729; 95% CI, 0.551 to 0.965; P = 0.024), and ORR (69.1% vs. 42.3%, odds ratio, 3.090; 95% CI, 2.280 to 4.189; P < 0.001). Cetuximab β plus FOLFIRI exhibited manageable toxicity without novel safety signals. This study demonstrated that cetuximab β plus FOLFIRI provided significant clinical benefits as a first-line treatment for patients with RAS/BRAF wild-type mCRC. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI therapy led to prolonged median PFS and OS while maintaining a manageable safety profile, offering a new treatment option for this patient population.
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Affiliation(s)
- Yuankai Shi
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, PR China.
| | - Yi Ba
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
- Tianjin Medical University Cancer Institute & Hospital, Tianjin, PR China.
| | - Junye Wang
- Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Jianping Xiong
- The First Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Kangsheng Gu
- The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Yigui Chen
- Fujian Cancer Hospital, Fuzhou, PR China
| | - Zhendong Zheng
- General Hospital of Northern Theater Command, Shenyang, PR China
| | - Zishu Wang
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, PR China
| | - Weijian Guo
- Fudan University Shanghai Cancer Center, Shanghai, PR China
| | - Ying Cheng
- Jilin Cancer Hospital, Changchun, PR China
| | - Xianli Yin
- Hunan Cancer Hospital, Changsha, PR China
| | - Yunpeng Liu
- The First Hospital of China Medical University, Shenyang, PR China
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, PR China
| | - Enxiao Li
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
| | - Qi Li
- Shanghai General Hospital, Shanghai, PR China
| | | | - Wei Li
- The First Hospital of Jilin University, Changchun, PR China
| | - Da Jiang
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Jingdong He
- Huai'an First People's Hospital, Huai'an, PR China
| | - Jiansi Chen
- Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China
| | - Jianguo Sun
- The Second Affiliated Hospital of Army Medical University, Chongqing, PR China
| | - Sheng Hou
- State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, Taizhou Mabtech Pharmaceutical Co. Ltd, Taizhou, PR China
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37
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Emiloju O, Miao R, Alese O. The Evolving Role of Immunotherapy for Gastroesophageal Malignancies. Ann Surg Oncol 2025:10.1245/s10434-025-17386-7. [PMID: 40332652 DOI: 10.1245/s10434-025-17386-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/13/2025] [Indexed: 05/08/2025]
Abstract
The incorporation of immunotherapy has transformed the treatment landscape for advanced, unresectable, or metastatic gastroesophageal cancers (GECs), with improved survival outcomes. These improvements in outcomes for advanced GECs have led to clinical trials evaluating the role of immunotherapy in patients with resectable early-stage GECs. However, there remains a high burden of morbidity and mortality, and ongoing trials utilizing novel immunotherapy agents and combinations are underway. This review summarizes the findings of previous and ongoing clinical trials related to immunotherapy for patients with early- and late-stage GECs.
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Affiliation(s)
| | - Ruoyu Miao
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Olatunji Alese
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
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Wang Q, Yuan F, Zuo X, Li M. Breakthroughs and challenges of organoid models for assessing cancer immunotherapy: a cutting-edge tool for advancing personalised treatments. Cell Death Discov 2025; 11:222. [PMID: 40335487 PMCID: PMC12059183 DOI: 10.1038/s41420-025-02505-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/16/2025] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Organoid models are powerful tools for evaluating cancer immunotherapy that provide a more accurate representation of the tumour microenvironment (TME) and immune responses than traditional models. This review focuses on the latest advancements in organoid technologies, including immune cell co-culture, 3D bioprinting, and microfluidic systems, which enhance the modelling of TME and facilitate the assessment of immune therapies such as immune checkpoint inhibitors (ICIs), CAR-T therapies, and oncolytic viruses. Although these models have great potential in personalised cancer treatment, challenges persist in immune cell diversity, long-term culture stability, and reproducibility. Future developments integrating artificial intelligence (AI), multi-omics, and high-throughput platforms are expected to improve the predictive power of organoid models and accelerate the clinical translation of immunotherapy.
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Affiliation(s)
- Qian Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China
| | - Fangwei Yuan
- Department of Thoracic Surgery, Lian Shui County People's Hospital, Huaian, 223400, Jiangsu, PR China
| | - Xianglin Zuo
- Biobank of Jiangsu Cancer Hospital (Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University), Nanjing, 210000, Jiangsu, PR China.
| | - Ming Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China.
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China.
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Nomikos IN, Kosmas C, Gkretsi V. Tumor molecular signatures: bridging the bench and the operating room. Am J Surg 2025; 246:116393. [PMID: 40378496 DOI: 10.1016/j.amjsurg.2025.116393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 05/19/2025]
Abstract
Contemporary diagnostic and therapeutic strategies for many solid tumors rely on understanding the Mismatch Repair (MMR) system, a fundamental DNA repair mechanism responsible for correcting errors introduced during DNA replication. Pathology reports written for tumors excised in surgery, often indicate the expression status of MMR proteins. This is of significant clinical value, as loss of MMR protein expression is associated with the accumulation of DNA replication errors. The MMR system recognizes and replaces mismatched nucleotides, particularly in microsatellite regions. These are short, repetitive non-coding DNA sequences prone to replication errors. When MMR proteins are inactivated by genetic or epigenetic alterations, MMR deficiency (dMMR) occurs, preventing repair and leading to microsatellite instability (MSI). MSI is a hallmark of Lynch syndrome, which is commonly associated with colorectal cancer (CRC) and endometrial cancer. This work highlights the clinical utility of MMR protein and MSI status as molecular signatures and discusses diagnostic, prognostic, and therapeutic implications. Understanding these molecular changes supports clinicians in making informed therapeutic decisions and may improve patient outcomes by providing personalized treatments to fit individual tumor profiles.
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Affiliation(s)
- Iakovos N Nomikos
- Rea Maternity Hospital, Athens, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | | | - Vasiliki Gkretsi
- Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Metastasis and Adhesion Group, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus
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40
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Awosika JA, Gulley JL, Pastor DM. Deficient Mismatch Repair and Microsatellite Instability in Solid Tumors. Int J Mol Sci 2025; 26:4394. [PMID: 40362635 PMCID: PMC12072705 DOI: 10.3390/ijms26094394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/26/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors generated during DNA replication and recombination. A defective MMR system results in genome-wide instability and the progressive accumulation of mutations. Tumors exhibiting deficient MMR (dMMR) and/or high levels of microsatellite instability (termed "microsatellite instability high", or MSI-H) have been shown to possess fundamental differences in clinical, pathological, and molecular characteristics, distinguishing them from their "microsatellite stable" (MSS) counterparts. Molecularly, they are defined by a high mutational burden, genetic instability, and a distinctive immune profile. Their distinct genetic and immunological profiles have made dMMR/MSI-H tumors particularly amenable to treatment with immune checkpoint inhibitors (ICIs). The ongoing development of biomarker-driven therapies and the evaluation of novel combinations of immune-based therapies, with or without the use of conventional cytotoxic treatment regimens, continue to refine treatment strategies with the goals of maximizing therapeutic efficacy and survival outcomes in this distinct patient population. Moreover, the resultant knowledge of the mechanisms by which these features are suspected to render these tumors more responsive, overall, to immunotherapy may provide information regarding the potential optimization of this therapeutic approach in tumors with proficient MMR (pMMR)/MSS tumors.
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Affiliation(s)
- Joy A. Awosika
- Gastrointestinal Malignancies Section, Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - James L. Gulley
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Danielle M. Pastor
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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41
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Cartwright D, Kidd AC, Ansel S, Ascierto ML, Spiliopoulou P. Oncogenic Signalling Pathways in Cancer Immunotherapy: Leader or Follower in This Delicate Dance? Int J Mol Sci 2025; 26:4393. [PMID: 40362630 PMCID: PMC12072740 DOI: 10.3390/ijms26094393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/01/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.
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Affiliation(s)
- Douglas Cartwright
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Andrew C. Kidd
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Sonam Ansel
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Maria Libera Ascierto
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
| | - Pavlina Spiliopoulou
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
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42
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Bachet JB, de Gramont A, Raeisi M, Rakez M, Goldberg RM, Tebbutt NC, Van Cutsem E, Haller DG, Hecht JR, Mayer RJ, Lichtman SM, Benson AB, Sobrero AF, Tabernero J, Adams R, Zalcberg JR, Grothey A, Yoshino T, André T, Shi Q, Chibaudel B. Characteristics of Patients and Prognostic Factors Across Treatment Lines in Metastatic Colorectal Cancer: An Analysis From the Aide et Recherche en Cancérologie Digestive Database. J Clin Oncol 2025:JCO2401968. [PMID: 40324123 DOI: 10.1200/jco-24-01968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/22/2025] [Accepted: 03/14/2025] [Indexed: 05/07/2025] Open
Abstract
PURPOSE Several lines of treatment can be used sequentially in patients with metastatic colorectal cancer. We investigated the evolution of patient/tumor characteristics and their prognostic impact across treatment lines to develop an overall prognostic score (OPS). PATIENTS AND METHODS Individual patient data from 48 randomized trials were analyzed. The end point was overall survival (from random assignment to death). Missing data were imputed. The complete data set was then separated into construction (80%) and validation sets (20%). The Cox's model was used to define risk groups for survival using the OPS. The discrimination capability was assessed in each treatment-line via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices. Internal validation was done in the validation set. RESULTS A total of 37,560 patients (26,974 in first-line [1L], 7,693 in second-line [2L], and 2,893 in third-line [3L]) were analyzed. Some clinical, biological, and molecular characteristics of patients/tumors included in therapeutic trials evolve over the lines. Seven independent prognostic variables were retained in the final multivariate model common to all lines: Eastern Cooperative Oncology Group performance status, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase, alkaline phosphatase, and the number of metastatic sites. The OPS was used to define four patient subgroups with significantly different prognoses in 1L, 2L, and 3L, separately, with adequate C-indices: 0.65, 0.66, and 0.69 in the construction set and 0.65, 0.66, and 0.68 in the validation set, respectively. The OPS was not predictive, with 3L drugs (v placebo) or subsequent line (2L/1L or 3L/2L) extending survival in all prognostic groups. CONCLUSION The same prognostic model using practical variables can be used before all treatment lines. The OPS could better stratify patients in future clinical trials and help to therapeutic decision in routine practice.
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Affiliation(s)
- Jean-Baptiste Bachet
- Hepato-gastroenterology and Digestive Oncology Department, Pitié Salpêtrière Hospital, APHP, Sorbonne Université, Paris, France
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Cancérologie Paris Ouest, Levallois-Perret, France
- ARCAD Foundation, Paris, France
| | | | - Manel Rakez
- Statistical Unit, ARCAD Foundation, Paris, France
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Institute, Morgantown, WV
| | - Niall C Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Daniel G Haller
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | | | | | - Stuart M Lichtman
- Wilmot Cancer Institute Geriatric Oncology Research Group, University of Rochester, Rochester, NY
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University's Feinberg School of Medicine, Chicago, IL
| | | | - Josep Tabernero
- Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
| | - John R Zalcberg
- Department of Medical Oncology, Monash University School of Public Health and Preventive Medicine, Alfred Health, Melbourne, VIC, Australia
| | | | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Thierry André
- ARCAD Foundation, Paris, France
- Department of Medical Oncology, Saint Antoine Hospital, APHP, Sorbonne Université, Paris, France
| | - Qian Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Cancérologie Paris Ouest, Levallois-Perret, France
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43
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Boka HJ, Engel RM, Georges C, McMurrick PJ, Abud HE. Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer. Mol Cancer 2025; 24:130. [PMID: 40312719 PMCID: PMC12046799 DOI: 10.1186/s12943-025-02327-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 04/08/2025] [Indexed: 05/03/2025] Open
Abstract
Colorectal cancer (CRC) is stratified by heterogeneity between disease sites, with proximal right-sided CRC (RCRC) multifactorial in its distinction from distal left-sided CRC (LCRC). Notably, right-sided tumors are associated with aggressive disease characteristics which culminate in poor clinical outcomes for these patients. While factors such as mutational profile and patterns of metastasis have been suggested to contribute to differences in therapy response, the exact mechanisms through which RCRC resists effective treatment have yet to be elucidated. In response, recent analyzes, including those utilizing whole genome sequencing, transcriptional profiling, and single-cell analyses, have demonstrated that key molecular differences exist between disease sites, with differentially expressed genes spanning a diverse range of cellular functions. Here, we review and contextualize the most recent data on molecular biomarkers found to exhibit discordance between RCRC and LCRC, and highlight candidates for further investigation, including those which present promise for future clinical application. Given the present disparity in survival outcomes for RCRC patients, we expect the prognostic biomarkers presented in our review to be useful in establishing future directions for the side-specific treatment of CRC.
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Affiliation(s)
- Harrison J Boka
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Rebekah M Engel
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Christine Georges
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Paul J McMurrick
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Helen E Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia.
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44
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Holch JW, Ohnmacht AJ, Stintzing S, Heinrich K, Weiss L, Probst V, Stahler A, Fischer von Weikersthal L, Decker T, Kiani A, Kaiser F, Heintges T, Kahl C, Kullmann F, Link H, Höffkes HG, Moehler M, Modest DP, Menden MP, Heinemann V. FOLFIRI with cetuximab or bevacizumab in RAS wild-type metastatic colorectal cancer: Refining first-line treatment selection by combining clinical parameters: A post hoc analysis of the randomized open-label phase III trial FIRE-3/AIO KRK0306. Eur J Cancer 2025; 220:115388. [PMID: 40179821 DOI: 10.1016/j.ejca.2025.115388] [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: 02/07/2025] [Revised: 03/12/2025] [Accepted: 03/21/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Primary tumor sidedness (PTS) with discrimination of left-sided (LC) and right-sided tumors (RC) guides patient selection for targeted first-line therapy in RAS wild-type (RAS-WT) metastatic colorectal cancer (mCRC). This study assessed the hypothesis whether considering PTS with additional clinical parameters better predicts the treatment benefit of targeted first-line treatment. METHODS In FIRE-3, first-line treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI) plus cetuximab (FOLFIRI/Cet) was compared to FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC and unresectable metastasis. We evaluated whether combining PTS with number of metastatic sites (NOM), liver-limited disease status (LLD), age, sex, or carcinoembryonic antigen level (CEA) better predicts treatment benefit regarding overall survival (OS). Here, Cox regression models with second-order interactions were applied. Further, the results were validated by policy learning and Lasso regression analysis. FINDINGS Among 400 RAS-WT mCRC patients, combining PTS with LLD status in a Cox regression model outperformed PTS alone for predicted treatment benefit (P = 0·005; c‑index=0·603). Significant OS benefit from FOLFIRI/Cet over FOLFIRI/Bev was observed in LC/non-LLD patients (HR=0·62; 95 %-confidence interval [CI]=0·46-0·82; P = 0·002), but mitigated in LC/LLD patients (HR=0·83; 95 %-CI=0·53-1·29; P = 0·400). In RC/non-LLD patients, FOLFIRI/Bev demonstrated a significant OS advantage over FOLFIRI/Cet (HR=2·09; 95 %‑CI=1·20-3·63; P = 0·010). However, RC/LLD patients showed potential benefit from FOLFIRI/Cet, though not statistically significant (HR=0·59; 95 %-CI=0·25-1·39; P = 0·218). INTERPRETATION Incorporating PTS and LLD status might improve selection of targeted first-line treatment in RAS-WT mCRC patients. FOLFIRI/Cet appears to be particularly beneficial for LC/non-LLD patients with mitigated benefit in patients with LC/LLD. In contrast, FOLFIRI/Bev is significantly favoured over FOLFIRI/Cet in patients with RC/non-LLD. Notably, RC/LLD patients may still benefit from anti-EGFR therapy despite right-sided primary tumor. These results are hypothesis-generating and warrant further validation.
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Affiliation(s)
- Julian Walter Holch
- Department of Medicine III, University Hospital, LMU Munich, Germany; Comprehensive Cancer Center Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany.
| | - Alexander J Ohnmacht
- Computational Health Center, Helmholtz Munich, Neuherberg, Germany; Department of Biology, LMU Munich, Germany
| | - Sebastian Stintzing
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology (CCM), Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, LMU Munich, Germany; Comprehensive Cancer Center Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Lena Weiss
- Department of Medicine III, University Hospital, LMU Munich, Germany; Comprehensive Cancer Center Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Victoria Probst
- Department of Medicine III, University Hospital, LMU Munich, Germany; Comprehensive Cancer Center Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Arndt Stahler
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology (CCM), Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | | | - Alexander Kiani
- Klinikum Bayreuth GmbH, Bayreuth, Germany and CCC Erlangen-EMN, Germany
| | - Florian Kaiser
- Praxis Hämatologie/Onkologie/Palliativmedizin-Tagesklinik, Landshut, Germany und VK&K Studien GbR, Landshut, Germany
| | - Tobias Heintges
- Department of Medicine II, Städtische Kliniken Neuss, Germany
| | - Christoph Kahl
- Städtisches Klinikum Magdeburg, Hämatologie/ Onkologie, Magdeburg, Germany; Department of Hematology, Oncology, and Palliative Care, University of Rostock, Rostock, Germany
| | | | - Hartmut Link
- Department of Medicine I, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany
| | | | - Markus Moehler
- Medical Department 1, Johannes-Gutenberg Universität Mainz, Germany
| | - Dominik Paul Modest
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology (CCM), Berlin, Germany
| | - Michael P Menden
- Computational Health Center, Helmholtz Munich, Neuherberg, Germany; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Germany; Comprehensive Cancer Center Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Liu X, Wan L, Zhao R, Chen S, Peng W, Yang F, Zhang H. Mismatch Repair Status and Clinico-radiological Feature-Based Model for Pre-treatment Evaluation of Perineural Invasion and Prognosis in Stage I-III Rectal Cancer. Acad Radiol 2025:S1076-6332(25)00299-5. [PMID: 40318973 DOI: 10.1016/j.acra.2025.03.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 05/07/2025]
Abstract
RATIONALE AND OBJECTIVES To develop and validate a predictive model for the pre-treatment evaluation of perineural invasion (PNI) status and to examine its prognostic stratification effectiveness in patients with stage I-III rectal cancer (RC) based on mismatch repair (MMR) status, clinical data, and magnetic resonance imaging (MRI) evaluated features. MATERIALS AND METHODS This retrospective study included 815 patients with stage I-III RC who underwent MRI scans from January 2016 to November 2023 and were randomly assigned to the training and validation cohorts. MMR status, clinical data, and MRI-evaluated features associated with PNI status were identified as independent predictors for developing a predictive model by univariable and multivariable logistic regression analyses in the training cohort. The receiver operating characteristic curves and the area under the curves (AUCs) were utilized to evaluate the diagnostic performance of the prediction model in both the training and validation cohorts. The Kaplan-Meier survival curves and Cox proportional hazards regression analysis were utilized to evaluate the prognostic stratification value of the model in both the training and validation cohorts. RESULTS The predictive model developed with independent predictors, including deficient MMR (odds ratio [OR]=0.434, P=0.021), male gender (OR=1.578, P=0.013), MRI-evaluated tumor morphology (partly annular, OR=3.257, P<0.001; annular, OR=5.184, P<0.001), tumor stage (T3, OR=1.953, P=0.004; T4, OR=2.627, P=0.013), extramural vascular invasion (OR=1.736, P=0.041), tumor deposit (OR=3.902, P<0.001) and mesorectal fascia involvement (OR=2.679, P=0.023), achieved AUCs of 0.748 (95% confidence interval [CI]: 0.711-0.785, P<0.001) and 0.719 (95% CI: 0.640-0.798, P<0.001) in the training and validation cohorts, respectively. The Kaplan-Meier survival curves show effectively prognostic stratification for disease-free survival (DFS), distant metastasis-free survival (DMFS), and recurrence-free survival (RFS) between predicted PNI-positive and PNI-negative patients (both P<0.05). Cox regression analysis indicated that predicted PNI-positive status was a significant risk factor associated with inferior DFS and DMFS in both training and validation cohorts (both P<0.05). The predicted PNI-positive status was a significant risk factor associated with inferior RFS in the training cohort (P=0.002); however, no significant association was observed in the validation cohort (P=0.104). CONCLUSION The developed prediction model for evaluating the PNI status of RC prior to treatment showing acceptable performance and helping with prognostic stratification, which may assist in personalized treatment decisions.
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Affiliation(s)
- Xiangchun Liu
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Lijuan Wan
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Rui Zhao
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Shuang Chen
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Wenjing Peng
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Fan Yang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Hongmei Zhang
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
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Price T, Lugowska I, Chawla SP, Falchook G, Subbiah V, Monzon JG, Arkenau HT, Hui M, Kuboki Y, Dziadziuszko R, Shibaki R, Hong MH, Tan D, Rocha Lima CM, Wang K, Hindoyan A, Shi W, Wong H, Kistler M, Prenen H. A phase I, open-label, multicentre, first-in-human study to evaluate safety, pharmacokinetics and efficacy of AMG 404, a PD-1 inhibitor, in patients with advanced solid tumours. BMJ Open 2025; 15:e088578. [PMID: 40316348 PMCID: PMC12049887 DOI: 10.1136/bmjopen-2024-088578] [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: 05/10/2024] [Accepted: 04/04/2025] [Indexed: 05/04/2025] Open
Abstract
OBJECTIVE To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours. DESIGN First-in-human phase I study comprising eight dose expansion cohorts, including cohorts with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%). SETTING Conducted across 28 global sites. PARTICIPANTS This study enrolled adult patients with histologically or cytologically confirmed metastatic or locally advanced solid tumours not amenable to curative treatment with surgery or radiation. The inclusion criteria included a life expectancy of >3 months, ≥1 measurable or evaluable lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1, an Eastern Cooperative Oncology Group performance status of ≤2 and adequate haematological, renal and hepatic function. Patients with prior treatment with checkpoint inhibitors, primary brain tumour or untreated or symptomatic brain metastases and leptomeningeal disease and history of other malignancy within the past 2 years were excluded. INTERVENTIONS The planned doses were 240 mg, 480 mg and 1050 mg of AMG 404 administered every 4 weeks (Q4W). PRIMARY AND SECONDARY OUTCOME MEASURES Primary endpoints were dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, changes in vital signs and clinical laboratory tests. Secondary endpoints included PK parameters, incidence of antidrug (AMG 404) antibodies and antitumour activity assessed per modified RECIST V.1.1 (objective response, duration of response, progression-free survival (PFS), disease control and duration of stable disease). RESULTS A total of 171 patients were enrolled; 168 were treated. Median (range) follow-up was 36.3 weeks (1.6-137.1). No DLTs were observed. Grade 3 and serious treatment-related adverse events occurred in 16 (9.5%) and 12 (7.1%) patients, respectively. The 480 mg Q4W dose was selected as the recommended phase II dose. AMG 404 serum exposure increased approximately dose proportionally. The objective response rate (80% CI) was 19.6% (15.7-24.1) for the overall population and 36.6% (26.4-47.8) and 30.8% (14.2-52.3) for cohorts with MSI-H tumours (n=41) and NSCLC/PDL1-H (n=13), respectively. The overall disease control rate (80% CI) was 54.8% (49.5-59.9). The median (80% CI) PFS was 3.7 (3.5-4.5) months for the overall population and 14.8 (9.0-not estimable) and 4.4 (2.2-9.7) months for cohorts with MSI-H tumours and NSCLC/PDL1-H, respectively. CONCLUSIONS AMG 404 monotherapy was tolerable at the tested doses, with encouraging antitumour activity observed across tumour types. TRIAL REGISTRATION NUMBER NCT03853109.
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MESH Headings
- Humans
- Female
- Male
- Middle Aged
- Aged
- Adult
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Neoplasms/drug therapy
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Lung Neoplasms/drug therapy
- Aged, 80 and over
- Immune Checkpoint Inhibitors/pharmacokinetics
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Dose-Response Relationship, Drug
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Affiliation(s)
- Timothy Price
- The Queen Elizabeth Hospital, Woodville, Adelaide, Australia
| | - Iwona Lugowska
- Maria Sklodowska-Curie Institute of Oncology Warsaw, Warszawa, Poland
| | - Sant P Chawla
- Sarcoma Oncology Center, Santa Monica, California, USA
| | - Gerald Falchook
- Sarah Cannon Research Institute at HealthONE, Denver, Colorado, USA
| | - Vivek Subbiah
- University of Texas MD Anderson Cancer Centre, Houston, Texas, USA
| | | | | | - Mun Hui
- Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
| | | | | | | | - Min Hee Hong
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Daniel Tan
- National Cancer Centre Singapore, SingHealth, and Duke-NUS Medical School, Singapore
| | | | | | | | - Weibing Shi
- Amgen Inc San Francisco, South San Francisco, California, USA
| | - Hansen Wong
- Amgen Inc San Francisco, South San Francisco, California, USA
| | - Mira Kistler
- Amgen Inc San Francisco, South San Francisco, California, USA
| | - Hans Prenen
- University Hospital Antwerp, Edegem, Antwerp, Belgium
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Fischer AK, Kroesen A, Büttner R. [Secondary malignant neoplasms with underlying Lynch syndrome and coincidental ulcerative colitis]. CHIRURGIE (HEIDELBERG, GERMANY) 2025; 96:415-420. [PMID: 40029372 PMCID: PMC12014831 DOI: 10.1007/s00104-025-02251-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/27/2025] [Indexed: 03/05/2025]
Affiliation(s)
- Anne Kristin Fischer
- Institut für Pathologie, Universität zu Köln, Kerpener Str. 62, 50937, Köln, Deutschland.
| | - Anton Kroesen
- Krankenhaus Porz am Rhein, Urbacher Weg 19, 51149, Köln, Deutschland
| | - Reinhard Büttner
- Institut für Pathologie, Universität zu Köln, Kerpener Str. 62, 50937, Köln, Deutschland
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48
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Eikenboom EL, Nasar N, Seier K, Gönen M, Spaander MCW, O'Reilly EM, Jarnagin WR, Drebin J, D'Angelica MI, Kingham TP, Balachandran VP, Soares KC, Wagner A, Wei AC. Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas. Ann Surg Oncol 2025; 32:3568-3577. [PMID: 39656390 DOI: 10.1245/s10434-024-16621-x] [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: 06/07/2024] [Accepted: 11/19/2024] [Indexed: 04/24/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare. METHODS This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts. RESULTS Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%]). CONCLUSION Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy.
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Affiliation(s)
- Ellis L Eikenboom
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Clinical Genetics, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Naaz Nasar
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Seier
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R Jarnagin
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey Drebin
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael I D'Angelica
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin C Soares
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anja Wagner
- Department of Clinical Genetics, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Alice C Wei
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Al Maqrashi ZAA, Chan SWS, Siddiqui Z, Dotan E. Oncology: What You May Have Missed in 2024. Ann Intern Med 2025; 178:S89-S109. [PMID: 40163865 DOI: 10.7326/annals-25-00963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Over the past 5 decades, substantial advances in oncology have reshaped cancer care, reflecting the dynamic role of internal medicine physicians in patients' journey from screening to diagnosis, treatment, and surveillance. This review highlights 10 landmark studies from 2024 that address emerging therapies and evolving clinical standards. Immunotherapy remains a central focus, with checkpoint inhibitors redefining the management of solid tumors and showing expanded applications across disease sites and earlier stages of disease. Targeted therapies and antibody-drug conjugates, including trastuzumab deruxtecan and enfortumab vedotin, are enhancing precision treatment options in metastatic cancer. Meanwhile, advances in supportive care, such as magnetic resonance imaging-guided prostate cancer screening, ponsegromab for cachexia, and celiac plexus radiosurgery for pain, show enhanced symptom management and quality of life for patients. These innovations highlight the critical role of multidisciplinary approaches, where internal medicine physicians contribute to co-management and toxicity monitoring, ultimately optimizing patient care. By staying current with these developments, internal medicine physicians are positioned to navigate complex oncologic care, ensuring that the benefits of novel therapies are maximized while mitigating their challenges.
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Affiliation(s)
- Zainab Ali Amer Al Maqrashi
- Department of Oncology, McMaster University, and Juravinski Cancer Centre, Hamilton, Ontario, Canada (Z.A.A.A.M., S.W.S.C., Z.S.)
| | - Sze Wah Samuel Chan
- Department of Oncology, McMaster University, and Juravinski Cancer Centre, Hamilton, Ontario, Canada (Z.A.A.A.M., S.W.S.C., Z.S.)
| | - Zeba Siddiqui
- Department of Oncology, McMaster University, and Juravinski Cancer Centre, Hamilton, Ontario, Canada (Z.A.A.A.M., S.W.S.C., Z.S.)
| | - Efrat Dotan
- Penn Medicine, Ann B. Barshinger Cancer Institute, Lancaster General Health, Lancaster, Pennsylvania (E.D.)
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50
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Miller CH, Vemuri A, Lengyel E, Lastra RR. Adaptive immune response and PD-1/ PD-L1 status in chemotherapy treated high grade serous carcinoma is dependent on chemotherapy response score. Hum Pathol 2025; 159:105800. [PMID: 40389122 DOI: 10.1016/j.humpath.2025.105800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 05/16/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
BACKGROUND Platinum-based chemotherapy and debulking surgery is the standard of care for patients with advanced tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response scoring (CRS) system is a histopathologic scoring system developed to measure response to neoadjuvant chemotherapy with prognostic implications. Omental samples with high CRS have greater inflammatory cell infiltrates, but the immunophenotype of infiltrating immune cells and PD-L1 expression of the residual tumor has not been well-defined. DESIGN Twenty cases of patients with FIGO stage IIIA to IIIC HGSC undergoing interval debulking after receiving 3-4 rounds of chemotherapy were selected. 6/20 cases of omental samples were graded as CRS 1, 7/20 were graded CRS 2, and 7/20 were graded CRS 3. The following immunohistochemical stains were performed: CD8, CD4, Foxp3, PD1, and PD-L1. The total number of tumor-infiltrating lymphocytes was recorded, and each case was given a PD-L1 combined positive score (CPS) and tumor proportion score (TPS). RESULTS There was a significantly greater number of CD8+ T cells, PD-1+ T cells, CD4+ T cells, and Foxp3+ T cells in CRS 3-scored cases compared to CRS 1 scored cases (p-values: 0.0018, 0.0224, 0.0071, and 0.0136, respectively). CRS 3-scored cases had a greater PD-L1 CPS (CRS 3 CPS 13 ± 8.2 versus CRS 1 CPS 0 ± 0; p-value: 0.0485). CONCLUSIONS Tubo-ovarian high-grade serous carcinoma with greater response to neoadjuvant treatment have significantly greater T cell infiltrate and greater PD-L1 combined positive score, highlighting a potential role of the CRS as a predictive biomarker for immune checkpoint blockade therapy.
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Affiliation(s)
| | - Anusha Vemuri
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Ernst Lengyel
- Department of Obstetrics and Gynecology/ Section of Gynecologic Oncology, University of Chicago, IL, USA
| | - Ricardo R Lastra
- Department of Pathology, University of Chicago, Chicago, IL, USA.
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