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Gallois C, Sroussi M, André T, Mouillet-Richard S, Agueeff N, Mulot C, Vernerey D, Louvet C, Bachet JB, Dourthe LM, Mazard T, Jary M, Coutzac C, Lecaille C, Tabernero J, Van Laethem JL, Lepage C, Emile JF, de Reyniès A, Taieb J, Laurent-Puig P. Prognostic Models From Transcriptomic Signatures of the Tumor Microenvironment and Cell Cycle in Stage III Colon Cancer From PETACC-8 and IDEA-France Trials. J Clin Oncol 2025; 43:1765-1776. [PMID: 39889251 PMCID: PMC12084023 DOI: 10.1200/jco.23.02262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/08/2024] [Accepted: 12/23/2024] [Indexed: 02/02/2025] Open
Abstract
PURPOSE The objective of this work was to establish prognostic models in stage III colon cancer (CC) on the basis of transcriptomic signatures of the tumor microenvironment (TME) and cell cycle from the PETACC-8 (training set) and IDEA-France (validation set) trials. PATIENTS AND METHODS 3'RNA sequencing was performed in 1,733 patients from the PETACC-8 trial and 1,248 patients from the IDEA-France trial. Four transcriptomic signatures were analyzed: T-cell and macrophage M2 signatures, the expression of CXCL13, and a score on the basis of the Oncotype DX CC Recurrence Score using the same formula from the stromal score and the cell cycle score. The Immune Proliferative Stromal (IPS) score was defined as the number of dichotomized signatures that fall under the category of a dismal prognosis (from 0 to 4). Time to recurrence (TTR) was defined as the time from the date of random assignment to local and/or metastatic relapse and/or death because of CC, whichever occurs first. RESULTS High Oncotype-like and M2 scores and low CXCL13 expression and T-cell score were associated with a shorter TTR. A multivariable model including these signatures and all known prognostic factors applied to the IDEA-France cohort by obtaining a value of this model for each patient showed TTR significantly different depending on the quartile of this value and a 3-year rate of patients without recurrence ranging from 56% for the lowest quartile to 89% for the highest quartile (P < .0001). The IPS score was significantly associated with TTR in multivariable analysis. CONCLUSION Using transcriptomic data of patients with stage III CC from two large-scale adjuvant trials, a prognostic model on the basis of signatures of the TME and the cell cycle provides important information in addition to known prognostic factors for patient stratification on risk of recurrence.
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Affiliation(s)
- Claire Gallois
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
- Digestive Oncology Department, Institut du Cancer Paris CARPEM, APHP, APHP Centre, Hôpital Européen G. Pompidou, Université Paris Cité, Paris, France
| | - Marine Sroussi
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
- Institut Chimie Biologie Innovation—Laboratoire de BioChimie, ESPCI, UMR8231 CNRS, Université PSL, Paris, France
| | - Thierry André
- Department of Medical Oncology, Hôpital Saint Antoine, Sorbonne Université, Paris, France
| | - Sophie Mouillet-Richard
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
| | - Natacha Agueeff
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
| | - Claire Mulot
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
| | - Dewi Vernerey
- Methodology and Quality of Life Unit in Oncology, University of Besançon, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, INSERM, Unité Mixte de Recherche 1098, RIGHT Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Franche-Comté University, Besançon University Hospital, Besançon, France
| | - Christophe Louvet
- Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France
| | - Jean-Baptiste Bachet
- Department of Hepato-Gastroenterology and Digestive Oncology, Pitié-Salpêtriére Hospital, APHP, Sorbonne Université, Paris, France
| | | | - Thibault Mazard
- Department of Medical Oncology, IRCM, INSERM, ICM, University of Montpellier, Montpellier, France
| | - Marine Jary
- Department of Digestive and Hepatobiliary Surgery, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
| | - Clélia Coutzac
- Department of Medical Oncology, Centre Leon Berard, University Claude Bernard Lyon, Lyon, France
| | - Cédric Lecaille
- Cancerology Department, Bordeaux Nord Polyclinic, Bordeaux, France
| | - Josep Tabernero
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
| | - Jean-Luc Van Laethem
- Department of Digestive Oncology, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Côme Lepage
- Hepatogastroenterology and Digestive Oncology Department, Dijon Bourgogne Hospital, University of Burgundy and Franche Comté, Dijon, France
| | - Jean-François Emile
- EA4340 BECCOH, Service de Pathologie, Hôpital Ambroise Paré, AP-HP, Université de Versailles SQY, Boulogne, France
| | - Aurélien de Reyniès
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
- Laboratoire SeqOIA, Paris, France
| | - Julien Taieb
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
- Digestive Oncology Department, Institut du Cancer Paris CARPEM, APHP, APHP Centre, Hôpital Européen G. Pompidou, Université Paris Cité, Paris, France
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM, Université Paris Cité, Sorbonne Université, Paris, France
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Reitsam NG, Offermans K, Simons CCJM, Grosser B, Zimmermann J, Grabsch HI, Märkl B, van den Brandt PA. Prognostic and Predictive Value of SARIFA-status Within Molecular Subgroups of Colorectal Cancer: Insights From the Netherlands Cohort Study. Am J Surg Pathol 2025:00000478-990000000-00520. [PMID: 40340947 DOI: 10.1097/pas.0000000000002408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
We recently proposed Stroma AReactive Invasion Front Areas (SARIFA), defined as direct tumor-adipocyte interaction at the invasion front, as a novel hematoxylin-and-eosin (H&E)-based histopathological prognostic biomarker in various cancers. Given that microsatellite instability, BRAF, and RAS mutation status are routinely tested for colorectal cancers (CRC), studying SARIFA's additional prognostic value within these molecular subgroups is crucial. In addition, exploring whether the survival benefit from adjuvant therapy differs according to SARIFA-status may enhance patient treatment and outcome. SARIFA-status, BRAF, RAS, and DNA mismatch repair (MMR) status were available for 1726 CRC patients from the prospective Netherlands Cohort Study (NLCS, 1986-2006). In this study, we investigated (1) the relationship between SARIFA-status and CRC molecular characteristics, (2) the prognostic value of SARIFA-status within these molecular subgroups, and (3) whether SARIFA-status was associated with survival benefit from adjuvant therapy. SARIFA-positive CRCs more frequently showed a BRAF mutation compared to SARIFA-negative CRCs (P<0.001). BRAF-mutant/MMR-proficient CRCs were enriched in SARIFA-positive cases. SARIFA-positivity was associated with poor CRC-specific (HRrange: 1.47 to 1.78) and overall survival (HRrange: 1.35 to 1.70) within all molecular subgroups except MMR-deficient CRCs. Patients with SARIFA-positive CRC showed a CRC-specific survival benefit from adjuvant therapy compared to surgery alone (HRCRC-specific: 0.59; 95% CI: 0.44-0.79), while no CRC-specific survival benefit was observed for patients with SARIFA-negative CRC. To conclude, our results indicate that SARIFA-positivity is more common in the aggressive subset of BRAF-mutant and BRAF-mutant/MMR-proficient CRCs. Moreover, SARIFA-positivity provides additional prognostic value within molecular subgroups based on BRAF, RAS, and MMR status, suggesting that it may enhance prognostic stratification of CRC patients.
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Affiliation(s)
- Nic G Reitsam
- Pathology, Medical Faculty, University of Augsburg
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | - Kelly Offermans
- Department of Epidemiology, GROW Research Institute for Oncology and Reproduction
| | - Colinda C J M Simons
- Department of Epidemiology, GROW Research Institute for Oncology and Reproduction
| | - Bianca Grosser
- Pathology, Medical Faculty, University of Augsburg
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | | | - Heike I Grabsch
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Bruno Märkl
- Pathology, Medical Faculty, University of Augsburg
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | - Piet A van den Brandt
- Department of Epidemiology, GROW Research Institute for Oncology and Reproduction
- Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands
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Kang D, Li J, Li Y, Xu J, Yang J, Zhang Z. Prognostic significance of KRAS, NRAS, BRAF, and PIK3CA mutations in stage II/III colorectal cancer: A retrospective study and meta-analysis. PLoS One 2025; 20:e0320783. [PMID: 40279317 PMCID: PMC12027030 DOI: 10.1371/journal.pone.0320783] [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: 10/12/2024] [Accepted: 02/25/2025] [Indexed: 04/27/2025] Open
Abstract
The prognostic significance of KRAS and BRAF mutations is well-established in metastatic colorectal cancer (CRC) but remains uncertain in early-stage tumors. This study retrospectively analyzed 47 stage II/III CRC patients undergoing curative surgery to assess the association of mutations in KRAS, NRAS, BRAF, and PIK3CA with overall survival (OS) and disease-free survival (DFS). Additionally, a meta-analysis was conducted to validate the prognostic relevance of these gene mutations. We included post hoc analyses of phase III randomized controlled trials (RCTs) in stage II/III patients receiving adjuvant therapy after curative resection in the meta-analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using a random-effect model in the overall population, stratified subgroups adjusted for microsatellite instability (MSI) status, and within MSI-high (MSI-H) and microsatellite-stable (MSS) populations. In the retrospective cohort, mutations in KRAS, NRAS, BRAF, and PIK3CA were identified in 29.8%, 4.3%, 8.5%, and 14.9% of patients, respectively. No significant association between individual genes and survival was observed. However, in MSS patients, concurrent mutations were significantly associated with shorter OS and DFS (log-rank test, P < 0.05). The meta-analysis incorporated 13 eligible studies, including 15,034 patients. Pooled analyses revealed that KRAS and BRAF mutations were significantly linked to poor OS (KRAS: HR = 1.25, 95%CI: 1.06-1.47, P = 0.008; BRAF: HR = 1.43, 95%CI: 1.26-1.63, P < 0.001) and DFS (KRAS: HR = 1.36, 95%CI: 1.21-1.53, P < 0.001; BRAF: HR = 1.21, 95%CI: 1.02-1.44, P = 0.032). The prognostic impact of BRAF mutation increased with MSI adjustment compared those without MSI adjustment. In MSS tumors, KRAS-mutant patients demonstrated significantly shorter DFS (HR = 1.63, 95%CI: 1.25-2.13, P < 0.001), while BRAF-mutant patients exhibited reduced OS (HR = 1.53, 95%CI: 1.24-1.89, P < 0.001) and DFS (HR = 1.72, 95%CI: 1.20-2.46, P = 0.003) compared to wildtype patients. Conversely, no significant survival differences were found between mutant and wildtype patients in the MSI-H population. Although PIK3CA mutation was nominally associated with OS (HR = 0.86, 95%CI: 0.75-1.00, P = 0.046), the pooled result lacked robustness. In conclusion, KRAS and BRAF mutations had a negative prognostic impact on MSS stage II/III CRC patients receiving adjuvant therapy following curative resection. These patients may benefit from more effective adjuvant treatment strategies.
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Affiliation(s)
- Di Kang
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Jing Li
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Yangyang Li
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Jingquan Xu
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Jianlei Yang
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Zili Zhang
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
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Mechahougui H, Gutmans J, Gouasmi R, Smekens L, Friedlaender A. BRAF Targeting Across Solid Tumors: Molecular Aspects and Clinical Applications. Int J Mol Sci 2025; 26:3757. [PMID: 40332392 PMCID: PMC12027668 DOI: 10.3390/ijms26083757] [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: 03/08/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
BRAF mutations are critical drivers in cancers such as melanoma, colorectal cancer, and non-small-cell lung cancer. The most common mutation, BRAF V600E, is a key therapeutic target. Targeted treatments with BRAF and MEK inhibitors have significantly improved progression-free and overall survival in melanoma patients. However, in cancers like metastatic colorectal cancer, BRAF mutations are associated with poor outcomes due to aggressive disease behavior and resistance to conventional chemotherapy. Despite progress, resistance to BRAF/MEK inhibitors remains a major challenge, often driven by secondary mutations in the mitogen-activated protein kinase (MAPK) pathway, activation of alternative pathways such as phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), or changes in the tumor microenvironment. These challenges have motivated ongoing research into combining BRAF inhibitors with immunotherapies to enhance and prolong treatment effectiveness. Future research must also account for the role of the cancer's tissue of origin, as the biological context significantly influences response to targeted therapies, highlighting the need for a deeper understanding of tumor biology, micro-environment, and genetics.
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Affiliation(s)
- Hiba Mechahougui
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (J.G.); (L.S.)
| | - James Gutmans
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (J.G.); (L.S.)
| | - Roumaïssa Gouasmi
- Cancer Research Center of Lyon, CNRS UMR5286, Inserm U1052, University of Lyon, 69100 Lyon, France;
| | - Laure Smekens
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (J.G.); (L.S.)
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Zhang J, Zhu H, Liu W, Miao J, Mao Y, Li Q. Prognostic and predictive molecular biomarkers in colorectal cancer. Front Oncol 2025; 15:1532924. [PMID: 40308511 PMCID: PMC12040681 DOI: 10.3389/fonc.2025.1532924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Precision medicine has brought revolutionary changes to the diagnosis and treatment of cancer patients, and is currently a hot and challenging research topic. Currently, the treatment regimens for most colorectal cancer (CRC) patients are mainly determined by several biomakers, including Microsatellite Instability (MSI), RAS, and BRAF. However, the roles of promising biomarkers such as HER-2, consensus molecular subtypes (CMS), and circulating tumor DNA (ctDNA) in CRC are not yet fully clear. Therefore, it is urgent to explore the potential of these emerging biomarkers in the diagnosis and treatment of CRC patients. In this paper, we discuss recent advances in CRC biomarkers, especially clinical data, and focus on the roles of biomarkers in prognosis, prediction, treatment strategies, and the intrinsic connections with clinical pathological features, hoping to promote better precision medicine for colorectal cancer.
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Affiliation(s)
- Jianzhi Zhang
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Hao Zhu
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wentao Liu
- Department of General Surgery, Affiliated Drum Tower Hospital, JiangSu University, Nanjing, China
| | - Ji Miao
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Yonghuan Mao
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Qiang Li
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
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Nielsen AT, Saqi IK, Justesen TF, Madsen MT, Gögenur I, Orhan A. The prognostic impact of tumor mutations and tumor-infiltrating lymphocytes in patients with localized pMMR colorectal cancer - A systematic review and meta-analysis. Crit Rev Oncol Hematol 2025; 211:104714. [PMID: 40188978 DOI: 10.1016/j.critrevonc.2025.104714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/21/2025] [Accepted: 03/28/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Tumor mutations and the composition of the tumor microenvironment have prognostic and therapeutic significance in colorectal cancer (CRC). However, immunotherapy remains a challenge for patients with proficient mismatch repair (pMMR) CRC. In this paper, the association between tumor-infiltrating lymphocytes (TILs) and tumor mutations on survival outcomes in patients with localized pMMR CRC was examined. METHODS A systematic review of the literature and a meta-analysis were conducted in accordance with the PRISMA guidelines. The literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The outcomes of interest were overall survival, disease-free survival, and cancer-specific survival. The risk of bias was assessed through the Newcastle-Ottawa Scale and the quality of the cumulative evidence was evaluated through the modified GRADE approach. FINDINGS In total, 8498 articles were screened for eligibility and 44 articles were included in the meta-analysis with 33,704 patients in total. Patients with high infiltration of any TILs showed significantly improved overall survival (HR = 0.57, 95 % CI: 0.49-0.67, I2: 0 %), especially for the subgroup of CD3 + (HR = 0.52, 95 % CI: 0.38-0.71, I2: 0 %) and CD8 + (HR = 0.60, 95 % CI: 0.37-0.99, I2: 10 %) TILs. Patients with BRAF mutation (HR = 2.68, 95 % CI: 1.47-4.89, I2: 83 %) and KRAS mutation (HR = 1.25, 95 % CI: 1.18-1.33, I2: 0 %) showed decreased overall survival. INTERPRETATION High infiltration of TILs, especially CD3 + and CD8 + , was associated with significantly improved survival, while BRAF and KRAS mutations were correlated with worse survival outcomes for patients with non-metastatic pMMR CRC.
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Affiliation(s)
- Amalie Thomsen Nielsen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark.
| | - Ida Kolukisa Saqi
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark
| | | | | | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Adile Orhan
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark
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Kong Y, Huang X, Cao X, Tang F, Zhou X. Early Recurrence of Colorectal Liver Metastasis (Number ≤ 5 and Largest Diameter ≤ 3 cm) after Resection or Thermal Ablation: a Multi-center Study of Patterns, Safety, Survival and Risk Factors. J Gastrointest Cancer 2025; 56:77. [PMID: 40072796 DOI: 10.1007/s12029-025-01200-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2025] [Indexed: 03/14/2025]
Abstract
OBJECTIVE To compare early recurrence patterns, safety, survival and investigate the clinical risk factors of early recurrence (ER) after liver resection or thermal ablation (TA) for patients with colorectal liver metastases (CRLM) with number ≤ 5 and largest diameter ≤ 3 cm. MATERIALS AND METHODS This retrospective study included patients with CRLM who underwent liver resection or TA between January 2016 and December 2021 at two hospitals in China. The Kaplan-Meier method and log-rank test were used to assess recurrence-free survival (RFS) and overall survival (OS). Risk factors for ER were analysed using univariate and multivariate Cox regression analyses. RESULTS 303 patients with 632 liver metastases were enrolled. The most common early recurrence pattern was intrahepatic recurrence (IHR) in resection group and TA group. There was no significant difference in 6-month RFS rate (65.81% vs 66.23%) and median OS (P = 0.10) between two groups. Patients without ER had better OS than those with ER (P < 0.05). The incidence of serious complications (P = 0.013), length of hospitalization (P < 0.01), and albumin-bilirubin (ALBI) score (P = 0.038) in TA group were significantly better than resection group. The diameter of liver metastases (HR: 4.89, 95% CI: 1.16-20.60; P = 0.031) and clinical risk score (CRS) (HR: 1.86, 95% CI: 1.06-3.25; P = 0.029) were independent risk factors for ER. CONCLUSION For CRLM with largest diameter ≤ 3 cm and number ≤ 5, the efficacy of receiving resection or TA is comparable, and the safety of TA is better. TA may be considered as the first-line local treatment option for patients with CRLM.
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Affiliation(s)
- Yaqing Kong
- Department of Interventional Therapy, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaoyu Huang
- Department of Interventional Therapy, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaojing Cao
- Department of Interventional Therapy, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fan Tang
- Department of Interventional Therapy, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiang Zhou
- Department of Interventional Therapy, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Abdelgadir O, Kuo YF, Khan MF, Okorodudu AO, Cheng YW, Dong J. Mortality Outcome Associated with Specific KRAS, NRAS, and BRAF Hot-Spot Mutations in Metastatic Colorectal Cancer Patients: A Retrospective Cohort Study. Diagnostics (Basel) 2025; 15:590. [PMID: 40075837 PMCID: PMC11899597 DOI: 10.3390/diagnostics15050590] [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: 01/22/2025] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objective: The prognostic value of specific hot-spot mutations within KRAS, NRAS, and BRAF genes in metastatic colorectal cancer (mCRC) genes remains debatable. This study explores whether certain KRAS, NRAS, and BRAF mutations are associated with the risk of all-cause mortality in mCRC. Methods: We retrospectively analyzed records of 494 patients with mCRC treated at the University of Texas Medical Branch between January 2016 and July 2023. Data on genetic mutations and clinicopathological features were collected for this analysis. We estimated survival probabilities and conducted multivariable Cox proportional hazards regression to evaluate the impact of specific mutations on all-cause mortality risk. Results:KRAS c.35G>T (p.Gly12Val) and c.34G>T (p.Gly12Cys) mutations were significantly associated with an increased risk of all-cause mortality in the overall mCRC population and the treated mCRC subgroup. KRAS c.38G>A (p.Gly13Asp) was significantly associated with an increased risk of all-cause mortality in the treated mCRC subgroup but BRAF c.1799T>A (p.Val600Glu) was significantly associated with an increased risk of all-cause mortality in the overall mCRC population. No significant association was observed between NRAS mutations and mortality risk in mCRC, possibly due to their lower frequency or different biological effects compared to KRAS and BRAF mutations. Conclusions: These findings suggest that specific KRAS [c.35G>T (p.Gly12Val), c.34G>T (p.Gly12Cys), and c.38G>A (p.Gly13Asp)] and BRAF c.1799T>A (p.Val600Glu) mutations may have prognostic value in mCRC. However, given the single-center study design and lack of direct therapeutic implications, larger multicenter studies are needed to substantiate these results and better define the clinical relevance of these mutations.
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Affiliation(s)
- Omer Abdelgadir
- Graduate School of Biomedical Science, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yong-Fang Kuo
- School of Public and Population Health, University of Texas Medical Branch, Galveston, TX 77555, USA;
| | - M. Firoze Khan
- Department of Pathology, University Texas Medical Branch, Galveston, TX 77555, USA; (M.F.K.); (A.O.O.)
| | - Anthony O. Okorodudu
- Department of Pathology, University Texas Medical Branch, Galveston, TX 77555, USA; (M.F.K.); (A.O.O.)
| | - Yu-Wei Cheng
- Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Jianli Dong
- Department of Pathology, University Texas Medical Branch, Galveston, TX 77555, USA; (M.F.K.); (A.O.O.)
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Liu Z, Li Y, Wang S, Wang Y, Sui M, Liu J, Chen P, Wang J, Zhang Y, Dang C, Hou P. Genome-wide CRISPR screening identifies PHF8 as an effective therapeutic target for KRAS- or BRAF-mutant colorectal cancers. J Exp Clin Cancer Res 2025; 44:70. [PMID: 40001243 PMCID: PMC11853609 DOI: 10.1186/s13046-025-03338-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Mutations in KRAS and BRAF genes are prevalent in colorectal cancer (CRC), which strikingly promote tumorigenesis and lead to poor response to a variety of treatments including immunotherapy by activating the MAPK/ERK pathway. Thus, there is an urgent need to discover effective therapeutic targets and strategies. METHODS CRISPR-Cas9 lentiviral knockout library was used to screen the suppressors of anti-PD1 immunotherapy. Bioinformatic analysis was used to analyze the correlation between PHF8 expression and immune indicators in CRC. In vitro and in vivo experiments were utilized to determine the effects of PHF8 on the immune indexes and malignant phenotypes of CRC cells. qRT-PCR, western blotting, immunohistochemical (IHC) staining, and chromatin immunoprecipitation (ChIP)-qPCR assays were used to determine the regulatory effects of PHF8 on PD-L1, KRAS, BRAF, and c-Myc and the regulatory effect c-Myc/miR-22-3p signaling axis on PHF8 expression in CRC cells. RESULTS This study identified histone lysine demethylase PHF8 as a negative regulator for the efficacy of anti-PD1 therapy and found that it was highly expressed in CRCs and strongly associated with poor patient survival. Functional studies showed that PHF8 played an oncogenic role in KRAS- or BRAF-mutant CRC cells, but not in wild-type ones. Mechanistically, PHF8 up-regulated the expression of PD-L1, KRAS, BRAF, and c-Myc by increasing the levels of transcriptional activation marks H3K4me3 and H3K27ac and decreasing the levels of transcriptional repression mark H3K9me2 within their promoter regions, promoting immune escape and tumor progression. Besides, our data also demonstrated that PHF8 was up-regulated by the c-Myc/miR-22-3p signaling axis to form a positive feedback loop. Targeting PHF8 substantially improved the efficacy of anti-PD1 therapy and inhibited the malignant phenotypes of KRAS- or BRAF-mutant CRC cells. CONCLUSION Our data demonstrate that PHF8 may be an effective therapeutic target for KRAS- or BRAF-mutant CRCs.
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Affiliation(s)
- Zhao Liu
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yiqi Li
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, P.R. China
| | - Simeng Wang
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yubo Wang
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Mengjun Sui
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Jiaxin Liu
- Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Pu Chen
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Jianling Wang
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yuchen Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Chengxue Dang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
| | - Peng Hou
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
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10
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Chuang J, Chen Y, Wang J. Narrative review of neoadjuvant therapy in patients with locally advanced colon cancer. Kaohsiung J Med Sci 2025; 41:e12926. [PMID: 39717937 PMCID: PMC11827549 DOI: 10.1002/kjm2.12926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 11/28/2024] [Accepted: 12/10/2024] [Indexed: 12/25/2024] Open
Abstract
Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide, with more than 1.9 million new cases reported in 2020, and is associated with major survival challenges, particularly in patients with locally advanced colon cancer (LACC). LACC often involves T4 invasion or extensive nodal involvement and requires a multidisciplinary approach for management. Radical surgery followed by adjuvant chemotherapy remains the primary treatment strategy for LACC. However, achieving complete tumor resection (R0) is challenging because locally advanced colon tumors typically infiltrate adjacent organs or nodes. Advancements in LACC treatment have involved neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiotherapy (NACRT), and neoadjuvant immunotherapy (NAIT). Studies such as FOxTROT and PRODIGE 22 have demonstrated that NACT, particularly with FOLFOX or CAPOX, can lead to major tumor downstaging, improved survival rates, and increased R0 resection rates. Predictive biomarkers, such as mismatch repair (MMR) status and T stage, are crucial in identifying candidates who may benefit from NACT. NACRT has demonstrated promise in enhancing tumor regression, particularly in patients with rectal cancer, underscoring its potential for use with LACC. NAIT, particularly for deficient MMR tumors, has emerged as a novel approach, with studies such as NICHE-2 and NICHE-3 reporting excellent pathologic responses and pathologic complete responses. Integrating these therapies can enhance the surgical and survival outcomes of patients with LACC, highlighting the importance of personalized treatment strategies based on tumor characteristics and response to neoadjuvant interventions. This review discusses the evolving landscape of LACC management, focusing on optimizing treatment approaches for improved patient outcomes.
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Affiliation(s)
- Jen‐Pin Chuang
- Chiayi HospitalMinistry of Health and WelfareChiayiTaiwan
- Department of Surgery, Faculty of Medicine, College of MedicineNational Cheng Kung UniversityTainanTaiwan
- Department of SurgeryNational Cheng Kung University HospitalTainanTaiwan
| | - Yen‐Chen Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Department of Surgery, Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
| | - Jaw‐Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Department of Surgery, Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
- Center for Cancer ResearchKaohsiung Medical UniversityKaohsiungTaiwan
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11
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Ekmekciu I, Zucha DM, Christmann J, Wisser S, Heuer V, Sargin B, Hollerbach S, Lamberti C, Müller L, Lugnier C, Verdoodt B, Denz R, Terzer T, Feder I, Reinacher-Schick A, Tannapfel A, Tischoff I. Exploring the molecular profile of localized colon cancer: insights from the AIO Colopredict Plus registry. Front Oncol 2024; 14:1434791. [PMID: 39628993 PMCID: PMC11612501 DOI: 10.3389/fonc.2024.1434791] [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: 05/18/2024] [Accepted: 09/11/2024] [Indexed: 12/06/2024] Open
Abstract
Introduction Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted. Methods A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates. Results This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively). Discussion These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.
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Affiliation(s)
- Ira Ekmekciu
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | | | - Sarah Wisser
- Institute of Pathology, Ruhr University, Bochum, Germany
| | - Vera Heuer
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Buelent Sargin
- Hematology and Medical Oncology, St-Marien-Hospital Lunen, Lunen, Germany
| | - Stephan Hollerbach
- Department of Gastroenterology, Allgemeines Krankenhaus (AKH) Celle, Celle, Germany
| | | | | | - Celine Lugnier
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Robin Denz
- Department of Medical Informatics, Biometrics and Epidemiology, Ruhr University, Bochum, Germany
| | - Tobias Terzer
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Inke Feder
- Institute of Pathology, Ruhr University, Bochum, Germany
| | - Anke Reinacher-Schick
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Iris Tischoff
- Institute of Pathology, Ruhr University, Bochum, Germany
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12
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Zhang RX, Wu XJ, Wan DS, Lin JZ, Ding PR, Liao LE, Lei J, Lu ZH, Li LR, Chen G, Kong LH, Wang FL, Zhang J, Fan WH, Jiang W, Zhou WH, Li C, Li Y, Li XY, Peng JH, Pan ZZ. Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial. Int J Surg 2024; 110:6622-6631. [PMID: 38652147 PMCID: PMC11487029 DOI: 10.1097/js9.0000000000001301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/23/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND The authors aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS The authors performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection ( n =341) or curative surgical resection alone ( n =344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients [3-year disease-free survival (DFS): 91.1 vs. 90.0%, P =0.328; 3-year OS: 94.4 vs. 95.9%, P =0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P =0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P =0.032). Meanwhile, patients with colon cancer and abnormal pretreatment carcinoembryonic antigen (CEA) levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P =0.029 and OS: HR=0.476, 95% CI: 0.223-1.017, P =0.049). CONCLUSIONS Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.
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Affiliation(s)
- Rong-xin Zhang
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Xiao-jun Wu
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - De-sen Wan
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Jun-zhong Lin
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Pei-rong Ding
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Le-en Liao
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Jian Lei
- Department of Gastrointestinal Surgery, The First Affifiliated Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Zhen-hai Lu
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Li-ren Li
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Gong Chen
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Ling-heng Kong
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Fu-long Wang
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Jian Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmology, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Wen-hua Fan
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Wu Jiang
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Wen-hao Zhou
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Cong Li
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Yuan Li
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Xue-ying Li
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Jian-hong Peng
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
| | - Zhi-zhong Pan
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou
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13
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Ochman B, Limanówka P, Mielcarska S, Kula A, Dawidowicz M, Wagner W, Hudy D, Szrot M, Piecuch JZ, Piecuch J, Czuba Z, Świętochowska E. Associations of SEMA7A, SEMA4D, ADAMTS10, and ADAM8 with KRAS, NRAS, BRAF, PIK3CA, and AKT Gene Mutations, Microsatellite Instability Status, and Cytokine Expression in Colorectal Cancer Tissue. Curr Issues Mol Biol 2024; 46:10218-10248. [PMID: 39329961 PMCID: PMC11431007 DOI: 10.3390/cimb46090609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/11/2024] [Accepted: 09/13/2024] [Indexed: 09/28/2024] Open
Abstract
Semaphorins (SEMAs), ADAM, and ADAMTS family members are implicated in various cancer progression events within the tumor microenvironment across different cancers. In this study, we aimed to evaluate the expression of SEMA7A, SEMA4D, ADAM8, and ADAMTS10 in colorectal cancer (CRC) in relation to the mutational landscape of KRAS, NRAS, BRAF, PIK3CA, and AKT genes, microsatellite instability (MSI) status, and clinicopathological features. We also examined the associations between the expression of these proteins and selected cytokines, chemokines, and growth factors, assessed using a multiplex assay. Protein concentrations were quantified using ELISA in CRC tumors and tumor-free surgical margin tissue homogenates. Gene mutations were evaluated via RT-PCR, and MSI status was determined using immunohistochemistry (IHC). GSEA and statistical analyses were performed using R Studio. We observed a significantly elevated expression of SEMA7A in BRAF-mutant CRC tumors and an overexpression of ADAM8 in KRAS 12/13-mutant tumors. The expression of ADAMTS10 was decreased in PIK3CA-mutant CRC tumors. No significant differences in the expression of the examined proteins were observed based on MSI status. The SEMA7A and SEMA4D expressions were correlated with the expression of numerous cytokines associated with various immune processes. The potential immunomodulatory functions of these molecules and their suitability as therapeutic targets require further investigation.
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Affiliation(s)
- Błażej Ochman
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (P.L.); (S.M.); (W.W.); (D.H.)
| | - Piotr Limanówka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (P.L.); (S.M.); (W.W.); (D.H.)
| | - Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (P.L.); (S.M.); (W.W.); (D.H.)
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland; (A.K.); (M.D.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland; (A.K.); (M.D.)
| | - Wiktor Wagner
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (P.L.); (S.M.); (W.W.); (D.H.)
| | - Dorota Hudy
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (P.L.); (S.M.); (W.W.); (D.H.)
| | - Monika Szrot
- Department of General and Bariatric Surgery and Emergency Medicine in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 10 Marii Curie-Skłodowskiej, 41-800 Zabrze, Poland; (M.S.); (J.P.)
| | - Jerzy Zbigniew Piecuch
- Department of General and Bariatric Surgery and Emergency Medicine in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 10 Marii Curie-Skłodowskiej, 41-800 Zabrze, Poland; (M.S.); (J.P.)
| | - Jerzy Piecuch
- Department of General and Bariatric Surgery and Emergency Medicine in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 10 Marii Curie-Skłodowskiej, 41-800 Zabrze, Poland; (M.S.); (J.P.)
| | - Zenon Czuba
- Department of Microbiology and Immunology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland;
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (P.L.); (S.M.); (W.W.); (D.H.)
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14
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Yang Q, Qu R, Lu S, Zhang Y, Zhang Z, Fu W. Biological and Clinical Characteristics of Proximal Colon Cancer: Far from Its Anatomical Subsite. Int J Med Sci 2024; 21:1824-1839. [PMID: 39113889 PMCID: PMC11302569 DOI: 10.7150/ijms.97574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
Colorectal cancer is a heterogeneous disease which can be divided into proximal colon cancer, distal colon cancer and rectal cancer according to the anatomical location of the tumor. Each anatomical location of colorectal cancer exhibits distinct characteristics in terms of incidence, clinical manifestations, molecular phenotypes, treatment, and prognosis. Notably, proximal colon cancer differs significantly from cancers of other anatomical subsites. An increasing number of studies have highlighted the presence of unique tumor biological characteristics in proximal colon cancer. Gaining a deeper understanding of these characteristics will facilitate accurate diagnosis and treatment approaches.
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Affiliation(s)
- Qing Yang
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Ruize Qu
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Siyi Lu
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Yi Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Zhipeng Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
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15
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Lecuelle J, Truntzer C, Basile D, Laghi L, Greco L, Ilie A, Rageot D, Emile JF, Bibeau F, Taïeb J, Derangere V, Lepage C, Ghiringhelli F. Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts. EBioMedicine 2024; 105:105207. [PMID: 38880067 PMCID: PMC11233898 DOI: 10.1016/j.ebiom.2024.105207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/18/2024] [Accepted: 06/03/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables. METHODS We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression. FINDINGS CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS. INTERPRETATION In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination. FUNDING This research received no external funding.
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Affiliation(s)
- Julie Lecuelle
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
| | - Caroline Truntzer
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France
| | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Molecular Gastroenterology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Luana Greco
- Molecular Gastroenterology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alis Ilie
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
| | - David Rageot
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
| | - Jean-François Emile
- Paris-Saclay University, Versailles SQY University (UVSQ), EA4340-BECCOH, Assistance Publique-Hôpitaux de Paris (AP-HP), Ambroise Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France
| | - Fréderic Bibeau
- Service d'Anatomie et Cytologie Pathologiques, CHU Côte de Nacre, Normandie Université, Caen, France; Department of Pathology, Besançon University Hospital, Besançon, France
| | - Julien Taïeb
- Institut du Cancer Paris Cancer Research for Personalized Medicine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique, Sorbonne Université, Université Sorbonne Paris Cité, Université de Paris, Paris, France; Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, AP-HP Centre, Université Paris Cité, Paris, France
| | - Valentin Derangere
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy Franche-Comté, Dijon, France
| | - Come Lepage
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; University of Burgundy Franche-Comté, Dijon, France; Fédération Francophone de Cancérologie Digestive, Centre de Randomisation Gestion Analyse, EPICAD LNC 1231, Dijon, France; Service d'Hépato-gastroentérologie et Oncologie digestive, CHU de Dijon, France
| | - François Ghiringhelli
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy Franche-Comté, Dijon, France; Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
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16
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Taieb J, Basile D, Seligmann J, Argiles G, André T, Gallois C, Goldberg RM, Yothers G, Sobrero A, Meyerhardt JA, Souglakos J, Labianca R, Iveson T, Church DN, Arnold D, Tie J, Gill S, Laurent-Puig P, Yoshino T, Lonardi S, Shi Q. Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts. Eur J Cancer 2024; 206:114118. [PMID: 38810317 DOI: 10.1016/j.ejca.2024.114118] [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: 02/19/2024] [Revised: 05/01/2024] [Accepted: 05/04/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.
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Affiliation(s)
- Julien Taieb
- Institut du Cancer Paris CARPEM, Gastroenterology and Digestive Oncology Department, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, France.
| | - Debora Basile
- Division of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | | | | | - Thierry André
- Sorbonne Université and department of Medical Oncology, Hospital Saint Antoine and INSERM 938 and SIRIC CURAMUS, Paris, France
| | - Claire Gallois
- Institut du Cancer Paris CARPEM, Gastroenterology and Digestive Oncology Department, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, France
| | - Richard M Goldberg
- West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center, Morgantown, WV
| | - Greg Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Alberto Sobrero
- Department of Medical Oncology, IRCCS San Martino, Genoa, Italy
| | | | - John Souglakos
- Department of Medical Oncology, University General Hospital of Heraklion, 71110 Heraklion, Greece
| | | | - Tim Iveson
- University Hospital Southampton NHS Trust, Southampton, United Kingdom
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Department of Oncology and Hematology, AK Altona, Hamburg, Germany
| | - Jeanne Tie
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia; Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | | | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, EPIGENETEC, 75006 Paris, France
| | | | - Sara Lonardi
- Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Qian Shi
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN, USA
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17
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Gu R, Fang H, Wang R, Dai W, Cai G. A comprehensive overview of the molecular features and therapeutic targets in BRAF V600E-mutant colorectal cancer. Clin Transl Med 2024; 14:e1764. [PMID: 39073010 PMCID: PMC11283586 DOI: 10.1002/ctm2.1764] [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: 05/07/2024] [Revised: 06/23/2024] [Accepted: 07/03/2024] [Indexed: 07/30/2024] Open
Abstract
As one of the most prevalent digestive system tumours, colorectal cancer (CRC) poses a significant threat to global human health. With the emergence of immunotherapy and target therapy, the prognosis for the majority of CRC patients has notably improved. However, the subset of patients with BRAF exon 15 p.V600E mutation (BRAFV600E) has not experienced remarkable benefits from these therapeutic advancements. Hence, researchers have undertaken foundational investigations into the molecular pathology of this specific subtype and clinical effectiveness of diverse therapeutic drug combinations. This review comprehensively summarised the distinctive molecular features and recent clinical research advancements in BRAF-mutant CRC. To explore potential therapeutic targets, this article conducted a systematic review of ongoing clinical trials involving patients with BRAFV600E-mutant CRC.
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Affiliation(s)
- Ruiqi Gu
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Hongsheng Fang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Renjie Wang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Weixing Dai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Guoxiang Cai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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18
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Abumustafa W, Castven D, Becker D, Salih SS, Manzoor S, Zamer BA, Talaat I, Hamad M, Marquardt JU, Muhammad JS. Inhibition of PRMT5-mediated regulation of DKK1 sensitizes colorectal cancer cells to chemotherapy. Cell Signal 2024; 119:111166. [PMID: 38588876 DOI: 10.1016/j.cellsig.2024.111166] [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: 02/14/2024] [Revised: 03/29/2024] [Accepted: 04/05/2024] [Indexed: 04/10/2024]
Abstract
The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.
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Affiliation(s)
- Wafaa Abumustafa
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Darko Castven
- First Medical Department, University Medical Centre Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Diana Becker
- University Medical Centre of the Johannes Gutenberg, University Mainz, Mainz, Germany
| | - Shahenaz Shaban Salih
- Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Batoul Abi Zamer
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Iman Talaat
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Mawieh Hamad
- Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Jens Uwe Marquardt
- First Medical Department, University Medical Centre Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical and Health Sciences, and College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
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19
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Bi S, Zhu J, Huang L, Feng W, Peng L, Leng L, Wang Y, Shan P, Kong W, Zhu S. Comprehensive Analysis of the Function and Prognostic Value of TAS2Rs Family-Related Genes in Colon Cancer. Int J Mol Sci 2024; 25:6849. [PMID: 38999959 PMCID: PMC11241446 DOI: 10.3390/ijms25136849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/09/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.
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Affiliation(s)
- Suzhen Bi
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Jie Zhu
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland;
| | - Liting Huang
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Wanting Feng
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Lulu Peng
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Liangqi Leng
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Yin Wang
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Peipei Shan
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
| | - Weikaixin Kong
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland;
| | - Sujie Zhu
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China; (S.B.); (L.H.); (W.F.); (L.P.); (L.L.); (Y.W.); (P.S.)
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20
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Maione F, Oddo D, Galvagno F, Falcomatà C, Pandini M, Macagno M, Pessei V, Barault L, Gigliotti C, Mira A, Corti G, Lamba S, Riganti C, Castella B, Massaia M, Rad R, Saur D, Bardelli A, Di Nicolantonio F. Preclinical efficacy of carfilzomib in BRAF-mutant colorectal cancer models. Mol Oncol 2024; 18:1552-1570. [PMID: 38348572 PMCID: PMC11161726 DOI: 10.1002/1878-0261.13595] [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: 07/27/2023] [Revised: 11/28/2023] [Accepted: 01/18/2024] [Indexed: 06/09/2024] Open
Abstract
Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T-cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.
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Affiliation(s)
- Federica Maione
- Department of OncologyUniversity of TorinoTorinoItaly
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
| | - Daniele Oddo
- Department of OncologyUniversity of TorinoTorinoItaly
| | - Federica Galvagno
- Department of OncologyUniversity of TorinoTorinoItaly
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
| | - Chiara Falcomatà
- Institute of Molecular Oncology and Functional GenomicsSchool of Medicine, Technical University of MunichMunichGermany
- Center for Translational Cancer Research (TranslaTUM), School of MedicineTechnical University of MunichMunichGermany
| | - Marta Pandini
- Tumor Microenvironment UnitIstituto di Ricovero e Cura a Carattere Scientifico Humanitas Research HospitalMilanItaly
- Department of Biomedical SciencesHumanitas UniversityMilanItaly
| | | | | | | | | | - Alessia Mira
- Department of OncologyUniversity of TorinoTorinoItaly
| | | | - Simona Lamba
- Department of OncologyUniversity of TorinoTorinoItaly
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
| | | | - Barbara Castella
- Laboratory of Blood Tumor Immunology (LBTI), Molecular Biotechnology Center “Guido Tarone” (MBC)University of TurinTurinItaly
| | - Massimo Massaia
- Laboratory of Blood Tumor Immunology (LBTI), Molecular Biotechnology Center “Guido Tarone” (MBC)University of TurinTurinItaly
- SC EmatologiaAzienda Ospedaliera S. Croce e CarleCuneoItaly
| | - Roland Rad
- Institute of Molecular Oncology and Functional GenomicsSchool of Medicine, Technical University of MunichMunichGermany
- Tumor Microenvironment UnitIstituto di Ricovero e Cura a Carattere Scientifico Humanitas Research HospitalMilanItaly
- German Cancer ConsortiumHeidelbergGermany
| | - Dieter Saur
- Institute of Molecular Oncology and Functional GenomicsSchool of Medicine, Technical University of MunichMunichGermany
- Tumor Microenvironment UnitIstituto di Ricovero e Cura a Carattere Scientifico Humanitas Research HospitalMilanItaly
- German Cancer ConsortiumHeidelbergGermany
- Department of Internal Medicine II, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany
| | - Alberto Bardelli
- Department of OncologyUniversity of TorinoTorinoItaly
- IFOM ETSThe AIRC Institute of Molecular OncologyMilanItaly
| | - Federica Di Nicolantonio
- Department of OncologyUniversity of TorinoTorinoItaly
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
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21
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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22
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Zeng H, Zhong X, Liu W, Liang B, Xue X, Yu N, Xu D, Wang X, Lin S. Predicting treatment failure in stage III colon cancer patients after radical surgery. Front Oncol 2024; 14:1397468. [PMID: 38817900 PMCID: PMC11137277 DOI: 10.3389/fonc.2024.1397468] [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: 03/07/2024] [Accepted: 04/25/2024] [Indexed: 06/01/2024] Open
Abstract
Purpose The aim to assess treatment failure in patients with stage III colon cancer who underwent radical surgery and was analyzed using the nomogram. Methods Clinical factors and survival outcomes for stage III colon cancer patients registered in the SEER database from 2018 to 2019 were analyzed, with patients split into training and testing cohorts (7:3 ratio). A total of 360 patients from the First Affiliated Hospital of Longyan served as an external validation cohort. Independent predictors of treatment failure were identified using logistic regression analyses. The nomograms was evaluated by concordance index (C-index), calibration curves, and the area under the curve (AUC), decision curve analysis (DCA) and clinical impact curves (CIC) assessed the clinical utility of nomograms versus TNM staging. Results The study included 4,115 patients with stage III colon cancer. Multivariate logistic analysis age, tumor site, pT stage, pN stage, chemotherapy, pretreatment CEA levels, number of harvested lymph nodes, perineural invasion and marital status were identified as independent risk factors for treatment failure. The C-indices for the training and testing sets were 0.853 and 0.841. Validation by ROC and calibration curves confirmed the stability and reliability of the model. DCA showed that the net clinical effect of the histogram was superior to that of the TNM staging system, while CIC highlighted the potentially large clinical impact of the model. Conclusions The developed Nomogram provides a powerful and accurate tool for clinicians to assess the risk of treatment failure after radical surgery in patients with stage III colon cancer.
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Affiliation(s)
- Hao Zeng
- Department of Gastroenterology and Anorectal Surgery, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Xuejing Zhong
- Department of Science and Education, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China
| | - Wenxin Liu
- Department of Anaesthesia, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Baofeng Liang
- Department of Gastroenterology and Anorectal Surgery, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Xueyi Xue
- Department of Gastroenterology and Anorectal Surgery, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Nong Yu
- Department of Gastroenterology and Anorectal Surgery, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Dongbo Xu
- Department of Gastroenterology and Anorectal Surgery, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Xiaojie Wang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Shuangming Lin
- Department of Gastroenterology and Anorectal Surgery, Longyan First Hospital, Fujian Medical University, Longyan, China
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23
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Orlandi E, Giuffrida M, Trubini S, Luzietti E, Ambroggi M, Anselmi E, Capelli P, Romboli A. Unraveling the Interplay of KRAS, NRAS, BRAF, and Micro-Satellite Instability in Non-Metastatic Colon Cancer: A Systematic Review. Diagnostics (Basel) 2024; 14:1001. [PMID: 38786299 PMCID: PMC11120454 DOI: 10.3390/diagnostics14101001] [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: 03/21/2024] [Revised: 04/30/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Microsatellite Instability (MSI-H) occurs in approximately 15% of non-metastatic colon cancers, influencing patient outcomes positively compared to microsatellite stable (MSS) cancers. This systematic review focuses on the prognostic significance of KRAS, NRAS, and BRAF mutations within MSI-H colon cancer. Through comprehensive searches in databases like MEDLINE, EMBASE, and others until 1 January 2024, we selected 8 pertinent studies from an initial pool of 1918. These studies, encompassing nine trials and five observational studies involving 13,273 patients, provided insights into disease-free survival (DFS), survival after recurrence, and overall survival. The pooled data suggest that while KRAS and BRAF mutations typically predict poorer outcomes in MSS colorectal cancer, their impact is less pronounced in MSI contexts, with implications varying across different stages of cancer and treatment responses. In particular, adverse effects of these mutations manifest significantly upon recurrence rather than affecting immediate DFS. Our findings confirm the complex interplay between genetic mutations and MSI status, emphasizing the nuanced role of MSI in modifying the prognostic implications of KRAS, NRAS, and BRAF mutations in colon cancer. This review underscores the importance of considering MSI alongside mutational status in the clinical decision-making process, aiming to tailor therapeutic strategies more effectively for colon cancer patients.
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Affiliation(s)
- Elena Orlandi
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Mario Giuffrida
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| | - Serena Trubini
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Enrico Luzietti
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| | - Massimo Ambroggi
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Elisa Anselmi
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Patrizio Capelli
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| | - Andrea Romboli
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
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24
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Chu CH, Lai IL, Jong BK, Chiang SF, Tsai WS, Hsieh PS, Yeh CY, You JF. The prognostic and predictive significance of perineural invasion in stage I to III colon cancer: a propensity score matching-based analysis. World J Surg Oncol 2024; 22:129. [PMID: 38734718 PMCID: PMC11088143 DOI: 10.1186/s12957-024-03405-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain. METHODS We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures. RESULTS PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease. CONCLUSIONS Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present.
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Affiliation(s)
- Chun-Hui Chu
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - I-Li Lai
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - Bor-Kang Jong
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - Sum-Fu Chiang
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - Wen-Sy Tsai
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - Pao-Shiu Hsieh
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - Chien-Yuh Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 5, Fuxing Street, Guishan District, Taoyuan City, 33305, Taiwan.
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25
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Damianou A, Liang Z, Lassen F, Vendrell I, Vere G, Hester S, Charles PD, Pinto-Fernandez A, Santos A, Fischer R, Kessler BM. Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex. Life Sci Alliance 2024; 7:e202302245. [PMID: 38453365 PMCID: PMC10921066 DOI: 10.26508/lsa.202302245] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/09/2024] Open
Abstract
KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute to ∼30% of human solid tumours, including lung adenocarcinoma, pancreatic, and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. However, the precise signalling cascades these mutations affect are poorly understood. Here, APEX2 proximity labelling was used to profile the molecular environment of WT, G12D, G13D, and Q61H-activating KRAS mutants under starvation and stimulation conditions. Through quantitative proteomics, we demonstrate the presence of known KRAS interactors, including ARAF and LZTR1, which are differentially captured by WT and KRAS mutants. Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.
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Affiliation(s)
- Andreas Damianou
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Zhu Liang
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Frederik Lassen
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Iolanda Vendrell
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | - Svenja Hester
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Philip D Charles
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Adan Pinto-Fernandez
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Alberto Santos
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Center for Health Data Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Roman Fischer
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Benedikt M Kessler
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Lecomte T, Tougeron D, Chautard R, Bressand D, Bibeau F, Blanc B, Cohen R, Jacques J, Lagasse JP, Laurent-Puig P, Lepage C, Lucidarme O, Martin-Babau J, Panis Y, Portales F, Taieb J, Aparicio T, Bouché O. Non-metastatic colon cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatments, and follow-up (TNCD, SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFP, AFEF, and SFR). Dig Liver Dis 2024; 56:756-769. [PMID: 38383162 DOI: 10.1016/j.dld.2024.01.208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 01/25/2024] [Accepted: 01/28/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022. METHODS These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022. RESULTS Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended. CONCLUSION French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient.
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Affiliation(s)
- Thierry Lecomte
- Department of Hepatogastroenterology and Digestive Oncology, Tours University Hospital, Tours, France; Inserm UMR 1069, Nutrition, Croissance et Cancer, Université de Tours, Tours, France.
| | - David Tougeron
- Department of Hepatogastroenterology, Poitiers University Hospital, Poitiers, France
| | - Romain Chautard
- Department of Hepatogastroenterology and Digestive Oncology, Tours University Hospital, Tours, France; Inserm UMR 1069, Nutrition, Croissance et Cancer, Université de Tours, Tours, France
| | - Diane Bressand
- Department of Hepatogastroenterology and Digestive Oncology, Tours University Hospital, Tours, France
| | - Frédéric Bibeau
- Department of Pathology, Besançon University Hospital, Besançon, France
| | - Benjamin Blanc
- Department of Digestive Surgery, Dax Hospital, Dax, France
| | - Romain Cohen
- Sorbonne Université, Department of Medical Oncology, Saint-Antoine hospital, AP-HP, Inserm, Unité Mixte de Recherche Scientifique 938 et SiRIC CURAMUS, Saint-Antoine Research Center, Paris, France
| | - Jérémie Jacques
- Department of Hepatogastroenterology, Limoges University Hospital, Limoges, France
| | - Jean-Paul Lagasse
- Department of Hepatogastroenterology and Digestive Oncology, Orléans University Hospital, Orléans, France
| | - Pierre Laurent-Puig
- Department of Biology, AP-HP, European Georges Pompidou Hospital, Paris, France
| | - Come Lepage
- Department of Hepatogastroenterology and Digestive Oncology, Dijon University Hospital, Dijon, France
| | - Olivier Lucidarme
- Department of Radiology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Jérôme Martin-Babau
- Armoricain Center of Radiotherapy, Radiology and Oncology, Côtes D'Armor Private Hospital, Plérin, France
| | - Yves Panis
- Department of Colorectal Surgery, AP-HP, Beaujon Hospital, Clichy, France
| | - Fabienne Portales
- Department of Medical Oncology, Institut du Cancer de Montpellier, Montpellier, France
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, Paris, France
| | - Thomas Aparicio
- Department of Gastroenterology and Digestive Oncology, AP-HP, Saint-Louis Hospital, Paris, France
| | - Olivier Bouché
- Department of Digestive Oncology, Reims, CHU Reims, France
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27
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Huang Y, Zheng D, Zhou Z, Wang H, Li Y, Zheng H, Tan J, Wu J, Yang Q, Tian H, Lin L, Li Z, Li T. The research advances in Kirsten rat sarcoma viral oncogene homolog (KRAS)-related cancer during 2013 to 2022: a scientometric analysis. Front Oncol 2024; 14:1345737. [PMID: 38706597 PMCID: PMC11066287 DOI: 10.3389/fonc.2024.1345737] [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: 12/05/2023] [Accepted: 04/08/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Cancer represents a significant global public health concern. In recent years, the incidence of cancer has been on the rise worldwide due to various factors, including diet, environment, and an aging population. Simultaneously, advancements in tumor molecular biology and genomics have led to a shift from systemic chemotherapy focused on disease sites and morphopathology towards precise targeted therapy for driver gene mutations. Therefore, we propose a comprehensive review aimed at exploring the research hotspots and directions in the field of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers over the past decade, providing valuable insights for cancer treatment strategies. Specifically, we aim to present an intellectual landscape using data obtained from the Web of Science (WoS) regarding KRAS mutation. Methods Bibliometrix, VOSviewer, CiteSpace, and HistCite were employed to conduct scientometric analyses on national publications, influential authors, highly cited articles, frequent keywords, etc. Results A total of 16,609 publications met the screening criteria and exhibited a consistent annual growth trend overall. Among 102 countries/regions, the United States occupied the vast majority share of the published volume. The journal Oncotarget had the highest circulation among all scientific publications. Moreover, the most seminal articles in this field primarily focus on biology and targeted therapies, with overcoming drug resistance being identified as a future research direction. Conclusion The findings of the thematic analysis indicate that KRAS mutation in lung cancer, the prognosis following B-Raf proto-oncogene, serine/threonine kinase (BRAF) or rat sarcoma (RAS) mutations, and anti-epidermal growth factor receptor (EGFR)-related lung cancer are the significant hotspots in the given field. Considering the significant advancements made in direct targeting drugs like sotorasib, it is anticipated that interest in cancers associated with KRAS mutations will remain steadfast.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Zhiyang Li
- Department of Thyroid, Breast and Hernia Surgery, General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Tianyu Li
- Department of Thyroid, Breast and Hernia Surgery, General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
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28
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Patel A, Gulhati P. Molecular Landscape and Therapeutic Strategies against Colorectal Cancer. Cancers (Basel) 2024; 16:1551. [PMID: 38672633 PMCID: PMC11049251 DOI: 10.3390/cancers16081551] [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: 03/07/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Although the overall incidence of CRC is decreasing, the incidence of young-onset CRC, characterized by a diagnosis of CRC before age 50, is increasing. Outcomes for CRC patients are improving, partly due to comprehensive molecular characterization of tumors and novel therapeutic strategies. Advances in genomic and transcriptomic analyses using blood- and tumor-tissue-based sequencing have facilitated identification of distinct tumor subtypes harboring unique biological characteristics and therapeutic vulnerabilities. These insights have led to the development and incorporation of targeted therapies and immunotherapy in CRC treatment. In this review, we discuss the molecular landscape and key oncogenes/tumor suppressors contributing to CRC tumorigenesis, metastasis, and therapeutic resistance. We also discuss personalized therapeutic strategies for subsets of CRC patients and provide an overview of evolving novel treatments being evaluated in clinical trials.
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Affiliation(s)
- Aakash Patel
- Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
| | - Pat Gulhati
- Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
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29
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Elez E, Cubillo A, Alfonso PG, Middleton MR, Chau I, Alkuzweny B, Alcasid A, Zhang X, Van Cutsem E. Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study. BMC Cancer 2024; 24:446. [PMID: 38600471 PMCID: PMC11007903 DOI: 10.1186/s12885-024-12153-5] [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: 03/14/2023] [Accepted: 03/20/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). METHODS In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. RESULTS In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. CONCLUSIONS The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC. TRIAL REGISTRATION NCT03271047 (09/01/2017).
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Affiliation(s)
- Elena Elez
- Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Antonio Cubillo
- Centro Integral, Oncológico Clara Campal, HM CIOCC, Madrid, Spain
- Facultad HM Hospitales de Ciencias de La Salud UCJC, 28050, Madrid, Spain
| | - Pilar Garcia Alfonso
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain
| | - Mark R Middleton
- Department of Oncology, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Ian Chau
- Gastrointestinal Unit, Royal Marsden Hospital, London & Surrey, UK
| | | | | | | | - Eric Van Cutsem
- University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
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30
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Iyer KK, Poel D, Miggelenbrink A, Kerkhof W, Janssen J, Bakkerus L, de Jong L, van den Hombergh E, Nagtegaal ID, Tauriello DVF, van Erp NP, Verheul HMW. High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids. BJC REPORTS 2024; 2:29. [PMID: 39516561 PMCID: PMC11523998 DOI: 10.1038/s44276-024-00042-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/11/2023] [Accepted: 01/20/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Most tyrosine kinase inhibitors (TKIs) have failed in clinical trials for metastatic colorectal cancer (mCRC). To leverage the additional lower-affinity targets that most TKIs have, high-dose regimens that trigger efficacy are explored. Here, we studied unprecedented drug exposure-response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs). METHODS We investigated the cytotoxic anti-tumour effect of high-dose, short-term (HDST) TKI treatment on 5 PDTOs. Sunitinib, cediranib and osimertinib were selected based on favourable physicochemical and pharmacokinetic properties. Intra-tumoroid TKI concentrations were measured using a clinically validated LC/MS-MS method. Cell death was determined using an enzyme activity assay, immunofluorescent staining and western blotting. RESULTS Most PDTOs tested were sensitive to sunitinib and cediranib, but all to osimertinib. Furthermore, HDST osimertinib treatment effectively blocks organoid growth. This treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. Mechanistically, HDST osimertinib treatment induced apoptosis in treated PDTOs. CONCLUSION Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. Additionally, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.
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Affiliation(s)
- Kirti K Iyer
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Dennis Poel
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Anne Miggelenbrink
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Wouter Kerkhof
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Jorien Janssen
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Lotte Bakkerus
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Loek de Jong
- Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Erik van den Hombergh
- Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Daniele V F Tauriello
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Medical Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Nielka P van Erp
- Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands.
- Department of Medical Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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Xu M, Zhao X, Wen T, Qu X. Unveiling the role of KRAS in tumor immune microenvironment. Biomed Pharmacother 2024; 171:116058. [PMID: 38171240 DOI: 10.1016/j.biopha.2023.116058] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/03/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a "hot" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a "colder" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.
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Affiliation(s)
- Miao Xu
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China
| | - Xing Zhao
- Department of Pediatrics, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China
| | - Ti Wen
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China.
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Zhang X, Ma H, He Y, He W, Chen N, Li Y, Zhong W, Wu G, Zhou X, Hua H, Ye F, Cai H, Jiang W. Reclassification of RAS/BRAF allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer. Ther Adv Med Oncol 2024; 16:17588359231225035. [PMID: 38293276 PMCID: PMC10826380 DOI: 10.1177/17588359231225035] [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: 07/03/2023] [Accepted: 12/13/2023] [Indexed: 02/01/2024] Open
Abstract
Background Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Methods Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. Results A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091). Conclusion In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.
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Affiliation(s)
- Xiang Zhang
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- First Clinical Medical College, Lanzhou University, Lanzhou, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Haizhong Ma
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
| | - Yinjun He
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Wenguang He
- Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nan Chen
- Departments of Colorectal Surgery, Yuyao Hospital of Traditional Chinese Medicine, Yuyao, China
| | - Yandong Li
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weixiang Zhong
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guosheng Wu
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xile Zhou
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hanju Hua
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Ye
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Cai
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Chengguan District, Lanzhou City, Gansu Province, China, 730000
| | - Weiqin Jiang
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District Hangzhou, Zhejiang Province China, 310003
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Li H, Zhang Y, Feng Y, Hu X, Bi L, Zhu H, Wang Y. Predictors based on cuproptosis closely related to angiogenesis predict colorectal cancer recurrence. Front Oncol 2024; 13:1322421. [PMID: 38264748 PMCID: PMC10805227 DOI: 10.3389/fonc.2023.1322421] [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: 10/26/2023] [Accepted: 12/05/2023] [Indexed: 01/25/2024] Open
Abstract
Up to one-third of colorectal cancer (CRC) patients experience recurrence after radical surgery, and it is still very difficult to assess and predict the risk of recurrence. Angiogenesis is the key factor of recurrence as metastasis of CRC is closely related to copper metabolism. Expression profiling by microarray from two datasets in Gene Expression Omnibus (GEO) was selected for quality control, genome annotation, normalization, etc. The identified angiogenesis-derived and cuproptosis-related Long non-coding RNAs (lncRNAs) and clinical data were screened and used as predictors to construct a Cox regression model. The stability of the model was evaluated, and a nomogram was drawn. The samples were divided into high-risk and low-risk groups according to the linear prediction of the model, and a Kaplan-Meier survival analysis was performed. In this study, a model was established to predict the postoperative recurrence of colon cancer, which exhibits a high prediction accuracy. Furthermore, the negative correlation between cuproptosis and angiogenesis was validated in colorectal cancer cell lines and the expression of lncRNAs in vitro was examined.
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Affiliation(s)
- Haoran Li
- Oncology Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yingru Zhang
- Oncology Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanyuan Feng
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xueqing Hu
- Oncology Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ling Bi
- Oncology Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huirong Zhu
- Oncology Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Wang
- Oncology Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Grabski IN, Heymach JV, Kehl KL, Kopetz S, Lau KS, Riely GJ, Schrag D, Yaeger R, Irizarry RA, Haigis KM. Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum. Cancer Epidemiol Biomarkers Prev 2024; 33:158-169. [PMID: 37943166 PMCID: PMC10841605 DOI: 10.1158/1055-9965.epi-23-0262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/02/2023] [Accepted: 11/07/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues. METHODS We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival. RESULTS KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by PCA, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types. CONCLUSIONS KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions. IMPACT Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.
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Affiliation(s)
- Isabella N. Grabski
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - John V. Heymach
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenneth L. Kehl
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ken S. Lau
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Gregory J. Riely
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Deborah Schrag
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rafael A. Irizarry
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kevin M. Haigis
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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Caughey BA, Strickler JH. Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies. Drugs 2024; 84:27-44. [PMID: 38109010 DOI: 10.1007/s40265-023-01980-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2023] [Indexed: 12/19/2023]
Abstract
Kirsten rat sarcoma virus (KRAS) is one of the most important and frequently mutated oncogenes in cancer and the mutational prevalence is especially high in many gastrointestinal malignancies, including colorectal cancer and pancreatic ductal adenocarcinoma. The KRAS protein is a small GTPase that functions as an "on/off" switch to activate downstream signaling, mainly through the mitogen-activated protein kinase pathway. KRAS was previously considered undruggable because of biochemical constraints; however, recent breakthroughs have enabled the development of small-molecule inhibitors of KRAS G12C. These drugs were initially approved in lung cancer and have now shown substantial clinical activity in KRAS G12C-mutated pancreatic ductal adenocarcinoma as well as colorectal cancer when combined with anti-EGFR monoclonal antibodies. Early data are encouraging for other gastrointestinal cancers as well and many other combination strategies are being investigated. Several new KRAS G12C inhibitors and novel inhibitors of other KRAS alterations have recently entered the clinic. These molecules employ a variety of innovative mechanisms and have generated intense interest. These novel drugs are especially important as KRAS G12C is rare in gastrointestinal malignancies compared with other KRAS alterations, representing potentially groundbreaking advances. Soon, the rapidly evolving landscape of novel KRAS inhibitors may substantially shift the therapeutic landscape for gastrointestinal cancers and offer meaningful survival improvements.
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Affiliation(s)
- Bennett A Caughey
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA.
| | - John H Strickler
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
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Tran CG, Goffredo P, Mott SL, Suraju MO, Kohn JF, Mishra A, Vauthey JN, Hassan I. Conditional Overall Survival After Diagnosis of Non-Metastatic Colon Cancer: Impact of Laterality, MSI, and KRAS Status. Ann Surg Oncol 2024; 31:142-151. [PMID: 37857983 DOI: 10.1245/s10434-023-14443-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND The prognostic relevance of laterality, microsatellite instability (MSI), and KRAS status in colon cancer has been established. However, their effect on conditional overall survival (COS) remains unknown. METHODS COS is the probability of surviving additional years after a time from diagnosis. The National Cancer Database (2010-2017) was queried for adults with non-metastatic colon cancer and known mutation status undergoing curative resection. COS was investigated at 2 years. RESULTS Of 4838 patients, 3716 survived at least 2 years: 15% had stage I, 38% stage II, and 46% stage III disease. Fifty-nine percent had a right-sided tumor, 16% were MSI-high, and 37% were mutated KRAS (mKRAS). The proportion of patients alive at 2 years was higher for stage I compared with stage II and III (65 vs. 61 vs. 54%). The 5-year overall survival for stage I-III was 80, 76, and 67% for the initial cohort, and 90, 88, and 86% for those alive at 2 years. After adjustment, higher pathologic T and N stage, tumor deposits, and no chemotherapy were associated with worse COS (p < 0.01). While laterality and MSI status were not associated with COS, mKRAS was independently associated with decreased COS (HR 1.35, 95% CI 1.12-1.62). CONCLUSION Patients with mKRAS had worse COS, suggesting that these mutations confer an aggressive biologic behavior, with patients remaining at higher risk of death 2 years after diagnosis. Routine evaluation of KRAS status should be considered in patients with non-metastatic disease for prognostication and to identify those who might benefit from modified surveillance protocols.
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Affiliation(s)
- Catherine G Tran
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Paolo Goffredo
- Division of Colon and Rectal Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Sarah L Mott
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Mohammed O Suraju
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Julia F Kohn
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Aditi Mishra
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Imran Hassan
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
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Baranov E, Nowak JA. Pathologic Evaluation of Therapeutic Biomarkers in Colorectal Adenocarcinoma. Surg Pathol Clin 2023; 16:635-650. [PMID: 37863556 DOI: 10.1016/j.path.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2023]
Abstract
Molecular testing is an essential component of the pathologic evaluation of colorectal carcinoma providing diagnostic, prognostic, and predictive therapeutic information. Mismatch repair status evaluation is required for all tumors. Advanced and metastatic tumors also require determination of tumor mutational burden, KRAS, NRAS, and BRAF mutation status, ERBB2 amplification status, and NTRK and RET gene rearrangement status to guide therapy. Multiple assays, including immunohistochemistry, microsatellite instability testing, MLH1 promoter methylation, and next-generation sequencing, are typically needed. Pathologists must be aware of these requirements to optimally triage tissue. Advances in colorectal cancer molecular diagnostics will continue to drive refinements in colorectal cancer personalized therapy.
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Affiliation(s)
- Esther Baranov
- Department of Pathology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Jonathan A Nowak
- Department of Pathology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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Kunt N, Araz M, Yildirim MS, Findik S, Kocak MZ, Eryilmaz MK, Artac M. The Effect of RAS/BRAF Mutation Status on Prognosis and Relapse Pattern in Early Stage Colon Cancers. J Gastrointest Cancer 2023; 54:1316-1321. [PMID: 37191843 DOI: 10.1007/s12029-023-00943-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE It is known that the RAS and BRAF mutations are predictive for targeted therapies in treating metastatic colon cancer and negatively affect the prognosis of the disease. However, there are limited studies in early-stage colon cancer about the relationship of this mutational condition with the prognosis and relapse pattern of the disease. In this study, we evaluated the effects of mutational status on the clinical pattern of recurrence and survival in early-stage colon cancer in addition to classical risk factors. METHODS Patients with early-stage colon cancer at the first time of diagnosis and developing recurrence or metastasis on following up were included in this study. Patients were divided into two groups according to the at the time of relapse RAS/BRAF mutation status: mutant or non-mutant/wild types. Then, mutation analysis was performed again from the early-stage tissue of the patients if available. The relationship between early-stage mutation status and progression-free survival (PFS), overall survival (OS), and relapse pattern was analyzed. RESULTS The number of patients with mutant and non-mutations in the early stage was 39 and 40, respectively. Mutant and non-mutant patients with stage 3 disease were similar (69% and 70%, respectively). OS (47.27 months vs. 67.53 months; p = 0.02) and PFS (25.12 vs. 38.13 months; p = 0.049) were statistically significantly lower in mutant patients, respectively. Most patients had distant metastases on both sides at recurrence (61.5% vs. 62.5%, respectively). There was no significant difference between mutant and non-mutant patients regarding distant metastasis and local recurrence rates (p = 0.657). A discordance of 11.4% between early-stage and late-stage tissue mutation status. CONCLUSION The presence of mutation in early-stage colon cancer is associated with shorter OS and PFS. The mutational status did not have a significant effect on the recurrence pattern. Because of the discordance of early-stage and late-stage mutational status, it is recommended to perform mutation analysis from tissue at relapse.
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Affiliation(s)
- Nazli Kunt
- Department of Internal Medicine, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey.
| | - Murat Araz
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Mahmut Selman Yildirim
- Department of Medical Genetics, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Siddika Findik
- Department of Pathology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Mehmet Zahid Kocak
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Melek Karakurt Eryilmaz
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Mehmet Artac
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
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Aljehani MA, Bien J, Lee JSH, Fisher GA, Lin AY. KRAS Sequence Variation as Prognostic Marker in Patients With Young- vs Late-Onset Colorectal Cancer. JAMA Netw Open 2023; 6:e2345801. [PMID: 38032636 PMCID: PMC10690478 DOI: 10.1001/jamanetworkopen.2023.45801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/05/2023] [Indexed: 12/01/2023] Open
Abstract
Importance The understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time. Objective To characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC. Design, Setting, and Participants This cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023. Main Outcomes and Measures CRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs. Results Among 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer. Conclusions and Relevance In this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.
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Affiliation(s)
| | - Jeffrey Bien
- Stanford University School of Medicine, Stanford, California
| | - Jerry S. H. Lee
- Ellison Institute of Technology, Los Angeles, California
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles
- Department of Chemical Engineering and Material Sciences, Viterbi School of Engineering, University of Southern California, Los Angeles
- Department of Quantitative and Computational Biology, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles
| | | | - Albert Y. Lin
- Stanford University School of Medicine, Stanford, California
- Division of Oncology, Department of Medicine, VA Palo Alto Medical Center, Palo Alto, California
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Taieb J, Sinicrope FA, Pederson L, Lonardi S, Alberts SR, George TJ, Yothers G, Van Cutsem E, Saltz L, Ogino S, Kerr R, Yoshino T, Goldberg RM, André T, Laurent-Puig P, Shi Q. Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials. Ann Oncol 2023; 34:1025-1034. [PMID: 37619846 PMCID: PMC10938565 DOI: 10.1016/j.annonc.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/05/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. PATIENTS AND METHODS We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. RESULTS Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. CONCLUSIONS Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.
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Affiliation(s)
- J Taieb
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Université Paris Cité, AP-HP, SIRIC CARPEM, Paris, France; Department of Oncology, Mayo Clinic, Rochester, USA.
| | | | - L Pederson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA
| | - S Lonardi
- Department of Oncology, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - S R Alberts
- Department of Oncology, Mayo Clinic, Rochester, USA
| | - T J George
- Department of Oncology, University of Florida and the University of Florida Health Cancer Center, Gainesville, USA
| | - G Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, USA
| | - E Van Cutsem
- Department of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - L Saltz
- Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - S Ogino
- Department of Pathology, Brigham & Women's Hospital, Boston, USA
| | - R Kerr
- Department of Oncology, Oxford University, Oxford, UK
| | - T Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - R M Goldberg
- Department of Oncology, West Virginia University Cancer Institute, Morgantown, USA; Mary Babb Randolph Cancer Center, Morgantown, USA
| | - T André
- Sorbonne Université, Department of Medical Oncology, Hôpital Saint-Antoine, Paris, France
| | - P Laurent-Puig
- Institut du cancer Paris CARPEM, AP-HP, Université Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France
| | - Q Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA
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Rasola C, Laurent-Puig P, André T, Falcoz A, Lepage C, Aparicio T, Bouché O, Lievre A, Mineur L, Bennouna J, Louvet C, Bachet JB, Borg C, Vernerey D, Lonardi S, Taieb J. Time to recurrence and its relation to survival after recurrence in patients resected for stage III colon cancer. Eur J Cancer 2023; 194:113321. [PMID: 37797388 DOI: 10.1016/j.ejca.2023.113321] [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: 06/25/2023] [Revised: 08/22/2023] [Accepted: 08/26/2023] [Indexed: 10/07/2023]
Abstract
BACKGROUND It is intuitively thought that early relapse is associated with poor survival after recurrence (SAR) in resected colon cancer (CC) patients, but this has never been formally studied. METHODS We pooled data from stage III patients treated with oxaliplatin-based adjuvant therapy in two phase III trials, to analyse time to recurrence (TTR) and its relationship with SAR. TTR and SAR were also studied according to molecular status (mismatch repair (MMR), RAS, and BRAFV600E). Early relapsing patients were defined as patients having a TTR event within 12 months after starting adjuvant chemotherapy. RESULTS 4548 stage III CC patients were included in the present analysis. Deficient MMR (dMMR) CC patients experienced fewer recurrences than proficient (p)MMR CC patients (18.8% versus 27.6%) but had a significantly shorter median TTR (mTTR; 0.74 versus 1.40 years, p < 0.0001). In pMMR patients, BRAF and RAS mutations were also associated with earlier mTTR as compared to double wild-type (WT) patients (0.99 versus 1.38 versus 1.54 years, respectively, p < 0.0001). Early recurrence occurred in 397 patients and was associated with a median SAR (2.2 versus 3.3 years, p = 0.0007). However, this association was mainly due to pMMR/RAS and BRAFV600E mutated tumours and was not confirmed in dMMR and pMMR/double WT subgroups. CONCLUSION In resected stage III CC treated with standard oxaliplatin-based adjuvant therapy, TTR varies between dMMR, pMMR/RAS, or BRAFV600E mutated and pMMR/double WT tumours. In addition, early relapse is associated with poor survival, mainly due to patients resected for a pMMR/RAS or BRAFV600E mutated tumour.
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Affiliation(s)
- Cosimo Rasola
- Department of Gastroenterology and GI Oncology, Georges Pompidou European Hospital, SIRIC CARPEM, Université Paris-Cité, Paris, France; Department of Oncology, Veneto Institute of Oncology IRCCS, Padua, Italy; Medical Oncology 3, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France; Institut du Cancer Paris CARPEM, AP-HP,Centre Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France
| | - Thierry André
- Sorbonne Université and Medical Oncology Department, Hôpital Saint-Antoine, Paris, France
| | - Antoine Falcoz
- University Hospital of Besançon, Methodology and Quality of Life Unit in Oncology, Besançon, France; INSERM, Établissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
| | - Come Lepage
- Gastroenterology and Digestive Oncology, Hôpital Universitaire Le Bocage, Dijon, France
| | - Thomas Aparicio
- Université Paris-Cité, Gastroenterology Department, Hôpital Saint Louis, APHP, Paris, France
| | | | - Astrid Lievre
- Digestive Unit, Hôpital Universitaire de Pontchaillou, Rennes, France
| | - Laurent Mineur
- Oncology Department, Clinique Sainte-Catherine, Avignon, France
| | - Jaafar Bennouna
- Department of Medical Oncology, Hôpital Foch, Suresnes, France
| | - Christophe Louvet
- Department of Medical Oncology, Institute Mutualiste Montsouris, Paris, France
| | - Jean Baptiste Bachet
- Sorbonne University, Hepatogastroenterology and Digestive Oncology Department, Pitié Salpêtrière hospital, APHP, Paris, France
| | - Christophe Borg
- Department of Medical Oncology, University Hospital of Besançon, France
| | - Dewi Vernerey
- University Hospital of Besançon, Methodology and Quality of Life Unit in Oncology, Besançon, France; INSERM, Établissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IRCCS, Padua, Italy; Medical Oncology 3, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Julien Taieb
- Department of Gastroenterology and GI Oncology, Georges Pompidou European Hospital, SIRIC CARPEM, Université Paris-Cité, Paris, France.
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Wu Z, Qin X, Zhang Y, Luo J, Luo R, Cai Z, Wang H. Effect of BRAF mutation on the prognosis for patients with colorectal cancer undergoing cytoreductive surgery for synchronous peritoneal metastasis. Gastroenterol Rep (Oxf) 2023; 11:goad061. [PMID: 37886242 PMCID: PMC10598839 DOI: 10.1093/gastro/goad061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 08/02/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023] Open
Abstract
Background KRAS/BRAF mutations (mutKRAS/mutBRAF) are unfavorable prognostic factors for colorectal cancer (CRC) metastases to the liver and lungs. However, their effects on the prognosis for patients with synchronous peritoneal metastasis (S-PM) of CRC after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are controversial. In the study, we aimed to determine the effects of mutKRAS/mutBRAF on the prognosis for patients with S-PM who received CRS. Methods A total of 142 patients diagnosed with S-PM between July 2007 and July 2019 were included in this study. The demographics, mutKRAS/mutBRAF status, overall survival (OS), and progression-free survival (PFS) of the patients were evaluated. The Kaplan-Meier method and log-rank test were used to estimate the difference in survival between groups. Results Among 142 patients, 68 (47.9%) showed mutKRAS and 42 (29.5%) showed mutBRAF. The median OS values were 8.4 and 34.3 months for patients with mutBRAF and BRAF wild-type, respectively (P < 0.01). However, KRAS status was not significantly associated with median OS (P = 0.76). Multivariate analysis revealed carcinoembryonic antigen, CRS, HIPEC, and mutBRAF as independent predictors for OS. Based on these findings, a nomogram was constructed. The C-index was 0.789 (95% confidence interval, 0.742-0.836), indicating good predictive ability of the model. Furthermore, the 1- and 2-year survival calibration plots showed good agreement between the predicted and actual OS rates. The area under curves of the 1- and 2-year survival predictions based on the nomogram were 0.807 and 0.682, respectively. Additionally, mutBRAF was significantly associated with lower PFS (P < 0.001). Conclusions mutBRAF is an independent prognostic risk factor for S-PM. The established nomogram predicted the OS of patients with CRC having S-PM with high accuracy, indicating its usefulness as a valuable prognostic tool for the designated patient cohort.
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Affiliation(s)
- Zhijie Wu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiusen Qin
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yuanxin Zhang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Luo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Rui Luo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Zonglu Cai
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Hui Wang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Chang CY, Lin CC, Lin HH, Lan YT, Chang SC, Wang HS, Yang SH, Chen WS, Lin JK, Jiang JK. The Negative Prognostic Impact of Lymph Node Skip Metastasis in Stage III Colon Cancer With pN1 Disease: A Single-Center and Retrospective Cohort Study. Dis Colon Rectum 2023; 66:e1032-e1042. [PMID: 36538674 PMCID: PMC10476599 DOI: 10.1097/dcr.0000000000002383] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Lymph node skip metastasis is a subgroup of lymph node metastatic patterns with low incidence in node-positive colon cancer. Its clinical significance is still unclear. OBJECTIVE This study aimed to investigate the prognostic impact of lymph node skip metastasis in stage III colon cancer. DESIGN This is a retrospective observational analysis. SETTINGS The study was conducted at the Taipei Veterans General Hospital. PATIENTS This study included patients with stage III colon cancer who underwent D3 lymphadenectomy between 2006 and 2015. MAIN OUTCOME MEASURES The patients were divided into a lymph node skip metastasis-positive group and a negative group. Recurrence-free survival and overall survival were compared using Kaplan-Meier curves and log-rank test. Cox regression was applied to identify related risk factors influencing survival. RESULTS A total of 461 patients were reviewed, and lymph node skip metastasis-positive patients represented 13.2% of our sample. Patients with lymph node skip metastasis tended to present with a higher proportion of right-sided cancer, lower positive lymph nodes, lower lymph node ratio, and higher mean BMI. Liver recurrence was more prevalent in the lymph node skip metastasis group ( p = 0.028) than in the negative group. The presence of lymph node skip metastasis was a negative prognostic factor for 5-year recurrence-free survival (51.4% vs 68.7%; p = 0.002) and 5-year overall survival (66.4% vs 80.4%; p = 0.024) in Kaplan-Meier curves and multivariate Cox regression. Subgroup analysis revealed the survival significance of recurrence-free survival ( p = 0.001) and overall survival ( p = 0.011) in lymph node skip metastasis with pN1 disease. LIMITATIONS This study was limited by its retrospective design, single-center nature, and sampling error. CONCLUSIONS Lymph node skip metastasis is an independent negative prognostic factor in stage III colon cancer with pN1 disease. More intensive surveillance may be necessary for patients of this subgroup. See Video Abstract at https://links.lww.com/DCR/C60 . IMPACTO PRONSTICO NEGATIVO DE LAS METSTASIS DISCONTNUAS GANGLIONARES LINFTICAS EN CASOS DE CNCER DE COLON ESTADIO III CON ENFERMEDAD PN ESTUDIO DE COHORTES RETROSPECTIVO MONOCENTRICO ANTECEDENTES:Las metástasis discontínuas ganglionares linfáticas, son un subgrupo de patrones metastásicos en los ganglios linfáticos con baja incidencia en el cáncer de colon con nódulos positivos. Su significado clínico aún no está claro.OBJETIVO:Estudio que tiene por objetivo el investigar el impacto pronóstico de las metástasis discontínuas de los ganglios linfáticos en el cáncer de colon de estadio III.DISEÑO:Análisis observacional retrospectivo.AJUSTES:El estudio se realizó en el Hospital General de Veteranos de Taipei.PACIENTES:Pacientes con cáncer de colon en estadio III que se sometieron a linfadenectomía D3 entre 2006 y 2015.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes se dividieron en un grupo positivo de metástasis discontínuas en los ganglios linfáticos y un otro grupo negativo. La sobrevida libre de recidiva y la sobrevida global, fueron comparadas mediante las curvas de Kaplan-Meier y la prueba de rango logarítmico. Se aplicó la regresión de Cox para identificar los factores de riesgo relacionados que influyeron en la sobrevida.RESULTADOS:Se revisaron un total de 461 casos, donde los pacientes positivos con metástasis en los ganglios linfáticos representaron el 13,2% de nuestra muestra. Los pacientes con metástasis discontínuas ganglionares linfáticas tendían a presentar una mayor proporción de cáncer localizado en el lado derecho del colon, presentar un menor numéro de ganglios linfáticos positivos y una proporción menor de ganglios linfáticos con un IMC promedio más alto. Las recidivas hepáticas fueron más prevalentes en el grupo de metástasis discontínuas ganglionares linfáticas ( p = 0,028) que en el grupo negativo. La presencia de metástasis discontínuas ganglionares linfáticas fué un factor de pronóstico negativo en la sobrevida libre de recidiva a 5 años (51,4% frente a 68,7%, p = 0,002) y la sobrevida general a 5 años (66,4% frente a 80,4%, p = 0,024) evaluada por las curvas de Kaplan-Meier y la regresión multivariada de Cox. El análisis de subgrupos reveló la importancia de la sobrevida libre de recidiva ( p = 0,001) y la sobrevida general ( p = 0,011) en los casos con metástasis discontínuas ganglionares linfáticas con enfermedad pN1.LIMITACIONES:Diseño retrospectivo, naturaleza de centro único y error de muestreo.CONCLUSIONES:Las metástasis discontínuas ganglionares linfáticas son un factor pronóstico negativo independiente en los casos de cáncer de colon estadio III con enfermedad pN1. Tal vez sea necesaria una mayor vigilancia de los pacientes en este subgrupo.Consulte Video Resumen en https://links.lww.com/DCR/C60 . (Traducción-Dr. Xavier Delgadillo ).
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Affiliation(s)
- Che-Yuan Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Chun-Chi Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Hung-Hsin Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Yuan-Tzu Lan
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Shih-Ching Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Huann-Sheng Wang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Shung-Haur Yang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
- National Yang Ming Chiao Tung University Hospital, Taipei City, Taiwan
| | - Wei-Shone Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Jen-Kou Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Jeng-Kai Jiang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
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Colle R, Lonardi S, Cachanado M, Overman MJ, Elez E, Fakih M, Corti F, Jayachandran P, Svrcek M, Dardenne A, Cervantes B, Duval A, Cohen R, Pietrantonio F, André T. BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors. Oncologist 2023; 28:771-779. [PMID: 37023721 PMCID: PMC10485382 DOI: 10.1093/oncolo/oyad082] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/03/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). PATIENTS AND METHODS Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. RESULTS Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. CONCLUSION In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.
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Affiliation(s)
- Raphael Colle
- Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
- Sorbonne University, SIRIC CURAMUS, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France
- Sorbonne University, Department of Clinical Pharmacology and Clinical Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique-Hôpitaux de Paris, Sorbonne University, St Antoine Hospital, Paris, France
| | - Sara Lonardi
- Oncology Department, Istituto Oncologico Veneto IOV-IRCSS, Padua, Italy
| | - Marine Cachanado
- Sorbonne University, Department of Clinical Pharmacology and Clinical Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique-Hôpitaux de Paris, Sorbonne University, St Antoine Hospital, Paris, France
| | - Michael J Overman
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elena Elez
- Department of Medical Oncology, Vall d’Hebron Barcelona Hospital Campus, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Francesca Corti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Priya Jayachandran
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Magali Svrcek
- Sorbonne University, SIRIC CURAMUS, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France
- Sorbonne University, Department of Pathology, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Antoine Dardenne
- Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Baptiste Cervantes
- Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Alex Duval
- Sorbonne University, SIRIC CURAMUS, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France
- Sorbonne University, Department of Clinical Pharmacology and Clinical Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique-Hôpitaux de Paris, Sorbonne University, St Antoine Hospital, Paris, France
| | - Romain Cohen
- Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
- Sorbonne University, SIRIC CURAMUS, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France
- Sorbonne University, Department of Clinical Pharmacology and Clinical Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique-Hôpitaux de Paris, Sorbonne University, St Antoine Hospital, Paris, France
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Thierry André
- Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
- Sorbonne University, SIRIC CURAMUS, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France
- Sorbonne University, Department of Clinical Pharmacology and Clinical Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique-Hôpitaux de Paris, Sorbonne University, St Antoine Hospital, Paris, France
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Woischke C, Michl M, Neumann J. [Molecular pathology of colorectal cancer]. PATHOLOGIE (HEIDELBERG, GERMANY) 2023; 44:279-286. [PMID: 37277480 DOI: 10.1007/s00292-023-01201-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/20/2023] [Indexed: 06/07/2023]
Abstract
In recent years, the treatment of colorectal carcinoma has experienced increasing individualization. In addition to RAS and BRAF mutational status that is firmly established in routine diagnostics, new therapeutic options evolved based on MSI and HER2 status as well as primary tumour localization. Offering the best targeted options in therapy requires new evidence-based decision-making algorithms regarding timing and scope of molecular pathological diagnostics in order for patients to receive an optimized therapy according to current treatment guidelines. New targeted therapies, some of which are about to be approved and for which pathology has to provide new molecular pathological biomarkers, will also play an increasingly important role in the future.
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Affiliation(s)
- Christine Woischke
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland
| | - Marlies Michl
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Ludwig-Maximilians-Universität München, München, Deutschland
- Facharztpraxis für Innere Medizin, Hämatologie und Onkologie mit Tagesklinik, Praxis Dr. Michl, München, Deutschland
| | - Jens Neumann
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland.
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Ahn HM, Kim DW, Oh HJ, Kim HK, Lee HS, Lee TG, Shin HR, Yang IJ, Lee J, Suh JW, Oh HK, Kang SB. Different oncological features of colorectal cancer codon-specific KRAS mutations: Not codon 13 but codon 12 have prognostic value. World J Gastroenterol 2023; 29:4883-4899. [PMID: 37701134 PMCID: PMC10494767 DOI: 10.3748/wjg.v29.i32.4883] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/06/2023] [Accepted: 07/31/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Approximately 40% of colorectal cancer (CRC) cases are linked to Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. KRAS mutations are associated with poor CRC prognosis, especially KRAS codon 12 mutation, which is associated with metastasis and poorer survival. However, the clinicopathological characteristics and prognosis of KRAS codon 13 mutation in CRC remain unclear. AIM To evaluate the clinicopathological characteristics and prognostic value of codon-specific KRAS mutations, especially in codon 13. METHODS This retrospective, single-center, observational cohort study included patients who underwent surgery for stage I-III CRC between January 2009 and December 2019. Patients with KRAS mutation status confirmed by molecular pathology reports were included. The relationships between clinicopathological characteristics and individual codon-specific KRAS mutations were analyzed. Survival data were analyzed to identify codon-specific KRAS mutations as recurrence-related factors using the Cox proportional hazards regression model. RESULTS Among the 2203 patients, the incidence of KRAS codons 12, 13, and 61 mutations was 27.7%, 9.1%, and 1.3%, respectively. Both KARS codons 12 and 13 mutations showed a tendency to be associated with clinical characteristics, but only codon 12 was associated with pathological features, such as stage of primary tumor (T stage), lymph node involvement (N stage), vascular invasion, perineural invasion, tumor size, and microsatellite instability. KRAS codon 13 mutation showed no associations (77.2% vs 85.3%, P = 0.159), whereas codon 12 was associated with a lower 5-year recurrence-free survival rate (78.9% vs 75.5%, P = 0.025). In multivariable analysis, along with T and N stages and vascular and perineural invasion, only codon 12 (hazard ratio: 1.399; 95% confidence interval: 1.034-1.894; P = 0.030) among KRAS mutations was an independent risk factor for recurrence. CONCLUSION This study provides evidence that KRAS codon 13 mutation is less likely to serve as a prognostic biomarker than codon 12 mutation for CRC in a large-scale cohort.
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Affiliation(s)
- Hong-Min Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Duck-Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Hyeon Jeong Oh
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Hyung Kyung Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul 03080, South Korea
| | - Tae Gyun Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Hye-Rim Shin
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - In Jun Yang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Jeehye Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Jung Wook Suh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Heung-Kwon Oh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
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Bachet JB, Laurent-Puig P, Meurisse A, Bouché O, Mas L, Taly V, Cohen R, Gornet JM, Artru P, Louafi S, Thirot-Bidault A, Baumgaertner I, Coriat R, Tougeron D, Lecomte T, Mary F, Aparicio T, Marthey L, Blons H, Vernerey D, Taieb J. Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study. Eur J Cancer 2023; 189:112934. [PMID: 37390800 DOI: 10.1016/j.ejca.2023.05.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/19/2023] [Accepted: 05/27/2023] [Indexed: 07/02/2023]
Abstract
PURPOSE Baseline circulating tumour DNA (ctDNA) is a potential prognostic marker in metastatic colorectal cancer (mCRC) patients. However, few studies have compared ctDNA with the usual prognostic factors, and no ctDNA cut-off has been proposed for daily use in clinical practice. PATIENTS AND METHODS Chemotherapy-naive patients with mCRC were prospectively included. Plasma samples were collected at diagnosis and analysed centrally by both NGS and methylation digital PCR. Baseline patient and disease characteristics, treatment regimens, and secondary surgeries were collected. The restricted cubic spline method was used to define the optimal cut-off of ctDNA mutated allelic frequency (MAF). Prognostic values were assessed on overall survival (OS) using Cox models. RESULTS From July 2015 to December 2016, 412 patients were included. ctDNA was undetectable in 83 patients (20%). ctDNA was an independent prognostic marker for OS considering the whole study population. The optimal cut-off for ctDNA MAF was 20% with median OS of 16.0 and 35.8 months for patients with MAF ≥20% and<20%, respectively (hazard ratio = 0.40; 95% confidence intervals: 0.31-0.51; P < 0.0001). The independent prognostic value of ctDNA MAF at 20% was confirmed in subgroups defined by RAS/BRAF status or resectability of metastases. Combining ctDNA MAF and carcinoembryonic antigen levels allowed us to define three different prognostic groups with median OS of 14.2, 21.1, and 46.4 months (P < 0.0001). CONCLUSION ctDNA with a MAF cut-off of 20% improves prognostication of chemotherapy-naïve mCRC patients and may be useful in the future for individualised therapeutic decisions and as a stratification factor in clinical trials. TRIAL REGISTRATION Clinicaltrials.gov, NCT02502656.
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Affiliation(s)
- Jean-Baptiste Bachet
- Department of Hepato-gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris, France; AGEO (Association des Gastroentérologues Oncologues), Paris, France; Sorbonne Universités, UPMC Université, Paris 06, France; Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France; Institut du cancer Paris CARPEM, AP-HP, Hopital européen Georges Pompidou, Paris, France.
| | - Aurelia Meurisse
- Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Besançon, France
| | - Olivier Bouché
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Hepato-Gastroenterology, CHU Reims, Reims, France
| | - Léo Mas
- Department of Hepato-gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris, France; AGEO (Association des Gastroentérologues Oncologues), Paris, France
| | - Valérie Taly
- Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France
| | - Romain Cohen
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Sorbonne Universités, UPMC Université, Paris 06, France; Department of Oncology, Hôpital Saint-Antoine, Paris, France
| | - Jean-Marc Gornet
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Saint-Louis, Paris, France
| | - Pascal Artru
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Ramsay Hôpital Privé Jean Mermoz, Lyon, France
| | - Samy Louafi
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France; Department of Gastroenterology, Groupe Hospitalier Nord Essonne, Longjumeau, France
| | - Anne Thirot-Bidault
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Kremlin Bicêtre, Le Kremlin-Bicêtre, France
| | - Isabelle Baumgaertner
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Oncology, Hôpital Henri Mondor, Créteil, France
| | - Romain Coriat
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Cochin, Université Paris Cité, Paris, France
| | - David Tougeron
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology and Hepatology, Centre Hospitalo-universitaire de Poitiers, Poitiers, France
| | - Thierry Lecomte
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hepatology and Digestive Oncology, Centre Hospitalo-universitaire de Tours, Tours, France
| | - Florence Mary
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Avicenne, Bobigny, France
| | - Thomas Aparicio
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Gastroenterology, Hôpital Saint-Louis, Paris, France; Department of Gastroenterology, Hôpital Antoine Béclère, Clamart, France
| | - Lysiane Marthey
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Department of Biochemistry, Hôpital Européen Georges Pompidou, Paris, France
| | - Hélène Blons
- Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France; Institut du cancer Paris CARPEM, AP-HP, Hopital européen Georges Pompidou, Paris, France
| | - Dewy Vernerey
- Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Besançon, France
| | - Julien Taieb
- AGEO (Association des Gastroentérologues Oncologues), Paris, France; Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne Université, Université Paris Cité, Paris, France; Institut du cancer Paris CARPEM, AP-HP, Hopital européen Georges Pompidou, Paris, France; Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France
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Cann CG, LaPelusa MB, Cimino SK, Eng C. Molecular and genetic targets within metastatic colorectal cancer and associated novel treatment advancements. Front Oncol 2023; 13:1176950. [PMID: 37409250 PMCID: PMC10319053 DOI: 10.3389/fonc.2023.1176950] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Colorectal cancer results in the deaths of hundreds of thousands of patients worldwide each year, with incidence expected to rise over the next two decades. In the metastatic setting, cytotoxic therapy options remain limited, which is reflected in the meager improvement of patient survival rates. Therefore, focus has turned to the identification of the mutational composition inherent to colorectal cancers and development of therapeutic targeted agents. Herein, we review the most up to date systemic treatment strategies for metastatic colorectal cancer based on the actionable molecular alterations and genetic profiles of colorectal malignancies.
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Affiliation(s)
- Christopher G. Cann
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Michael B. LaPelusa
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sarah K. Cimino
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cathy Eng
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
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Wang J, Tao Z, Wang B, Xie Y, Wang Y, Li B, Cao J, Qiao X, Qin D, Zhong S, Hu X. Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma. Front Oncol 2023; 13:1152681. [PMID: 37333810 PMCID: PMC10272849 DOI: 10.3389/fonc.2023.1152681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 05/19/2023] [Indexed: 06/20/2023] Open
Abstract
Introduction Cuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear. Methods Transcriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes. Results Our study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system. Discussion Our comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies.
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Affiliation(s)
- Jinyan Wang
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhonghua Tao
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Biyun Wang
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yizhao Xie
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ye Wang
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bin Li
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jianing Cao
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaosu Qiao
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Dongmei Qin
- Department of Pathology, Nanjing Jiangning Hospital, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Shanliang Zhong
- Center of Clinical Laboratory Science, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xichun Hu
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
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50
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Schwantes IR, Mayo SC. The genomics of liver metastases from colon and rectal cancer: An Invited Commentary (invitation from Lee Ocuin, MD and Kevin Behrns, MD) for the special issue of "Management of Advanced Primary and Secondary Liver Malignancies". Surgery 2023:S0039-6060(23)00167-8. [PMID: 37183133 DOI: 10.1016/j.surg.2023.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 03/30/2023] [Indexed: 05/16/2023]
Abstract
Over the past two decades, the treatment of patients with cancer has become increasingly structured around the identification of cancer mutations genetically driving the disease. Upfront knowledge of these data has implications for both the selection and omission of certain cytotoxic and targeted therapies. For patients with colon or rectal cancer metastatic to the liver, next-generation sequencing to identify these key mutational drivers should be done at the outset of diagnosis to understand the full spectrum of treatment options available to a patient. Mutational profiling for patients with colorectal liver metastasis initially led to the recognition of treatment resistance to epidermal growth factor inhibitors in patients with a KRAS mutation and now has expanded to include other targeted options. As the treatment options for patients with colorectal liver metastasis continue to evolve, it is increasingly important to integrate genomic data into selecting patients who will benefit from hepatic resection, ablative techniques, and liver-directed therapy. Herein, we review the most common mutations encountered in treating patients with colorectal liver metastasis, focusing specifically on epidermal growth factor receptor, KRAS/NRAS, BRAF, and the mismatch repair pathway with resultant implications to the medical and surgical treatment for these patients.
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Affiliation(s)
- Issac R Schwantes
- Oregon Health & Science University, Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Portland, OR
| | - Skye C Mayo
- Oregon Health & Science University, Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Portland, OR.
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