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Yang HC, Fu CF, Qiao LJ, Long GH, Yang LF, Yao B. Relationship between Helicobacter pylori infection and programmed death-ligand 1 in gastric cancer: A meta-analysis. World J Clin Oncol 2025; 16:102397. [DOI: 10.5306/wjco.v16.i4.102397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/04/2024] [Accepted: 02/06/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies worldwide, and Helicobacter pylori (HP) infection is a well-established risk factor for its development. Programmed death-ligand 1 (PD-L1) expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment. While HP infection and PD-L1 expression in GC may be linked, the relationship between them remains unclear, in part because there have been conflicting results reported from various studies.
AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.
METHODS A systematic literature review was conducted using PubMed, Embase, Cochrane Library, and Web of Science databases. Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included. Odds ratios and 95% confidence intervals were calculated to estimate the association. Heterogeneity was assessed using Cochrane’s Q test and I² statistic. A random-effects model was used due to significant heterogeneity across studies.
RESULTS Fourteen studies involving a total of 3069 patients with GC were included. The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues (odd ratio = 1.69, 95% confidence interval: 1.24-2.29, P < 0.001, I2 = 59%). Sensitivity analyses confirmed the robustness of these findings. Subgroup analyses did not show significant variation based on geographic region, sample size, or method of PD-L1 assessment. Publication bias was minimal, as shown by funnel plots and Egger’s regression test.
CONCLUSION HP infection is associated with increased PD-L1 expression in GC, suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
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Affiliation(s)
- Hong-Chang Yang
- Department of Gastroenterology, Longgang Central Hospital of Shenzhen, Shenzhen 518100, Guangdong Province, China
| | - Cheng-Feng Fu
- Department of Oncology, Tongren People’s Hospital, Tongren 554300, Guizhou Province, China
| | - Li-Jun Qiao
- Department of Basic Medical Sciences, Guizhou Health Vocational College, Tongren 554300, Guizhou Province, China
| | - Gen-He Long
- Department of School of Medicine, Guizhou Vocational and Technical College, Tongren 554300, Guizhou Province, China
| | - Li-Fen Yang
- Department of Oncology, Tongren People’s Hospital, Tongren 554300, Guizhou Province, China
| | - Biao Yao
- Department of Oncology, Tongren People’s Hospital, Tongren 554300, Guizhou Province, China
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Abate M, Stroobant E, Fei T, Lin YH, Shimada S, Drebin H, Chen E, Tang LH, Shah SP, Wolchok JD, Janjigian YY, Strong VE, Vardhana SA. Host Tissue Factors Predict Immune Surveillance and Therapeutic Outcomes in Gastric Cancer. Cancer Immunol Res 2025; 13:591-601. [PMID: 39786344 PMCID: PMC11964842 DOI: 10.1158/2326-6066.cir-23-0563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/25/2024] [Accepted: 01/07/2025] [Indexed: 01/12/2025]
Abstract
The immune composition of solid tumors is typically inferred from biomarkers, such as histologic and molecular classifications, somatic mutational burden, and PD-L1 expression. However, the extent to which these biomarkers predict the immune landscape in gastric adenocarcinoma-an aggressive cancer often linked to chronic inflammation-remains poorly understood. We leveraged high-dimensional spectral cytometry to generate a comprehensive single-cell immune landscape of tumors, normal tissue, and lymph nodes from patients in the Western Hemisphere with gastric adenocarcinoma. The immune composition of gastric tumors could not be predicted by traditional metrics such as tumor histology, molecular classification, mutational burden, or PD-L1 expression via IHC. Instead, our findings revealed that innate immune surveillance within tumors could be anticipated by the immune profile of the normal gastric mucosa. Additionally, distinct T-cell states in the lymph nodes were linked to the accumulation of activated and memory-like CD8+ tumor-infiltrating lymphocytes. Unbiased reclassification of patients based on tumor-specific immune infiltrate generated four distinct subtypes with varying immune compositions. Tumors with a T cell-dominant immune subtype, which spanned The Cancer Genome Atlas molecular subtypes, were exclusively associated with superior responses to immunotherapy. Parallel analysis of metastatic gastric cancer patients treated with immune checkpoint blockade showed that patients who responded to immunotherapy had a pretreatment tumor composition that corresponded to a T cell-dominant immune subtype from our analysis. Taken together, this work identifies key host-specific factors associated with intratumoral immune composition in gastric cancer and offers an immunological classification system that can effectively identify patients likely to benefit from immune-based therapies.
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Affiliation(s)
- Miseker Abate
- Gastric and Mixed Tumor 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
- Department of Surgery, New York-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA
| | - Emily Stroobant
- Gastric and Mixed Tumor 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
| | - Teng Fei
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ya-Hui Lin
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shoji Shimada
- Gastric and Mixed Tumor 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
- Digestive Disease Center, Showa University, Northern Yokohama Hospital, Yokohama, Japan
| | - Harrison Drebin
- Gastric and Mixed Tumor 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
- Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Eunise Chen
- Department of Surgery, University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL, USA
| | - Laura H. Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sohrab P. Shah
- Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jedd D. Wolchok
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Yelena Y. Janjigian
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vivian E. Strong
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Santosha A. Vardhana
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Yu ZH, Ma WQ, Ren JW, Zhang XT, Chu L. Role of Computed Tomography in Predicting Programmed Death Ligand-1 Positivity in Gastric Adenocarcinoma. J Multidiscip Healthc 2025; 18:609-621. [PMID: 39935434 PMCID: PMC11812451 DOI: 10.2147/jmdh.s495962] [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: 11/18/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Objective To examine the association between computed tomography (CT) imaging characteristics and programmed death ligand-1 (PD-L1) expression in patients with gastric adenocarcinoma (GAC), and to develop a nomogram model for prediction. Methods The patients were randomly allocated into a training set and a validation set at a ratio of 7:3. The training set was further divided into a PD-L1 positive group and a PD-L1 negative group, based on the combined positive score (CPS). Univariate and multivariate logistic regression analyses were performed to identify independent predictors of PD-L1 positivity. A nomogram was developed to assess the model's predictive performance, which was evaluated using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). It was also compared with the model established by previous study. Results Patients with PD-L1-positive gastric adenocarcinoma exhibited a higher prevalence of larger short diameters of lymph nodes (LNs) (≥ 1 cm), and lower CT attenuation values in the venous and delayed phases compared to those in the PD-L1-negative group. Short diameter of LNs, and CT attenuation values in the delayed phase were identified as independent predictors of PD-L1 positivity. The nomogram analysis indicated that CT attenuation values in the delayed phase were the most significant predictor of PD-L1 positivity, followed by short diameter of LNs. Conclusion The GAC prediction model based on the CT imaging features is effective in predicting PD-L1 expression levels and demonstrates strong clinical applicability.
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Affiliation(s)
- Zhi-Hong Yu
- Department of Ultrasound, Shanxi Provincial People’s Hospital, The Fifth Hospital of Shanxi Medical University, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, 030012, People’s Republic of China
| | - Wei-Qin Ma
- Department of CT/MRI, Lvliang People’s Hospital, Shanxi Province, Lvliang, Shanxi, 033000, People’s Republic of China
| | - Ji-Wei Ren
- Department of Radiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Xu-Ting Zhang
- Department of Radiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Lin Chu
- Department of Radiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China
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de Moraes FCA, Sano VKT, Silva BL, Silva ALS, Castro SCR, Kreuz M, Fernandes LR, Kelly FA, Burbano RMR. PD-1/PD-L1 Inhibitors Increase Pathological Complete Response in Locally Advanced Gastric Cancer: A Meta-analysis and Trial Sequential Analysis. J Gastrointest Cancer 2025; 56:49. [PMID: 39833372 DOI: 10.1007/s12029-024-01141-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND AND OBJECTIVE Gastric cancer (GC) remains a leading cause of morbidity and mortality worldwide. The current standard of care involves neoadjuvant chemotherapy (NACT) followed by radical gastrectomy. This study aims to evaluate the efficacy of neoadjuvant therapy with PD-1/PD-L1 inhibitors in comparison to chemotherapy alone for patients with locally advanced gastric cancer (LAGC). METHODS We conducted a systematic search of PubMed, Web of Science, and Embase to identify studies examining the addition of PD-1/PD-L1 inhibitors to neoadjuvant therapy for LAGC. Odds ratios (OR) were calculated for binary outcomes, such as pathological complete response (pCR), with corresponding 95% confidence intervals (CI). RESULTS Seven studies were included, encompassing a total of 1772 patients. Baseline median age ranged from 31 to 75 years. Most patients had an ECOG performance status score of 0 (942 patients), while 294 had an ECOG score of 1. The estimated pCR (OR 5.94, 95% CI 3.98-8.87; p < 0.000001) significantly favored the PD-1/PD-L1 inhibitors combined with chemotherapy over chemotherapy alone. Additionally, the incidence of certain adverse events increased significantly in the intervention group, including any-grade hypothyroidism (OR 4.55, 95% CI 2.27-9.10; p = 0.000019) and rash (OR 1.74, 95% CI 1.10-2.76; p = 0.017). Conversely, the control group showed a statistically significant lower incidence of grade ≥ 3 fatigue (OR 2.80, 95% CI 1.15-6.85; p = 0.024) compared to the intervention group. CONCLUSION This systematic review and meta-analysis indicate that the addition of PD-1/PD-L1 inhibitors to neoadjuvant chemotherapy is associated with a higher pathological complete response rate compared to chemotherapy alone in patients with locally advanced gastric cancer.
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Affiliation(s)
| | | | - Barbara Lins Silva
- Vancouver Island Health Authority, 1947 Cook St, Victoria, BC, V8T 3P7, Canada
| | | | | | - Michele Kreuz
- Lutheran University of Brazil, Rio Grande Do Sul, Canoas, 92425-020, Brazil
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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Chen H, Zheng Q, Jiang Y, Lin L, Yang Y. IDO1 Expression and CD8+ T-Cell Levels Are Useful Prognostic Biomarkers in Preoperative Gastric Cancer Specimens Before Neoadjuvant Chemotherapy. Appl Immunohistochem Mol Morphol 2025; 33:1-9. [PMID: 39636312 DOI: 10.1097/pai.0000000000001238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 06/05/2024] [Indexed: 12/07/2024]
Abstract
The tumor immune microenvironment occupies an important position in gastric cancer. In this study, we investigated the relationship between indoleamine 2,3-dioxygenase 1 (IDO1), programmed cell death 1 ligand (PD-L1) expressioon, and CD8+ T-cell levels and their efficacy and prognostic value in preoperative gastric cancer specimens before neoadjuvant chemotherapy (NAC). A total of 162 patients with locally advanced gastric cancer were collected in this study. IDO1, PD-L1 expression, and CD8+ T-cell levels in the biopsy samples was detected by immunohistochemical staining, and the relationship between these indexes and the patients' clinicopathological parameters, chemotherapeutic efficacy, and prognosis were investigated. The IDO1 positivity rate was 43.2%. High expression of IDO1 was significantly associated with poor chemotherapeutic efficacy, lymph node metastasis (P<0.05). The PD-L1 positivity rate (using the combined positive score) was 38.2%, and was not related to any clinicopathological variable. Higher CD8+ T-cell levels were associated with a lower rate of lymph node metastasis and lower ypTNM stage (P<0.05). Higher CD8+ T-cell levels were negatively correlated with IDO1 expression (r=-0.224, P<0.05) and positively correlated with PD-L1 expression (r=0.254, P<0.05). Cox regression analysis demonstrated that higher CD8+ T-cell levels was an independent risk factor for overall survival (OS) and the expression of IDO1 had a significantly poorer disease-free survival (DFS). Overexpression of IDO1 and lower CD8+ T-cell levels were associated with poor survival in patients with gastric cancer who received neoadjuvant chemotherapy, and overexpression of IDO1 were associated with the poor tumor response. Our data suggest that IDO1 and CD8 testing of biopsy specimens might be a simple and effective prognostic biomarker for gastric cancer, and IDO1 could predict efficacy of neoadjuvant chemotherapy in gastric cancer.
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Affiliation(s)
- Hu Chen
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - QiaoLin Zheng
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Yiting Jiang
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Yinghong Yang
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
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Costa M, Lopes Fernandes C, Magalhães H. Perioperative Treatment in Gastric Cancer: A Fast-Changing Field. Cancers (Basel) 2024; 16:4036. [PMID: 39682222 DOI: 10.3390/cancers16234036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Gastric cancer is the fifth most common cancer worldwide and its incidence is rising. Surgery is the only curative strategy and its association with perioperative chemotherapy is now standard treatment for most resectable tumors. Despite treatment advances, disease relapse is high, even in early stages, and continued improvement in curative treatment is imperative. With deeper knowledge of gastric cancer heterogeneity, molecular subtypes, and the tumor immune microenvironment, new standard treatment strategies may emerge in the near future. This paper provides a comprehensive review of the current treatment landscape in resectable gastric cancer and future perspectives for the next decade regarding new agents such as targeted therapies, immunotherapy, antibody-drug conjugates, and the combination of multiple treatment modalities.
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Affiliation(s)
- Mafalda Costa
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal
| | | | - Helena Magalhães
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal
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Queiroz FR, Braga LDC, Melo CPDS, Gomes MDS, do Amaral LR, Salles PGDO. Cluster classification of a Brazilian gastric cancer cohort reveals remarkable populational differences in normal p53 rate. EINSTEIN-SAO PAULO 2024; 22:eAO0508. [PMID: 39356938 PMCID: PMC11461015 DOI: 10.31744/einstein_journal/2024ao0508] [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: 03/10/2023] [Accepted: 02/09/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Queiroz et al. showed that the application of cluster methodology for classifying gastric cancer is suitable and efficient within a Brazilian cohort, which is known for its population heterogeneity. The study highlighted the potential utilization of this method within public health services due to its low-cost, presenting a viable means to improve the diagnosis and prognosis of gastric cancer. BACKGROUND Our Brazilian cohort with gastric cancer has a distinct distribution between mutated and normal p53. BACKGROUND New genetic marker-based classifications improve gastric cancer diagnosis accuracy. BACKGROUND Machine learning integration enhances predictive value in gastric cancer diagnosis. BACKGROUND Molecular biomarkers complement clinical decisions, advancing personalized medicine. OBJECTIVE Gastric adenocarcinoma remains an aggressive disease with a poor prognosis, as evidenced by a 5-year survival rate of approximately 31%. The histological classifications already proposed do not accurately reflect the high biological heterogeneity of this neoplasm, particularly in diverse populations, and new classification systems using genetic markers have recently been proposed. Following these newly proposed models, we aimed to assess the cluster distribution in a Brazilian cohort. Furthermore, we evaluated whether the inclusion of other clinical and histological parameters could enhance the predictive value. METHODS We used a previously described four-immunohistochemistry/EBER-ISH marker to classify a cohort of 30 Brazilian patients with gastric adenocarcinoma into five different clusters and compared the distribution with other genetically diverse populations. Furthermore, we used artificial intelligence methods to evaluate whether other clinical and pathological parameters could improve the results of the methodology. RESULTS Disclosing the genetic variability between populations, we observed a more balanced distribution of the aberrant/normal p53 ratio (0.6) between patients negative for the other markers tested, unlike previous studies with Asian and North American populations. In addition, decision tree analysis reinforced the efficiency of these new classifications, as the stratification accuracy was not altered with or without additional data. CONCLUSION Our study underscores the importance of local research in characterizing diverse populations and highlights the complementary role of molecular biomarkers in personalized medicine for gastric adenocarcinoma, enhancing diagnostic accuracy and potentially improving survival rates.
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Affiliation(s)
- Fábio Ribeiro Queiroz
- Instituto Mário PennaBelo HorizonteMGBrazilInstituto Mário Penna, Belo Horizonte, MG, Brazil.
| | | | | | - Matheus de Souza Gomes
- Universidade Federal de UberlândiaLaboratório de Bioinformática e Análises MolecularesPatos de MinasMGBrazilLaboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Patos de Minas, MG, Brazil.
| | - Laurence Rodrigues do Amaral
- Universidade Federal de UberlândiaLaboratório de Bioinformática e Análises MolecularesPatos de MinasMGBrazilLaboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Patos de Minas, MG, Brazil.
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9
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Bos J, Groen-van Schooten TS, Brugman CP, Jamaludin FS, van Laarhoven HWM, Derks S. The tumor immune composition of mismatch repair deficient and Epstein-Barr virus-positive gastric cancer: A systematic review. Cancer Treat Rev 2024; 127:102737. [PMID: 38669788 DOI: 10.1016/j.ctrv.2024.102737] [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: 02/13/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. METHODS A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. RESULTS In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. DISCUSSION AND CONCLUSION MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.
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Affiliation(s)
- J Bos
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - T S Groen-van Schooten
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - C P Brugman
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - F S Jamaludin
- Amsterdam UMC Location University of Amsterdam, Medical Library AMC, Meibergdreef 9, Amsterdam, the Netherlands
| | - H W M van Laarhoven
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - S Derks
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands.
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Baretton G, Lordick F, Gaiser T, Hofheinz R, Horst D, Lorenzen S, Möhler M, Röcken C, Schirmacher P, Stahl M, Thuss-Patience P, Tiemann K. [Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. German version]. PATHOLOGIE (HEIDELBERG, GERMANY) 2024; 45:51-58. [PMID: 38170268 PMCID: PMC10827825 DOI: 10.1007/s00292-023-01215-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/09/2023] [Indexed: 01/05/2024]
Abstract
As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD‑1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
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Affiliation(s)
- G Baretton
- Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland.
| | - F Lordick
- Medizinische Klinik II (Onkologie, Gastroenterologie, Hepatologie und Pneumologie) und Universitäres Krebszentrum Leipzig, Universitätsmedizin Leipzig, Leipzig, Deutschland.
| | - T Gaiser
- PATHOLOGIE SPEYER Gemeinschaftspraxis GbR, Speyer, Deutschland
| | - R Hofheinz
- Universitätsmedizin Mannheim, Mannheim, Deutschland
| | - D Horst
- Institut für Pathologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - S Lorenzen
- III. Medizinische Klinik, Klinikum rechts der Isar, München, Deutschland
| | - M Möhler
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - C Röcken
- Institut für Pathologie, Christian-Albrechts-Universität, Kiel, Deutschland
| | - P Schirmacher
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - M Stahl
- Klinik für Internistische Onkologie & Onkologische Palliativmedizin, KEM | Evang. Kliniken Essen-Mitte, Evang. Huyssens-Stiftung Essen-Huttrop, Essen, Deutschland
| | - P Thuss-Patience
- Charité Centrum Tumormedizin CC14, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - K Tiemann
- Institut für Hämatopathologie, Hamburg, Deutschland
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11
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Cheung KS, Chan AOO, Yu Wong BC. Intestinal‐type Gastric Cancer. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:120-138. [DOI: 10.1002/9781119756422.ch7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Steiniche T, Georgsen JB, Meldgaard P, Deitz AC, Ayers M, Pietanza MC, Zu K. Molecular epidemiology study of programmed death ligand 1 and ligand 2 protein expression assessed by immunohistochemistry in extensive-stage small-cell lung cancer. Front Oncol 2024; 13:1225820. [PMID: 38269020 PMCID: PMC10807038 DOI: 10.3389/fonc.2023.1225820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 12/04/2023] [Indexed: 01/26/2024] Open
Abstract
Objectives Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well understood. The current study was conducted to address these data gaps. Methods A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS. Results Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios [HRs], 0.35 [95% CI, 0.21-0.61] and 0.50 [95% CI, 0.31-0.82]); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 [95% CI, 0.22-0.75] and 0.44 [95% CI, 0.25-0.79] for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 [95% CI, 0.20-0.64]; adjusted HR, 0.36 [0.18-0.73]). Conclusion PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.
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Affiliation(s)
- Torben Steiniche
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Peter Meldgaard
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Mark Ayers
- Merck & Co., Inc., Rahway, NJ, United States
| | | | - Ke Zu
- Merck & Co., Inc., Rahway, NJ, United States
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13
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Noori M, Jafari-Raddani F, Davoodi-Moghaddam Z, Delshad M, Safiri S, Bashash D. Immune checkpoint inhibitors in gastrointestinal malignancies: an Umbrella review. Cancer Cell Int 2024; 24:10. [PMID: 38183112 PMCID: PMC10771001 DOI: 10.1186/s12935-023-03183-3] [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: 08/19/2023] [Accepted: 12/17/2023] [Indexed: 01/07/2024] Open
Abstract
In the Modern era, immune checkpoint inhibitors (ICIs) have been the cornerstone of success in the treatment of several malignancies. Despite remarkable therapeutic advances, complex matrix together with significant molecular and immunological differences have led to conflicting outcomes of ICI therapy in gastrointestinal (GI) cancers. As far we are aware, to date, there has been no study to confirm the robustness of existing data, and this study is the first umbrella review to provide a more comprehensive picture about ICIs' efficacy and safety in GI malignancies. Systematic search on PubMed, Scopus, Web of Science, EMBASE, and Cochrane library identified 14 meta-analyses. The pooled analysis revealed that ICIs application, especially programmed death-1 (PD-1) inhibitors such as Camrelizumab and Sintilimab, could partially improve response rates in patients with GI cancers compared to conventional therapies. However, different GI cancer types did not experience the same efficacy; it seems that hepatocellular carcinoma (HCC) and esophageal cancer (EC) patients are likely better candidates for ICI therapy than GC and CRC patients. Furthermore, application of ICIs in a combined-modal strategy are perceived opportunity in GI cancers. We also assessed the correlation of PD-L1 expression as well as microsatellite status with the extent of the response to ICIs; overall, high expression of PD-L1 in GI cancers is associated with better response to ICIs, however, additional studies are required to precisely elaborate ICI responses with respect to microsatellite status in different GI tumors. Despite encouraging ICI efficacy in some GI cancers, a greater number of serious and fatal adverse events have been observed; further highlighting the fact that ICI therapy in GI cancers is not without cost, and further studies are required to utmost optimization of this approach in GI cancers.
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Affiliation(s)
- Maryam Noori
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farideh Jafari-Raddani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Davoodi-Moghaddam
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahda Delshad
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Laboratory Sciences, School of Allied Medical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Saeid Safiri
- Department of Community Medicine, Faculty of Medicine, Social Determinants of Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Han Z, Wang N, Qiao Q, He X, Wang N. Association of PD-L1 Expression with Clinicopathologic Characters in Gastric Cancer: A Comprehensive Meta-analysis. Curr Med Chem 2024; 31:3198-3216. [PMID: 37921182 DOI: 10.2174/0109298673263784230922060257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/18/2023] [Accepted: 08/16/2023] [Indexed: 11/04/2023]
Abstract
PURPOSE The expression level of programmed death ligand-1(PD-L1) in patients with gastric cancer is the key to determining the use of immune drugs. The relationship between PD-L1 expression level and clinical characteristics is worth exploring. METHODS By setting the search terms correlated to PD-L1 and gastric cancer, a nearly comprehensive search was carried out in four major databases, and the deadline for searching was September 1, 2022. The retrieved documents were further screened by strict inclusion and exclusion criteria after removing the duplication. Next, the quality of the included studies was evaluated with the Newcastle-Ottawa Scale (NOS) scale. Finally, the STATA15.1 software was used to process data and draw plots, and the odds ratios (ORs) were adopted to assess the pooled effect size. RESULTS A total of 85 works of literature were included in this study through screening strictly, and detailed data were extracted after evaluating the quality of the literature. The process of analysis was conducted in the whole population, Asia-Africa population, European and American population, and Asian population with CPS≥1, amd all found that the expression of PD-L1 in gastric cancer was correlated with age, tumor size, EBV infection, Her-2 expression and microsatellite status. However, the subgroup of the region also found some differences in Asian and Western regions, which was interesting and worth studying further. The included research of this study did not have significant publish bias. CONCLUSION After careful analysis, this study found that age (>60 years), tumor size (>5cm), EBV infection (+), Her-2 expression (+), microsatellite status (MSI), and mismatch repair status (dMMR) were risk factors for positive expression of PD-L1 in gastric cancer.
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Affiliation(s)
- Zhuo Han
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Qing Qiao
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
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15
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Kim IH. Emerging Targets for Systemic Treatment of Gastric Cancer: HER2 and Beyond. J Gastric Cancer 2024; 24:29-56. [PMID: 38225765 PMCID: PMC10774754 DOI: 10.5230/jgc.2024.24.e6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/17/2024] Open
Abstract
In recent years, remarkable progress has been made in the molecular profiling of gastric cancer. This progress has led to the development of various molecular classifications to uncover subtype-specific dependencies that can be targeted for therapeutic interventions. Human epidermal growth factor receptor 2 (HER2) is a crucial biomarker for advanced gastric cancer. The recent promising results of novel approaches, including combination therapies or newer potent agents such as antibody-drug conjugates, have once again brought attention to anti-HER2 targeted treatments. In HER2-negative diseases, the combination of cytotoxic chemotherapy and programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors has become the established standard of care in first-line settings. In the context of gastric cancer, potential biomarkers such as PD-L1 expression, Epstein-Barr virus, microsatellite instability, and tumor mutational burden are being considered for immunotherapy. Recently, promising results have been reported in studies on anti-Claudin18.2 and fibroblast growth factor receptor 2 treatments. Currently, many ongoing trials are aimed at identifying potential targets using novel approaches. Further investigations will be conducted to enhance the progress of these therapies, addressing challenges such as primary and acquired resistance, tumor heterogeneity, and clonal evolution. We believe that these efforts will improve patient prognoses. Herein, we discuss the current evidence of potential targets for systemic treatment, clinical considerations, and future perspectives.
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Affiliation(s)
- In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea,.
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16
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Zou Y, Wang J, Zhang J, Guo Q, Song Z, Tang H. Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer. Oncol Lett 2024; 27:20. [PMID: 38058467 PMCID: PMC10696633 DOI: 10.3892/ol.2023.14153] [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: 05/11/2023] [Accepted: 10/11/2023] [Indexed: 12/08/2023] Open
Abstract
The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.
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Affiliation(s)
- Yunlian Zou
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Jinli Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Jinping Zhang
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Qiang Guo
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Zhengji Song
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Hui Tang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
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17
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Liu DHW, Grabsch HI, Gloor B, Langer R, Dislich B. Programmed death-ligand 1 (PD-L1) expression in primary gastric adenocarcinoma and matched metastases. J Cancer Res Clin Oncol 2023; 149:13345-13352. [PMID: 37491637 PMCID: PMC10587283 DOI: 10.1007/s00432-023-05142-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/27/2023]
Abstract
BACKGROUND Combination of immunotherapy and chemotherapy is recommended for first line treatment of gastric adenocarcinoma (GC) patients with locally advanced unresectable disease or metastatic disease. However, data regarding the concordance rate between PD-L1 combined positive score (CPS) in primary GC and matched regional lymph node metastasis (LNmet) or matched distant metastasis (Dmet) is limited. METHODS Tissue microarray sections from primary resected GC, LNmet and Dmet were immunohistochemically stained with anti-PD-L1 (clone SP263). PD-L1 expression was scored separately in tumour cells and immune cells and compared between matched primary GC, LNmet and/or Dmet. CPS was calculated and results for CPS cut-offs 1 and 5 were compared between matched samples. RESULTS 275 PD-L1 stained GC were analysed. 189 primary GC had matched LNmet. CPS cut-off 1 concordance rate between primary GC and LNmet was 77%. 23 primary GC had matched Dmet but no matched LNmet, CPS cut-off 1 concordance rate was 70%. 63 primary GC had both matched LNmet and matched Dmet, CPS cut-off 1 concordance rate of 67%. CPS cut-off 5 results were similar. The proportion of PD-L1 positive tumour cells increased from primary GC (26%) to LNmet (42%) and was highest in Dmet (75%). CONCLUSION Our study showed up to 33% discordance of PD-L1 CPS between primary GC and LNmet and/or Dmet suggesting that multiple biopsies of primary GC and metastatic sites might need to be tested before considering treatment options. Moreover, this is the first study that seems to suggest that tumour cells acquire PD-L1 expression during disease progression.
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Affiliation(s)
- Drolaiz H W Liu
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
- Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital and Johannes Kepler University, Krankenhausstraße 9, 4021, Linz, Austria
| | - Heike I Grabsch
- Department of Pathology, GROW School 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
| | - Beat Gloor
- Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, Bern, Switzerland
| | - Rupert Langer
- Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital and Johannes Kepler University, Krankenhausstraße 9, 4021, Linz, Austria.
| | - Bastian Dislich
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
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18
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Baretton GB, Lordick F, Gaiser T, Hofheinz R, Horst D, Lorenzen S, Moehler M, Röcken C, Schirmacher P, Stahl M, Thuss-Patience P, Tiemann K. Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. J Cancer Res Clin Oncol 2023; 149:16231-16238. [PMID: 37874352 PMCID: PMC10620316 DOI: 10.1007/s00432-023-05180-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 10/25/2023]
Abstract
As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
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Affiliation(s)
- Gustavo B Baretton
- Institute for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Florian Lordick
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology) and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany.
| | - T Gaiser
- Institute of Applied Pathology, 67346, Speyer, Germany
| | - R Hofheinz
- University Medicine Mannheim, Mannheim, Germany
| | - D Horst
- Institute of Pathology of the Charité-University Medicine Berlin, Berlin, Germany
| | - S Lorenzen
- Department of Medicine III, Klinikum Rechts der Isar, Munich, Germany
| | - M Moehler
- Department of Medicine I, University Medicine Mainz, Mainz, Germany
| | - C Röcken
- Institute of Pathology, Christian-Albrechts University, Kiel, Germany
| | - P Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - M Stahl
- Department of Oncology and Palliative Care, Kliniken Essen Mitte, Evangelische Huyssens-Stiftung, Essen-Huttrop, Essen, Germany
| | - P Thuss-Patience
- Charité Center of Tumor Medicine CC14, Charité Campus Virchow-University Medicine Berlin, Berlin, Germany
| | - K Tiemann
- Institute of Hematopathology, Hamburg, Germany
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19
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Hoshimoto A, Tatsuguchi A, Hamakubo R, Nishimoto T, Omori J, Akimoto N, Tanaka S, Fujimori S, Hatori T, Shimizu A, Iwakiri K. Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment. World J Gastroenterol 2023; 29:5566-5581. [PMID: 37970475 PMCID: PMC10642439 DOI: 10.3748/wjg.v29.i40.5566] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/04/2023] [Accepted: 10/23/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma (SBA) has different genomic profiles from gastric and colorectal cancers. Hence, it is essential to establish chemotherapeutic regimens based on SBA characteristics. The expression of programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2) in SBA is not fully understood. Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes (TILs); therefore, the status of TILs in the tumor microenvironment (TME) may influence their efficacy. The ratio of FoxP3+ to CD8+ T cells has been reported to be useful in predicting the prognosis of digestive system cancers. AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues. METHODS We performed immunohistochemical analysis for PD-L1, PD-L2, CD8, FoxP3, and DNA mismatch repair (MMR) proteins using formalin-fixed, paraffin-embedded tissues from 50 patients diagnosed with primary SBA. The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins, and finally evaluated using the combined positive score (CPS). We assessed CD8+ and FoxP3+ T cells in the intratumoral and tumor-surrounding stroma. Subsequently, we calculated and summed the ratio of FoxP3 to CD8+ T cell counts. Immune-related cell densities were graded as low or high. Immunohistochemical results were compared with clinicopathological factors and patient prognosis. The distribution of cancer-specific survival (CSS) was estimated using the Kaplan-Meier method, and the log-rank test was used to test for significant differences in CSS. A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS. RESULTS PD-L1 expression was positive in 34% in tumor cells (T-PD-L1) and 54% in tumor-infiltrating immune cells (I-PD-L1) of the cases examined. T-PD-L2 was positive in 34% and I-PD-L2 was positive in 42% of the cases. PD-L1 CPS ≥ 10 and PD-L2 CPS ≥ 10 were observed in 50% and 56% of the cases, respectively. Deficient MMR (dMMR) was 14% of the cases. T-PD-L1, I-PD-L1 and PD-L1 CPS ≥ 10 were all significantly associated with dMMR (P = 0.037, P = 0.009, and P = 0.005, respectively). T-PD-L1, I-PD-L1, and PD-L1 CPS ≥ 10 were all associated with deeper depth of invasion (P = 0.001, P = 0.024, and P = 0.002, respectively). I-PD-L2 expression and PD-L2 CPS ≥ 10 were significantly higher in the differentiated histological type (P = 0.015 and P = 0.030, respectively). The I-PD-L1 and I-PD-L2 levels were significantly associated with better CSS (P = 0.037 and P = 0.015, respectively). CD8-high was significantly associated with less lymph node metastasis (P = 0.047), less distant metastasis (P = 0.024), less peritoneal dissemination (P = 0.034), and earlier TNM stage (P = 0.047). The CD8-high group had better prognosis than the CD8-low group (P = 0.018). FoxP3 expression was not associated with any clinicopathological factors or prognosis. We found that patients with PD-L2 CPS ≥ 10 tended to have worse prognosis in the FoxP3/CD8-low group (P = 0.088). CONCLUSION The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status. Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.
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Affiliation(s)
- Aitoshi Hoshimoto
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Atsushi Tatsuguchi
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Ryohei Hamakubo
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takayoshi Nishimoto
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Jun Omori
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Naohiko Akimoto
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Shu Tanaka
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Shunji Fujimori
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Tsutomu Hatori
- Department of Pathology, Nippon Medical School, Chiba Hokusoh Hospital, Chiba 270-1694, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
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Kang J, Han KM, Jung H, Kim H. Prognostic Significance of Programmed Cell Death Ligand 1 Expression in High-Grade Serous Ovarian Carcinoma: A Systematic Review and Meta-Analysis. Diagnostics (Basel) 2023; 13:3258. [PMID: 37892079 PMCID: PMC10606661 DOI: 10.3390/diagnostics13203258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/09/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
(1) Background: High-grade serous ovarian carcinoma (HGSOC) is an aggressive subtype of ovarian cancer. Recent advances have introduced prognostic markers and targeted therapies. Programmed cell death ligand 1 (PD-L1) has emerged as a potential biomarker for HGSOC, with implications for prognosis and targeted therapy eligibility; (2) Methods: A literature search was conducted on major databases, and extracted data were categorized and pooled. Subgroup analysis was performed for studies with high heterogeneity. (3) Results: Data from 18 eligible studies were categorized and pooled based on PD-L1 scoring methods, survival analysis types, and endpoints. The result showed an association between high PD-L1 expression and a favorable prognosis in progression-free survival (HR = 0.53, 95% CI = 0.35-0.78, p = 0.0015). Subgroup analyses showed similar associations in subgroups of neoadjuvant chemotherapy patients (HR = 0.6, 95% CI = 0.4-0.88, p = 0.009) and European studies (HR = 0.59, 95% CI = 0.42-0.82, p = 0.0017). In addition, subgroup analyses using data from studies using FDA-approved PD-L1 antibodies suggested a significant association between favorable prognosis and high PD-L1 expression in a subgroup including high and low stage data in overall survival data (HR = 0.46, 95% CI = 0.3-0.73, p = 0.0009). (4) Conclusions: This meta-analysis revealed a potential association between high PD-L1 expression and favorable prognosis. However, caution is warranted due to several limitations. Validation via large-scale studies, with mRNA analysis, whole tissue sections, and assessments using FDA-approved antibodies is needed.
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Affiliation(s)
| | | | | | - Hyunchul Kim
- Department of Pathology, CHA Ilsan Medical Center, 1205 Jungang-ro, Ilsandong-gu, Goyang-si 10414, Republic of Korea; (J.K.); (K.M.H.)
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21
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Wang L, Geng H, Liu Y, Liu L, Chen Y, Wu F, Liu Z, Ling S, Wang Y, Zhou L. Hot and cold tumors: Immunological features and the therapeutic strategies. MedComm (Beijing) 2023; 4:e343. [PMID: 37638340 PMCID: PMC10458686 DOI: 10.1002/mco2.343] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision-making of cancer treatment.
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Affiliation(s)
- Lianjie Wang
- Department of Medical Oncology and Cancer InstituteShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Hui Geng
- Department of Internal MedicineShanghai International Medical CenterShanghaiChina
| | - Yujie Liu
- Department of NephrologyShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lei Liu
- Department of Medical Oncology and Cancer InstituteShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Yanhua Chen
- Department of the Tumor Research Center, Academy of Integrative MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Fanchen Wu
- Department of Medical Oncology and Cancer InstituteShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Zhiyi Liu
- Department of Medical Oncology and Cancer InstituteShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Shiliang Ling
- Department of Medical OncologyNingbo Hospital of Traditional Chinese Medicine, Zhejiang ProvinceNingboChina
| | - Yan Wang
- Department of Medical Oncology and Cancer InstituteShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lihong Zhou
- Department of Medical Oncology and Cancer InstituteShuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
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22
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Wan M, Ding Y, Ma X, Chen X, Xu X, Mao C, Qian J, Xiao C, Jiang H, Zheng Y, Teng L, Xu N. The Memorial Sloan Kettering Prognostic Score: Correlation with survival in patients with advanced gastric cancer. Cancer Med 2023; 12:19656-19666. [PMID: 37787070 PMCID: PMC10587931 DOI: 10.1002/cam4.6608] [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: 02/12/2023] [Revised: 07/16/2023] [Accepted: 09/22/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND Notwithstanding that the past decade has witnessed unprecedented medical progress, gastric cancer (GC) remains a leading cause of cancer death, highlighting the need for effective prognostic markers. The Memorial Sloan Kettering Prognostic Score (MPS) has been validated as a valuable prognostic tool for patients with metastatic pancreatic adenocarcinoma (mPDAC). This study aimed to assess the prognostic value of the MPS in advanced GC. METHODS Data from 367 patients were analyzed in the present study. The MPS for each patient was calculated based on the sum of scores based on the neutrophil-to-lymphocyte ratio and serum albumin levels. Multivariate analyses were performed to identify the independent clinicopathological parameters associated with overall survival (OS). Further subgroup analyses based on clinicopathological features were conducted. RESULTS Patients with MPS 0 (n = 161), MPS 1 (n = 158), and MPS 2 (n = 48) exhibited significantly different OS, with a median survival duration of 20.7 (95%CI: 12.2-29.2), 14.9 (95%CI: 12.5-17.3), and 12.7 (95%CI: 9.3-16.0) months, respectively (p < 0.001). Significant differences in survival were observed among different groups of patients receiving chemotherapy (18.5 months vs. 14.7 months vs. 11.0 months, p = 0.03) or the subgroup receiving chemotherapy plus immunotherapy as first-line treatment (32.6 months vs. 17.7 months vs. 12.7 months, p = 0.02). The MPS was identified as an independent prognostic factor in multivariate analysis. During subgroup analyses, MPS-low (MPS 0) was consistently associated with a better prognosis than MPS-high (MPS 1 or 2). CONCLUSIONS MPS is a practical, simple, and useful prognostic tool for patients with advanced GC. Further studies are warranted to validate its prognostic value in advanced GC.
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Affiliation(s)
- Mingyu Wan
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Yongfeng Ding
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xiaolu Ma
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xiaoyu Chen
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xin Xu
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Chenyu Mao
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Jiong Qian
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Cheng Xiao
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Haiping Jiang
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Yulong Zheng
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Lisong Teng
- Department of Surgical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Nong Xu
- Department of Medical OncologyThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
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23
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Wang Y, Wei X, Ke B, Liu J, Guo Y, Liu Y, Chen Y, Ding T, Wang Y, Meng B, Sun B, Zang F. Exploring the molecular characteristics of the malignant potential of gastric adenocarcinoma with enteroblastic differentiation. Histopathology 2023; 83:631-646. [PMID: 37356975 DOI: 10.1111/his.14998] [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: 02/19/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 06/27/2023]
Abstract
AIMS Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha-fetoprotein (AFP)-producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated. METHODS AND RESULTS In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) (P < 0.001). All distant metastases were observed in the GAED group, not the CGA group (P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV-encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53. Programmed cell death-ligand 1 (PD-L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2+ /EBV- /MSS/TP53+ /PD-L1+ . Next-generation sequencing analyses showed that mutations in the TOPI, ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma-, gland development-, and gastric cancer-related pathways. CONCLUSION The HER2+ /EBV- /MSS/TP53+ /PD-L1+ profile and hepatocellular carcinoma-related pathways may be significant in the malignant potential of GAED. In addition to anti-HER2 therapy, immune check-point inhibitors may be an effective treatment option for patients with GAED.
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Affiliation(s)
- Yong Wang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiyin Wei
- Public Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Ke
- Department of Gastric Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jia Liu
- Department of Colorectal Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yuhong Guo
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yanxue Liu
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yongzi Chen
- Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Tingting Ding
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yalei Wang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Meng
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Baocun Sun
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Fenglin Zang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Ulase D, Behrens HM, Krüger S, Heckl SM, Ebert U, Becker T, Röcken C. LAG3 in gastric cancer: it's complicated. J Cancer Res Clin Oncol 2023; 149:10797-10811. [PMID: 37311986 PMCID: PMC10423140 DOI: 10.1007/s00432-023-04954-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023]
Abstract
PURPOSE Lymphocyte activation gene 3 (LAG3) is thought to contribute to T cell exhaustion within the tumor microenvironment of solid tumors. This study aimed to analyze the spatial distribution of LAG3 + cells in relation to clinicopathological and survival data in a large set of 580 primary resected and neoadjuvantly treated gastric cancers (GC). METHODS LAG3 expression was evaluated in tumor center and invasive margin using immunohistochemistry and whole-slide digital image analysis. Cases were divided into LAG3-low and LAG3-high expression groups based on (1) median LAG3 + cell density, (2) cut-off values adapted to cancer-specific survival using Cutoff Finder application. RESULTS Significant differences in spatial distribution of LAG3 + cells were observed in primarily resected GC, but not in neoadjuvantly treated GC. LAG3 + cell density showed evident prognostic value at following cut-offs: in primarily resected GC, 21.45 cells/mm2 in tumor center (17.9 vs. 10.1 months, p = 0.008) and 208.50 cells/mm2 in invasive margin (33.8 vs. 14.7 months, p = 0.006); and in neoadjuvantly treated GC, 12.62 cells/mm2 (27.3 vs. 13.2 months, p = 0.003) and 123.00 cells/mm2 (28.0 vs. 22.4 months, p = 0.136), respectively. Significant associations were found between LAG3 + cell distribution patterns and various clinicopathological factors in both cohorts. In neoadjuvantly treated GC, LAG3 + immune cell density was found to be an independent prognostic factor of survival (HR = 0.312, 95% CI 0.162-0.599, p < 0.001). CONCLUSION In this study, a higher density of LAG3 + cells was associated with favorable prognosis. Current results support the need for extended analysis of LAG3. Differences in the distribution of LAG3 + cells should be considered, as they could influence clinical outcomes and treatment responses.
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Affiliation(s)
- Dita Ulase
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Hans-Michael Behrens
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Steffen M. Heckl
- Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Ulrike Ebert
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Thomas Becker
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
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Chen XJ, Wei CZ, Lin J, Zhang RP, Chen GM, Li YF, Nie RC, Chen YM. Prognostic Significance of PD-L1 Expression in Gastric Cancer Patients with Peritoneal Metastasis. Biomedicines 2023; 11:2003. [PMID: 37509642 PMCID: PMC10377298 DOI: 10.3390/biomedicines11072003] [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: 05/16/2023] [Revised: 07/07/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Recently, many studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in gastric cancer, but there is still controversy. Additionally, few studies have specifically investigated the expression of PD-L1 in patients with peritoneal metastasis. METHODS Immunohistochemistry was used to analyze the expression of PD-L1 in gastric cancer patients with peritoneal metastasis. The combined positive score (CPS) was calculated to evaluate the expression of PD-L1, and the clinicopathological data were analyzed to explore prognostic significance. RESULTS In total, 147 gastric cancer patients with peritoneal metastasis were enrolled. The negative PD-L1 expression was defined as a CPS < 1, and high PD-L1 expression was defined as a CPS ≥ 10. PD-L1 expression with CPS ≥ 1 and CPS-negative was detected in 67 (45.58%) and 80 (54.42%) patients, respectively. High PD-L1 expression at PD-L1 CPS ≥ 10 was detected in 21(14.29%) patients. The median overall survival (OS) was 18.53 months in the CPS < 10 group and 27.00 months in the CPS ≥ 10 group; the OS difference between the two groups was significant (p = 0.015). Multivariate analysis demonstrated that a poor Eastern Cooperative Oncology Group performance score (ECOG PS) (p = 0.002) and severe peritoneal metastasis (p = 0.033) were significantly associated with poor survival, while palliative chemotherapy (p = 0.002) and high PD-L1 expression (p = 0.008) were independent and significantly favorable prognostic factors. CONCLUSIONS Our study demonstrated that PD-L1 expression was widely presented in gastric cancer patients with peritoneal metastasis, while a CPS no less than 10 predicted better prognosis.
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Affiliation(s)
- Xiao-Jiang Chen
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Cheng-Zhi Wei
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Jun Lin
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Ruo-Peng Zhang
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Guo-Ming Chen
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Yuan-Fang Li
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Run-Cong Nie
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Yong-Ming Chen
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
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Sato Y, Okamoto K, Kawano Y, Kasai A, Kawaguchi T, Sagawa T, Sogabe M, Miyamoto H, Takayama T. Novel Biomarkers of Gastric Cancer: Current Research and Future Perspectives. J Clin Med 2023; 12:4646. [PMID: 37510761 PMCID: PMC10380533 DOI: 10.3390/jcm12144646] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/08/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Gastric cancer is a heterogeneous disease with diverse histological and genomic subtypes, making it difficult to demonstrate treatment efficacy in clinical trials. However, recent efforts have been made to identify molecular biomarkers with prognostic and predictive implications to better understand the broad heterogeneity of gastric cancer and develop effective targeted therapies for it. HER2 overexpression, HER2/neu amplification, MSI-H, and PD-L1+ are predictive biomarkers in gastric cancer, and a growing number of clinical trials based on novel biomarkers have demonstrated the efficacy of targeted therapies alone or in combination with conventional chemotherapy. Enrichment design clinical trials of targeted therapies against FGFR2b and claudin 18.2 have demonstrated efficacy in unresectable advanced gastric cancer. Nonetheless, it is essential to continuously validate promising molecular biomarkers and introduce them into clinical practice to optimize treatment selection and improve patient outcomes. In this review, we focused on established (PD-L1, HER2, MSI) and emerging biomarkers (FGFR2, CLDN18.2) in gastric cancer, their clinical significance, detection methods, limitations, and molecular agents that target these biomarkers.
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Affiliation(s)
- Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Yutaka Kawano
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Akinari Kasai
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tomoyuki Kawaguchi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tamotsu Sagawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo 060-0042, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
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27
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Siemsen W, Halske C, Behrens HM, Krüger S, Becker-Pauly C, Röcken C. The putative pleiotropic functions of meprin β in gastric cancer. Gastric Cancer 2023; 26:542-552. [PMID: 36976399 PMCID: PMC10284984 DOI: 10.1007/s10120-023-01385-2] [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: 11/06/2022] [Accepted: 03/15/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND The gastric microbiome and inflammation play a key role in gastric cancer (GC) by regulating the immune response in a complex manner and by inflammatory events supporting carcinogenesis. Meprin β is a zinc endopeptidase and participates in tissue homeostasis, intestinal barrier function and immunological processes. It influences local inflammatory processes, dysbiosis and the microbiome. Here, we tested the hypothesis that meprin β is expressed in GC and of tumor biological significance. PATIENTS AND METHODS Four hundred forty whole mount tissue sections of patients with therapy-naive GC were stained with an anti-meprin β antibody. The histoscore and staining pattern were analyzed for each case. Following dichotomization at the median histoscore into a "low" and "high" group, the expression was correlated with numerous clinicopathological patient characteristics. RESULTS Meprin β was found intracellularly and at the cell membrane of GC. Cytoplasmic expression correlated with the phenotype according to Lauren, microsatellite instability and PD-L1 status. Membranous expression correlated with intestinal phenotype, mucin-1-, E-cadherin-, β-catenin status, mucin typus, microsatellite instability, KRAS mutation and PD-L1-positivity. Patients with cytoplasmic expression of meprin β showed a better overall and tumor-specific survival. CONCLUSIONS Meprin β is differentially expressed in GC and has potential tumor biological relevance. It might function as a tumor suppressor or promotor depending on histoanatomical site and context.
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Affiliation(s)
- Wiebke Siemsen
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, House U33, 24105, Kiel, Germany
- Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
| | - Christine Halske
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, House U33, 24105, Kiel, Germany
- Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
| | - Hans-Michael Behrens
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, House U33, 24105, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, House U33, 24105, Kiel, Germany
| | | | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, House U33, 24105, Kiel, Germany.
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Mortezaee K, Majidpoor J, Kharazinejad E. The impact of hypoxia on tumor-mediated bypassing anti-PD-(L)1 therapy. Biomed Pharmacother 2023; 162:114646. [PMID: 37011483 DOI: 10.1016/j.biopha.2023.114646] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/04/2023] Open
Abstract
Extending the durability of response is the current focus in cancer immunotherapy with immune checkpoint inhibitors (ICIs). However, factors like non-immunogenic tumor microenvironment (TME) along with aberrant angiogenesis and dysregulated metabolic systems are negative contributors. Hypoxia is a key TME condition and a critical promoter of tumor hallmarks. It acts on immune and non-immune cells within TME in order for promoting immune evasion and therapy resistance. Extreme hypoxia is a major promoter of resistance to the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Hypoxia inducible factor-1 (HIF-1) acts as a key mediator of hypoxia and a critical promoter of resistance to the anti-PD-(L)1. Targeting hypoxia or HIF-1 can thus be an effective strategy for reinvigoration of cellular immunity against cancer. Among various strategies presented so far, the key focus is over vascular normalization, which is an approach highly effective for reducing the rate of hypoxia, increasing drug delivery into the tumor area, and boosting the efficacy of anti-PD-(L)1.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Islamic Republic of Iran.
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Islamic Republic of Iran
| | - Ebrahim Kharazinejad
- Department of Anatomy, Faculty of Medicine, Abadan University of Medical Sciences, Abadan, Islamic Republic of Iran.
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29
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Wang S, Zhou X, Niu S, Chen L, Zhang H, Chen H, Zhou F. Assessment of HER2 in Gastric-Type Endocervical Adenocarcinoma and its Prognostic Significance. Mod Pathol 2023; 36:100148. [PMID: 36841435 DOI: 10.1016/j.modpat.2023.100148] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/30/2023] [Accepted: 02/10/2023] [Indexed: 02/27/2023]
Abstract
As the most common type of human papillomavirus-independent endocervical adenocarcinomas (ECAs), gastric-type endocervical adenocarcinomas (GEAs) account for approximately 10% of all ECAs. Although anti-HER2 therapy has been proven effective in many cancers, it has not been used in ECAs, including GEAs, which is at least partly due to the lack of a well-defined guideline. Limited available data regarding HER2 in GEAs and ECAs have considerable variations likely caused by variations in the tumor type selection, testing methods, and scoring criteria. Here, we selected 58 GEA cases to examine the HER2 status using immunohistochemistry and fluorescent in situ hybridization and investigate the prognostic value and their association with other known or potential prognostic factors. When strong complete or lateral/basolateral membranous reactivity in ≥10% tumor cells was used to define HER2 positivity, relatively high prevalence of HER2 overexpression (10/58[17.2%]) and amplification (9/58 [15.5%]), as well as high immunohistochemistry-fluorescent in situ hybridization concordance rate (9/10 [90%]) was found in GEAs. A lateral/basolateral staining pattern ("U-shaped") was observed, at least focally, in most of HER2-positive (3+) and equivocal (2+) tumors. Notably, considerable heterogeneity of HER2 expression was observed in HER2 positive and equivocal cases (80.0% and 83.3%, respectively). HER2 overexpression and amplification were associated with worse progression-free survival (P = .047 and P = .032, respectively). Programmed death-ligand 1 expression was associated with worse progression-free survival (P = .032), whereas mutant-type p53 demonstrated no prognostic significance. Our work laid a solid foundation for the eventual development of a future standard HER2 testing guideline for GEAs.
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Affiliation(s)
- Su Wang
- Department of Pathology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China
| | - Xin Zhou
- Department of Pathology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China
| | - Shuang Niu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Lili Chen
- Department of Gynecology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China
| | - Huijuan Zhang
- Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hao Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas.
| | - Feng Zhou
- Department of Pathology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China.
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30
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Liu W, Huo G, Chen P. Efficacy of PD-1/PD-L1 inhibitors in advanced gastroesophageal cancer based on characteristics: a meta-analysis. Immunotherapy 2023. [PMID: 37190983 DOI: 10.2217/imt-2022-0305] [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: 05/17/2023] Open
Abstract
Objective: Evaluate the potency of anti-PD-1/PD-L1 antibodies in advanced gastroesophageal cancer patients with different clinical features. Methods: Randomized, controlled trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy in individuals with gastroesophageal cancer were retrieved. Results: 15 trials involving 9194 individuals were included. PD-1/PD-L1 inhibitors significantly improved overall survival (OS) but not progression-free survival. Significantly improved OS was observed in PD-L1 combined positive score ≥1, primary esophageal cancer, primary gastric cancer and Asian patients. Subgroup analysis revealed significant OS benefit achieved for esophageal squamous cell carcinoma, but not for esophageal adenocarcinoma. Conclusion: PD-1/PD-L1 inhibitors improved OS in advanced gastroesophageal carcinoma, especially in patients with esophageal cancer. Race, primary tumor sites and PD-L1 combined positive score can be used to predict the potency of immune checkpoint inhibitors.
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Affiliation(s)
- Wenjie Liu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention & Therapy of Tianjin; Tianjin's Clinical Research Center for Cancer; Tianjin, 300060, China
| | - Gengwei Huo
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention & Therapy of Tianjin; Tianjin's Clinical Research Center for Cancer; Tianjin, 300060, China
| | - Peng Chen
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention & Therapy of Tianjin; Tianjin's Clinical Research Center for Cancer; Tianjin, 300060, China
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31
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Pawluczuk E, Łukaszewicz-Zając M, Mroczko B. The Comprehensive Analysis of Specific Proteins as Novel Biomarkers Involved in the Diagnosis and Progression of Gastric Cancer. Int J Mol Sci 2023; 24:ijms24108833. [PMID: 37240178 DOI: 10.3390/ijms24108833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/12/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023] Open
Abstract
Gastric cancer (GC) cases are predicted to rise by 2040 to approximately 1.8 million cases, while GC-caused deaths to 1.3 million yearly worldwide. To change this prognosis, there is a need to improve the diagnosis of GC patients because this deadly malignancy is usually detected at an advanced stage. Therefore, new biomarkers of early GC are sorely needed. In the present paper, we summarized and referred to a number of original pieces of research concerning the clinical significance of specific proteins as potential biomarkers for GC in comparison to well-established tumor markers for this malignancy. It has been proved that selected chemokines and their specific receptors, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), specific proteins such as interleukin 6 (IL-6) and C-reactive protein (CRP), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), as well as DNA- and RNA-based biomarkers, and c-MET (tyrosine-protein kinase Met) play a role in the pathogenesis of GC. Based on the recent scientific literature, our review indicates that presented specific proteins are potential biomarkers in the diagnosis and progression of GC as well as might be used as prognostic factors of GC patients' survival.
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Affiliation(s)
- Elżbieta Pawluczuk
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Marta Łukaszewicz-Zając
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15a, 15-269 Bialystok, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15a, 15-269 Bialystok, Poland
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32
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Patruni S, Fayyaz F, Bien J, Phillip T, King DA. Immunotherapy in the Management of Esophagogastric Cancer: A Practical Review. JCO Oncol Pract 2023; 19:107-115. [PMID: 36409967 PMCID: PMC10022879 DOI: 10.1200/op.22.00226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 09/13/2022] [Accepted: 09/27/2022] [Indexed: 11/22/2022] Open
Abstract
Recent data support incorporation of immune checkpoint inhibitors into the treatment armamentarium for esophageal, gastroesophageal junction, and gastric (esophagogastric) cancer. This practical review focuses on clinical trials that influenced US Food and Drug Administration approvals and treatment guidelines in esophagogastric cancer, including the impact of location, stage, histology, human epidermal growth factor receptor 2 status, and PD-(L)1 expression on these guidelines. The role of immunotherapy in the locally advanced and metastatic setting is constantly expanding. Over the next few years, the many ongoing trials exploring immunotherapy are anticipated to bring new treatment regimens into the frontline setting with the potential to improve survival in patients with advanced disease.
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Affiliation(s)
- Sunita Patruni
- Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra, Feinstein Institute for Medical Research, Lake Success, NY
| | - Fatima Fayyaz
- Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra, Feinstein Institute for Medical Research, Lake Success, NY
| | - Jeffrey Bien
- Divisions of Hematology and Medical Oncology, Stanford Cancer Institute, Stanford, CA
| | - Tony Phillip
- Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra, Feinstein Institute for Medical Research, Lake Success, NY
| | - Daniel A. King
- Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra, Feinstein Institute for Medical Research, Lake Success, NY
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33
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Holm B, Barsuhn S, Behrens HM, Krüger S, Röcken C. The tumor biological significance of RNF43 and LRP1B in gastric cancer is complex and context-dependent. Sci Rep 2023; 13:3191. [PMID: 36823311 PMCID: PMC9950470 DOI: 10.1038/s41598-023-30294-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer in the world with a poor prognosis. Both RNF43 and LRP1B function as tumor suppressors in the Wnt signaling pathway and have been described to be frequently mutated in GC. In this study of a large and well characterized cohort of 446 GCs we explored the significance of expression of RNF43 and LRP1B and their correlations with clinicopathological patient characteristics. Immunostaining of whole mount tissue sections was documented with the histoscore. Dichotomized at the median, we separated the cohort into a low/negative and a high/positive group of RNF43 and LRP1B expression, respectively. Apart from the entire cohort, we also examined the intestinal and diffuse type GCs separately. Regarding the entire cohort, the expression of RNF43 and LRP1B correlated significantly with the Lauren phenotype and with each other. Interestingly, differences were noted regarding RNF43 between the intestinal and diffuse type GCs. Survival analysis of the intestinal type GCs showed that RNF43 low/negative GCs tended to have a better outcome compared with RNF43 high/positive GCs [24.5 months overall survival (OS) and 25.0 months tumor-specific survival (TSS) vs. 14.1 months OS and 17.9 months TSS, respectively]. To the contrary, diffuse type GCs with RNF43 low/negative had a worse outcome compared with RNF43 high/positive GCs (12.9 months OS and 18.2 months TSS vs. 17.1 months OS and 21.5 months TSS, respectively). On multivariate analysis, RNF43 low/negative versus high/positive was an independent prognosticator of survival in diffuse type GC (hazard ratio 2.393 for OS and 2.398 for TSS). These data support the contention that the expression and biological effect of RNF43 and LRP1B in GC is context-dependent.
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Affiliation(s)
- Bente Holm
- grid.9764.c0000 0001 2153 9986Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Stephan Barsuhn
- grid.9764.c0000 0001 2153 9986Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Hans-Michael Behrens
- grid.9764.c0000 0001 2153 9986Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Sandra Krüger
- grid.9764.c0000 0001 2153 9986Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany. .,Department of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, Arnold-Heller-Str. 3, Haus 14, 24105, Kiel, Germany.
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34
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Huo G, Liu W, Chen P. Efficacy of PD-1/PD-L1 inhibitors in gastric or gastro-oesophageal junction cancer based on clinical characteristics: a meta-analysis. BMC Cancer 2023; 23:143. [PMID: 36765356 PMCID: PMC9921519 DOI: 10.1186/s12885-023-10605-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/03/2023] [Indexed: 02/12/2023] Open
Abstract
PURPOSE Programmed death-1 (PD-1) and its ligand (PD-L1) inhibitors have been reported in several clinical trials for gastric cancer and gastroesophageal junction cancer (GC/GEJC). We presently carried out a meta analysis to evaluate the potency of PD-1/PD-L1 inhibitors in advanced GC/GEJC individuals with different clinical features and to determine patients more probably benefiting from the treatment. METHODS Randomized clinical trials (RCTs) in databases that compared PD-1/PD-L1 inhibitors to chemotherapy in patients with GC/GEJC published before May 2022 were retrieved. Basic characteristics were extracted from the included studies as well as hazard ratios (HR) and 95 percent confidence intervals (CI) for all individuals and subgroups. The inverse variance weighting method was used to evaluate pooled treatment data. FINDINGS Four RCTs involving 2,253 individuals were included. The results suggested that PD-1/PD-L1 inhibitors substantially enhanced overall survival (OS) (HR, 0.91; CI 95%, 0.83-1.00; p = 0.04) but not progression free survival (PFS) (HR, 1.17; CI 95%, 0.83-1.64; p = 0.38) in GC/GEJC individuals compared with chemotherapy. Significantly improved OS was observed in individuals aged < 65 years (HR, 0.84; p = 0.003), and men (HR, 0.88; p = 0.02), but not in individuals aged ≥ 65 years (HR, 0.97; p = 0.62), and women (HR, 0.98; p = 0.82). IMPLICATIONS PD-1/PD-L1 inhibitors improve OS but not PFS compared with chemotherapy in GC/GEJC. Age and sex could be used to predict the treatment potency of PD-1/PD-L1 inhibitors in GC/GEJC.
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Affiliation(s)
- Gengwei Huo
- grid.411918.40000 0004 1798 6427Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Wenjie Liu
- grid.411918.40000 0004 1798 6427Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China ,Department of Oncology, Jining NO.1 People’s Hospital, Jining, 272000 Shandong China
| | - Peng Chen
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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35
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Zhu Y, Zhu F, Ba H, Chen J, Bian X. Helicobacter pylori infection and PD-L1 expression in gastric cancer: A meta-analysis. Eur J Clin Invest 2023; 53:e13880. [PMID: 36164962 DOI: 10.1111/eci.13880] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/24/2022] [Accepted: 09/26/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND High expression of programmed death ligand-1 (PD-L1) has been related to good response to immunotherapy patients with gastric cancer (GC). However, the influence of Helicobacter pylori (HP) infection on PD-L1 expression in GC remains unknown. A meta-analysis was performed to evaluate the association between HP infection and PD-L1 expression in GC. METHODS Observational studies that investigated the relationship between HP infection and PD-L1 expression in patients with GC were obtained by search electronic databases, including PubMed, Embase, Cochrane's Library and Web of Science. A random-effect model incorporating the possible influence of between-study heterogeneity was used to pool the results. RESULTS Ten studies with 1870 patients with GC contributed to the meta-analysis. Pooled results showed that HP infection was significantly associated with the tumour expression of PD-L1 (odds ratio [OR]: 1.90, 95% confidence interval: 1.33-2.72, p < .001; I2 = 53%). Subgroup analyses showed that the association between HP infection and PD-L1 expression in GC was not significantly affected by sample size, methods for PD-L1 evaluation and quality score (p for subgroup analyses all >.05). However, a stronger association was observed in studies with higher prevalence of HP infection (≥35%, OR: 2.58) as compared with those with lower prevalence (<35%, OR: 1.45, p for subgroup difference = .04). CONCLUSION Helicobacter pylori infection in GC patients is associated with tumour expression of PD-L1, suggesting HP infection may be a predictor of good response to immunotherapy in GC.
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Affiliation(s)
- Yaodong Zhu
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - Fangyuan Zhu
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - He Ba
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - Jie Chen
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - Xiuliang Bian
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
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36
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Loss of Major Histocompatibility Complex Class I, CD8 + Tumor-infiltrating Lymphocytes, and PD-L1 Expression in Ovarian Clear Cell Carcinoma. Am J Surg Pathol 2023; 47:124-130. [PMID: 36221308 DOI: 10.1097/pas.0000000000001975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Ovarian clear cell carcinoma (OCCC), a chemoresistant ovarian cancer, shows a modest response to anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1) therapies. The effects of anti-PD-1/PD-L1 therapies rely on cytotoxic T-cell response, which is triggered by antigen presentation mediated by major histocompatibility complex (MHC) class I. The loss of MHC class I with simultaneous PD-L1 expression has been noted in several cancer types; however, these findings and their prognostic value have rarely been evaluated in OCCC. We collected data from 76 patients with OCCC for clinicopathologic analysis. Loss of MHC class I expression was seen in 44.7% of the cases including 39.3% to 47.4% of the PD-L1 + cases and was associated with fewer CD8 + tumor-infiltrating lymphocytes (TILs). PD-L1 positivity was associated with a higher number of CD8 + TILs. Cox proportional hazard models showed that high (≥50/mm 2 ) CD8 + TILs was associated with shorter disease-specific survival (hazard ratio [HR]=3.447, 95% confidence interval [CI]: 1.222-9.720, P =0.019) and overall survival (HR=3.053, 95% CI: 1.105-8.43, P =0.031). PD-L1 positivity using Combined Positive Score was associated with shorter progression-free survival (HR=3.246, 95% CI: 1.435-7.339, P =0.005), disease-specific survival (HR=4.124, 95% CI: 1.403-12.116, P =0.010), and overall survival (HR=4.489, 95% CI: 1.553-12.972, P =0.006). Loss of MHC class I may contribute to immune evasion and resistance to anti-PD-1/PD-L1 therapies in OCCC, and CD8 + TILs and PD-L1 positivity using Combined Positive Score may have a negative prognostic value.
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Venkatasamy A, Guerin E, Reichardt W, Devignot V, Chenard MP, Miguet L, Romain B, Jung AC, Gross I, Gaiddon C, Mellitzer G. Morpho-functional analysis of patient-derived xenografts reveals differential impact of gastric cancer and chemotherapy on the tumor ecosystem, affecting immune check point, metabolism, and sarcopenia. Gastric Cancer 2023; 26:220-233. [PMID: 36536236 PMCID: PMC9950243 DOI: 10.1007/s10120-022-01359-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/25/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Gastric cancer (GC) is an aggressive disease due to late diagnosis resulting from the lack of easy diagnostic tools, resistances toward immunotherapy (due to low PD-L1 expression), or chemotherapies (due to p53 mutations), and comorbidity factors, notably muscle atrophy. To improve our understanding of this complex pathology, we established patient-derived xenograft (PDX) models and characterized the tumor ecosystem using a morpho-functional approach combining high-resolution imaging with molecular analyses, regarding the expression of relevant therapeutic biomarkers and the presence of muscle atrophy. MATERIALS AND METHODS GC tissues samples were implanted in nude mice. Established PDX, treated with cisplatin or not, were imaged by magnetic resonance imaging (MRI) and analyzed for the expression of relevant biomarkers (p53, PD-L1, PD-1, HER-2, CDX2, CAIX, CD31, a-SAM) and by transcriptomics. RESULTS Three well-differentiated, one moderately and one poorly differentiated adenocarcinomas were established. All retained the architectural and histological features of their primary tumors. MRI allowed in-real-time evaluation of differences between PDX, in terms of substructure, post-therapeutic changes, and muscle atrophy. Immunohistochemistry showed differential expression of p53, HER-2, CDX2, a-SAM, PD-L1, PD-1, CAIX, and CD31 between models and upon cisplatin treatment. Transcriptomics revealed treatment-induced hypoxia and metabolic reprograming in the tumor microenvironment. CONCLUSION Our PDX models are representative for the heterogeneity and complexity of human tumors, with differences in structure, histology, muscle atrophy, and the different biomarkers making them valuable for the analyses of the impact of platinum drugs or new therapies on the tumor and its microenvironment.
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Affiliation(s)
- A Venkatasamy
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
- IHU-Strasbourg, Institute of Image-Guided Surgery, 67200, Strasbourg, France
- Medizin Physik, Universitätsklinikum Freiburg, Kilianstr. 5a, 70106, Freiburg, Germany
| | - E Guerin
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
| | - W Reichardt
- Medizin Physik, Universitätsklinikum Freiburg, Kilianstr. 5a, 70106, Freiburg, Germany
| | - V Devignot
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
| | - M P Chenard
- Pathology Department, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, 67098, Strasbourg Cedex, France
| | - L Miguet
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
| | - B Romain
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
- Digestive Surgery Department, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, 67098, Strasbourg Cedex, France
| | - A C Jung
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
- Laboratoire de Biologie Tumorale, Institut de Cancérologie Strasbourg Europe, 67200, Strasbourg, France
| | - I Gross
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
| | - C Gaiddon
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France
| | - G Mellitzer
- Streinth Lab (Stress Response and Innovative Therapies), Inserm UMR_S 1113 IRFAC, Interface Recherche Fondamental et Appliquée à la Cancérologie, 3 Avenue Molière, 67200, Strasbourg, France.
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Mansorunov D, Apanovich N, Kipkeeva F, Nikulin M, Malikhova O, Stilidi I, Karpukhin A. The Correlation of Ten Immune Checkpoint Gene Expressions and Their Association with Gastric Cancer Development. Int J Mol Sci 2022; 23:ijms232213846. [PMID: 36430322 PMCID: PMC9695628 DOI: 10.3390/ijms232213846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
In the immunotherapy based on immune checkpoint inhibition (IC), additional ICs are being studied to increase its effectiveness. An almost unstudied feature is the possible co-expression of ICs, which can determine the therapeutic efficacy of their inhibition. For the selection of promising ICs, information on the association of their expression with cancer development may be essential. We have obtained data on the expression correlation of ADAM17, PVR, TDO2, CD274, CD276, CEACAM1, IDO1, LGALS3, LGALS9, and HHLA2 genes in gastric cancer (GC). All but one, TDO2, have other IC genes with co-expression at some stage. At the metastatic stage, the expression of the IDO1 does not correlate with any other gene. The correlations are positive, but the expressions of the CD276 and CEACAM1 genes are negatively correlated. The expression of TDO2 and LGALS3 is associated with GC metastasis. The expression of TDO2 four-fold higher in metastatic tumors than in non-metastatic tumors, but LGALS3 was two-fold lower. The differentiation is associated with IDO1. The revealed features of TDO2, with a significant increase in expression at the metastatic stage and the absence of other IC genes with correlated expression indicates that the prospect of inhibiting TDO2 in metastatic GC. IDO1 may be considered for inhibition in low-differentiated tumors.
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Affiliation(s)
- Danzan Mansorunov
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Natalya Apanovich
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Fatimat Kipkeeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Maxim Nikulin
- Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, 115478 Moscow, Russia
| | - Olga Malikhova
- Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, 115478 Moscow, Russia
| | - Ivan Stilidi
- Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, 115478 Moscow, Russia
| | - Alexander Karpukhin
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
- Correspondence: ; Tel.: +7-499-324-12-39
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Kori M, Arga KY. Human oncogenic viruses: an overview of protein biomarkers in viral cancers and their potential use in clinics. Expert Rev Anticancer Ther 2022; 22:1211-1224. [PMID: 36270027 DOI: 10.1080/14737140.2022.2139681] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Although the idea that carcinogenesis might be caused by viruses was first voiced about 100 years ago, today's data disappointingly show that we have not made much progress in preventing and/or treating viral cancers in a century. According to recent studies, infections are responsible for approximately 13% of cancer development in the world. Today, it is accepted and proven by many authorities that Epstein-Barr virus (EBV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human Herpesvirus 8 (HHV8), Human T-cell Lymphotropic virus 1 (HTLV1) and highly oncogenic Human Papillomaviruses (HPVs) cause or/and contribute to cancer development in humans. AREAS COVERED Considering the insufficient prevention and/or treatment strategies for viral cancers, in this review we present the current knowledge on protein biomarkers of oncogenic viruses. In addition, we aimed to decipher their potential for clinical use by evaluating whether the proposed biomarkers are expressed in body fluids, are druggable, and act as tumor suppressors or oncoproteins. EXPERT OPINION Consequently, we believe that this review will shed light on researchers and provide a guide to find remarkable solutions for the prevention and/or treatment of viral cancers.
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Affiliation(s)
- Medi Kori
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.,Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
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Kim HN, Ahn S, Kim KM. Gastric cancer with Epstein-Barr virus heterogeneity: Evaluation of the frequency, clinicopathologic features, and genomic profiles. Pathol Res Pract 2022; 238:154108. [PMID: 36126450 DOI: 10.1016/j.prp.2022.154108] [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: 05/10/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/27/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P = 0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles.
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Affiliation(s)
- Han-Na Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soomin Ahn
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Kovaleva OV, Podlesnaya PA, Chang VL, Ognerubov NA, Gratchev AN, Kozlov NA, Stilidi IS, Kushlinskii NE. Comprehensive Analysis of Stromal and Serum Markers in Gastric Cancer. Acta Naturae 2022; 14:75-83. [PMID: 36694901 PMCID: PMC9844092 DOI: 10.32607/actanaturae.11753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/20/2022] [Indexed: 01/22/2023] Open
Abstract
A comprehensive analysis of the cell phenotype of the inflammatory infiltrate of the tumor stroma represents a promising area of molecular oncology. The study of not only soluble forms of various immunoregulatory molecules, but also their membrane-bound forms is also considered highly relevant. We performed a comprehensive analysis of tissue and circulating forms of the PD-1 and PD-L1 proteins, as well as macrophage and B-cell markers in the tumor stroma of gastric cancer, to assess their clinical and prognostic significance. The tumor and blood plasma samples from 63 gastric cancer patients were studied using ELISA and immunohistochemistry. Malignant gastric tumors were shown to be strongly infiltrated by B-cells, and their number was comparable to that of macrophages. For PU.1 expression, an association with tumor size was observed; i.e., larger tumors were characterized by fewer PU.1+ infiltrating cells (p = 0.005). No clinical significance was found for CD20 and CD163, but their numbers were higher at earlier stages of the disease and in the absence of metastases. It was also demonstrated that the PD-L1 content in tumor cells was not associated with the clinical and morphological characteristics of GC. At the same time, PD-L1 expression in tumor stromal cells was associated with the presence of distant metastases. The analysis of the prognostic significance of all the markers studied demonstrated that CD163 was statistically significantly associated with a poor prognosis for the disease (p = 0.019). In addition, PD-L1 expression in tumor cells tended to indicate a favorable prognosis (p = 0.122). The results obtained in this work indicate that the study of soluble and tissue markers of tumor stroma is promising in prognosticating the course of GC. The search for combinations of markers seems to be highly promising, with their comprehensive analysis capable of helping personalize advanced antitumor therapy.
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Affiliation(s)
- O. V. Kovaleva
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - P. A. Podlesnaya
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - V. L. Chang
- Medical Institute of G.P. Derzhavin Tambov State University, Tambov, 392000 Russia
| | - N. A. Ognerubov
- Medical Institute of G.P. Derzhavin Tambov State University, Tambov, 392000 Russia
| | - A. N. Gratchev
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - N. A. Kozlov
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - I. S. Stilidi
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - N. E. Kushlinskii
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
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Agnarelli A, Vella V, Samuels M, Papanastasopoulos P, Giamas G. Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications. Cancers (Basel) 2022; 14:cancers14184378. [PMID: 36139540 PMCID: PMC9496849 DOI: 10.3390/cancers14184378] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023] Open
Abstract
Simple Summary Gastric cancer is one of the most common malignant tumours worldwide, with the fifth and third highest morbidity and mortality, respectively, of all cancers. Survival is limited, as most of the patients are diagnosed at an advanced stage, and are not suitable for surgery with a curative intent. Chemotherapy has only modestly improved patients’ outcomes and is mainly given with a palliative intent. Immunotherapy has improved overall survival of patients with gastric cancer, and has thus become a new standard of care in clinic. In this review we discuss the strong molecular rationale for the administration of immunotherapy in this disease and analyse the clinical data supporting its use. Abstract Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.
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Fong C, Johnston E, Starling N. Neoadjuvant and Adjuvant Therapy Approaches to Gastric Cancer. Curr Treat Options Oncol 2022; 23:1247-1268. [PMID: 35980522 DOI: 10.1007/s11864-022-01004-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2022] [Indexed: 02/08/2023]
Abstract
OPINION STATEMENT Gastric cancer is an aggressive malignancy, requiring a multimodality approach to achieve optimal curative rates even when the disease is amenable to surgical resection. Neoadjuvant and adjuvant approaches differ across the globe-a preference for peri-operative chemotherapy exists in Europe, in contrast to the adoption of adjuvant chemotherapy in Asia and adjuvant chemoradiotherapy in North America. There are nuances and limitations associated with each therapeutic strategy and an understanding of these distinct approaches is integral to judicious clinical application of the available data. Although a multimodal approach provides a clear survival benefit above a surgical-only approach, data report low completion rates of adjuvant therapy components and strongly suggest a need to refine patient selection particularly for ongoing treatment in the post-operative period. This may be achieved using a risk-stratified strategy. Hence, there is a need to transition from a generalised approach to a multimodality treatment towards one guided by individual patient clinical features and biomarker profiles in order to improve tolerability and patient outcomes irrespective of geographical variation in clinical practice. While the evidences supporting molecular features such as microsatellite instability and predictive gene signatures are provocative, prospective validation is required before these can be confidently used to direct clinical decision-making.
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Affiliation(s)
- Caroline Fong
- Gastrointestinal/Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London, UK.
| | - Edwina Johnston
- Gastrointestinal/Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London, UK
| | - Naureen Starling
- Gastrointestinal/Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London, UK
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Drubay V, Nuytens F, Renaud F, Adenis A, Eveno C, Piessen G. Poorly cohesive cells gastric carcinoma including signet-ring cell cancer: Updated review of definition, classification and therapeutic management. World J Gastrointest Oncol 2022; 14:1406-1428. [PMID: 36160745 PMCID: PMC9412924 DOI: 10.4251/wjgo.v14.i8.1406] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/08/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
While the incidence of gastric cancer (GC) in general has decreased worldwide in recent decades, the incidence of diffuse cancer historically comprising poorly cohesive cells-GC (PCC-GC) and including signet ring cell cancer is rising. Literature concerning PCC-GC is scarce and unclear, mostly due to a large variety of historically used definitions and classifications. Compared to other histological subtypes of GC, PCC-GC is nevertheless characterized by a distinct set of epidemiological, histological and clinical features which require a specific diagnostic and therapeutic approach. The aim of this review was to provide an update on the definition, classification and therapeutic strategies of PCC-GC. We focus on the updated histological definition of PCC-GC, along with its implications on future treatment strategies and study design. Also, specific considerations in the diagnostic management are discussed. Finally, the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens (5-Fluorouracil, leucovorin, oxaliplatin and docetaxel), the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.
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Affiliation(s)
- Vincent Drubay
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive Surgery, Cambrai Hospital Center and Sainte Marie, Group of Hospitals of The Catholic Institute of Lille, Cambrai 59400, France
| | - Frederiek Nuytens
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive and Hepatobiliary/Pancreatic Surgery, AZ Groeninge Hospital, Kortrijk 8500, Belgium
| | - Florence Renaud
- Department of Pathology, University Lille Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Antoine Adenis
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
- Department of Medical Oncology, Montpellier Cancer Institute, Monpellier 34000, France
- IRCM, Inserm, University of Monpellier, Monpellier 34000, France
| | - Clarisse Eveno
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
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Chen Y, Bai B, Ying K, Pan H, Xie B. Anti-PD-1 combined with targeted therapy: Theory and practice in gastric and colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188775. [DOI: 10.1016/j.bbcan.2022.188775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 10/16/2022]
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Zhu M, Chen C, Foster NR, Hartley C, Mounajjed T, Salomao MA, Fruth BF, Beamer SE, Kim Y, Harrington SM, Pitot HC, Sanhueza CT, Feng Y, Herrmann J, McWilliams RR, Lucien F, Huang BQ, Ma WW, Bekaii-Saab TS, Dong H, Wigle D, Ahn DH, Hallemeier CL, Blackmon S, Yoon HH. Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction. Clin Cancer Res 2022; 28:3021-3031. [PMID: 35552651 PMCID: PMC10853040 DOI: 10.1158/1078-0432.ccr-22-0413] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/07/2022] [Accepted: 05/09/2022] [Indexed: 01/21/2023]
Abstract
PURPOSE This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. PATIENTS AND METHODS Patients with GEJ adenocarcinoma (cT1-3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. RESULTS We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS < 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1-expressing EVs was significantly associated with higher pCR. CONCLUSIONS Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.
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Affiliation(s)
- Mojun Zhu
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - Chunhua Chen
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Nathan R. Foster
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Christopher Hartley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Marcela A. Salomao
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, Arizona
| | - Briant F. Fruth
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Staci E. Beamer
- Department of Cardiovascular Surgery, Mayo Clinic, Phoenix, Arizona
| | - Yohan Kim
- Department of Urology, Mayo Clinic, Rochester, Minnesota
| | | | - Henry C. Pitot
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - Cristobal T. Sanhueza
- Medical Oncology, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Concepción, Chile
| | - Yening Feng
- Internal Medicine Residency Program, Department of Medicine, BronxCare Health System, Bronx, New York
| | - Joerg Herrmann
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Fabrice Lucien
- Department of Urology, Mayo Clinic, Rochester, Minnesota
| | - Bing Q. Huang
- Microscopy and Cell Analysis Core, Mayo Clinic, Rochester, Minnesota
| | - Wen Wee Ma
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - Tanios S. Bekaii-Saab
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Haidong Dong
- Department of Urology, Mayo Clinic, Rochester, Minnesota
| | - Dennis Wigle
- Department of Thoracic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Daniel H. Ahn
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona
| | | | - Shanda Blackmon
- Department of Thoracic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Harry H. Yoon
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
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Ribeiro HSC, Menezes JN, da Costa WL, F. de Jesus VH, Diniz AL, Godoy AL, de Farias IC, Torres SM, Neotti T, Mello CAL, Begnami MDFS, Dias‐Neto E, Riechelmann RP, Fernandez Coimbra FJ. PD‐L1 expression in gastric and gastroesophageal junction cancer patients treated with perioperative chemotherapy. J Surg Oncol 2022; 126:150-160. [DOI: 10.1002/jso.26929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/27/2022] [Accepted: 05/08/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Héber S. C. Ribeiro
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Wilson L. da Costa
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
- Department of Medicine/Epidemiology and Population Sciences Baylor College of Medicine Houston Texas USA
| | | | - Alessandro L. Diniz
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | - André L. Godoy
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Silvio M. Torres
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | - Tatiane Neotti
- Department of Pathology A. C. Camargo Cancer Center São Paulo Brazil
| | - Celso A. L. Mello
- Department of Clinical Oncology A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Emmanuel Dias‐Neto
- Laboratory of Medical Genomics A. C. Camargo Cancer Center São Paulo Brazil
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Koustas E, Trifylli EM, Sarantis P, Papadopoulos N, Karapedi E, Aloizos G, Damaskos C, Garmpis N, Garmpi A, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer-Current Treatment Options and Future Perspectives. Int J Mol Sci 2022; 23:6664. [PMID: 35743107 PMCID: PMC9224428 DOI: 10.3390/ijms23126664] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/12/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal (GI) cancer constitutes a highly lethal entity among malignancies in the last decades and is still a major challenge for cancer therapeutic options. Despite the current combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, the survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence tumor progression and the development of optimal therapeutic strategies for GI malignancies are urgently needed. Currently, the development and the assessment of the efficacy of immunotherapeutic agents in GI cancer are in the spotlight of several clinical trials. Thus, several new modalities and combinational treatments with other anti-neoplastic agents have been identified and evaluated for their efficiency in cancer management, including immune checkpoint inhibitors, adoptive cell transfer, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, and/or combinations thereof. Understanding the interrelation among the tumor microenvironment, cancer progression, and immune resistance is pivotal for the optimal therapeutic management of all gastrointestinal solid tumors. This review will shed light on the recent advances and future directions of immunotherapy for malignant tumors of the GI system.
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Affiliation(s)
- Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
| | - Nikolaos Papadopoulos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Eleni Karapedi
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Georgios Aloizos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Christos Damaskos
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Renal Transplantation Unit, ‘Laiko’ General Hospital, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Second Department of Propaedeutic Surgery, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Garmpi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
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Tumor Molecular Profiling in Hispanics: Moving Towards Precision Oncology and Health Equity. J Racial Ethn Health Disparities 2022; 10:1423-1431. [PMID: 35648382 PMCID: PMC10163076 DOI: 10.1007/s40615-022-01328-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor molecular profiling techniques, such as next-generation sequencing (NGS) to identify somatic genetic alterations, allow physicians to have a better understanding of the affected carcinogenic pathways and guide targeted therapy. The objective of our study was to characterize common somatic alterations and carcinogenic pathways among Puerto Rican Hispanics with solid tumors. METHODS We conducted a single-institution, retrospective study to characterize molecular tumor profiles using a 592-gene NGS platform. Actionable mutations with current or developing therapies targeting affected genes/pathways were highlighted. RESULTS Tumors from 50 Hispanic patients were evaluated using CARIS Life Science© NGS testing. The median age of our study population was 55 (range 21-84); 54% (n = 27) were males. The primary tumor sites were colorectal (n = 24), gastric (n = 5), breast (n = 4), and lung (n = 3). The most common genetic mutations identified were in TP53 (44%), APC (38%), and KRAS (32%); followed by alterations in EGFR (4%), HER2 (6%), and homologous recombinant deficiency genes (BRCA2, 6%). Genetic alterations were found in multiple signaling pathways particularly in the cell cycle control pathway, MAPK and Wnt/β-Catenin signaling pathways. Targetable biomarkers were identified in 27/50 (54.0%) of tumors. DISCUSSION Molecular profiling techniques, such as next-generation sequencing, have substantially expanded access to alterations in the cancer genome. Our findings demonstrated important actionable mutations in most of the tumors evaluated and support the integration of somatic mutation profiling in the evaluation of Hispanic cancer patients with advanced cancer to help guide therapeutic options.
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Rha SY, Ku GY, Kim HS, Chung HC, Amlashi FG, Maru DM, Fein CA, Tang LH, Zhou W, Wu T, Peter SA, Kelsen DP, Ajani JA. PD-L1 expression and overall survival in Asian and western patients with gastric cancer. Future Oncol 2022; 18:2623-2634. [PMID: 35616013 DOI: 10.2217/fon-2022-0103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Data are limited on PD-L1 expression and its association with overall survival (OS) in gastric cancer (GC) patients receiving routine care in different regions. Materials & methods: In a retrospective study, PD-L1 expression was assayed using the 22C3 pharmDx on GC tumor samples collected between 2003 and 2017 at South Korean and US cancer centers. PD-L1 positivity was defined as combined positive score (CPS) ≥1. The relationship between PD-L1 and OS was analyzed. Results: Of 574 GC tumor samples, 67.4% were CPS ≥1 (68.7% in Korean and 65.7% in US patients). PD-L1 expression was not associated with OS (adjusted hazard ratio: 0.94; 95% CI: 0.75-1.17). Conclusion: PD-L1 prevalence and its association with OS was similar between South Korean and US GC patients.
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Affiliation(s)
- Sun Young Rha
- Yonsei Cancer Center, Yonsei University Health System, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Songdang Institute for Cancer Research, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Geoffrey Y Ku
- Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
| | - Hyo Song Kim
- Yonsei Cancer Center, Yonsei University Health System, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hyun Cheol Chung
- Yonsei Cancer Center, Yonsei University Health System, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Songdang Institute for Cancer Research, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | | | | | - Carly A Fein
- Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
| | - Laura H Tang
- Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
| | - Wei Zhou
- Merck & Co., Inc., 126 E. Lincoln Ave. Rahway, 07065, USA
| | - Ting Wu
- Merck & Co., Inc., 126 E. Lincoln Ave. Rahway, 07065, USA
| | - Senaka A Peter
- Merck & Co., Inc., 126 E. Lincoln Ave. Rahway, 07065, USA
| | - David P Kelsen
- Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
| | - Jaffer A Ajani
- The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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