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Morimoto T, Fujito K, Goto R. Cost-Effectiveness Analysis of SOX Plus Bevacizumab Versus SOX Plus Cetuximab for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer in Japan. Clin Ther 2025; 47:347-354. [PMID: 40038004 DOI: 10.1016/j.clinthera.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 10/23/2024] [Accepted: 01/21/2025] [Indexed: 03/06/2025]
Abstract
PURPOSE In this study, we aimed to evaluate the cost-effectiveness of S-1 and oxaliplatin (SOX) plus bevacizumab (Bmab group) compared with SOX plus cetuximab (Cmab group) as a first-line treatment for patients with Kirsten rat sarcoma virus (KRAS) wild-type metastatic colorectal cancer (mCRC) in Japan from the perspective of healthcare payers. METHODS A partitioned survival model was developed using data from the randomized phase II Osaka Multicenter Study Group on Colorectal Cancer-1107 study, which included overall survival, progression-free survival, and treatment regimens for the Bmab and Cmab groups. Treatment costs were estimated from the Japanese medical claims database and the National Health Insurance drug price list. The utilities were derived from the literature. Outcomes were reported as incremental cost, incremental quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The willingness-to-pay (WTP) threshold was set at 7.5 million JPY per QALY. The time horizon of the model was set to 20 years. Sensitivity analyses were conducted to assess the uncertainty of the model for various parameters. FINDINGS Compared with the Cmab group, the Bmab group had an incremental cost of 911,373 JPY (6,528 USD), an incremental effectiveness of 0.79 QALY, and an ICER of 1,146,745 JPY (8,215 USD) per QALY. One-way sensitivity analysis showed that the cost of progressive disease treatment in the Bmab group had the greatest impact on the ICER. According to the probabilistic sensitivity analysis, the Bmab group had a 94.9% probability of being cost-effective compared with the Cmab group. IMPLICATIONS Considering a WTP threshold of 7.5 million JPY (approximately 53,700 USD) per QALY, Bmab might be a cost-effective treatment option for patients with KRAS wild-type mCRC in Japan. Further studies on economic evaluations based on personalized drugs and patient selection based on clinical and genetic information are warranted.
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Affiliation(s)
- Takashi Morimoto
- Graduate School of Health Management, Keio University, Fujisawa, Kanagawa, Japan.
| | - Kaori Fujito
- School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Rei Goto
- Graduate School of Health Management, Keio University, Fujisawa, Kanagawa, Japan; Graduate School of Business Administration, Keio University, Yokohama, Kanagawa, Japan
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Wismayer R, Matthews R, Whalley C, Kiwanuka J, Kakembo FE, Thorn S, Wabinga H, Odida M, Tomlinson I. The role of MLH1, MSH2 and MSH6 in the development of colorectal cancer in Uganda. BMC Cancer 2025; 25:792. [PMID: 40295928 PMCID: PMC12036241 DOI: 10.1186/s12885-025-14195-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 04/21/2025] [Indexed: 04/30/2025] Open
Abstract
INTRODUCTION In Uganda, colorectal cancer (CRC) is steadily increasing according to the Kampala Cancer Registry. In the West, microsatellite instability is detected in 90% of hereditary nonpolyposis colon cancers (HNPCC) which account for 1-2% of all CRC, and 15% of sporadic CRC. Germline mutations in MLH1 and MSH2 account for 90% of HNPCC in the West, whilst the remainder of cases are due to mutations in MSH6 and PMS2. The aim of this study was to determine the microsatellite instability (MSI) status and determine the proportions of MLH1, MSH2, and MSH6 pathological mutations in Ugandan CRC patients. METHODOLOGY This was a cross-sectional study carried out between 1st January 2008 to 15th September 2021. Patients were recruited prospectively from 16th September 2019 to 16th September 2021, from Masaka Regional Referral Hospital, Mulago National Referral Hospital, Uganda Martyrs' Hospital Lubaga and Mengo Hospital. From 1st January 2008 to 15th September 2019, CRC FFPE tissue blocks were obtained from the archives of the Department of Pathology, Makerere University. Data was abstracted from the medical case files for demographics, topography and stage. The histopathological subtype and grade of CRC were obtained by two consultant pathologists from the H&E slides. DNA was extracted from CRC formalin-fixed paraffin-embedded (FFPE) tissue blocks. Library preparation was completed using the Qiagen custom design panel. The custom panel represented 56 genes. The MLH-1, MSH2, MSH6, BRAF and KRAS genes were sequenced using the above library preparation and NGS sequencing. The MSI status was obtained if one of the MSI genes, MLH1, MSH2 or MSH6 was pathologically mutated. If none of the genes was pathologically mutated it was considered MSI negative, microsatellite stable (MSS). Immunohistochemistry was carried out to determine whether MLH1 and PMS2 was MMR proficient or deficient. Categorical data was summarized using frequencies and proportions corresponding to each of the three histopathological subtypes and MSI status subtypes. Continuous and categorical variables were analyzed using the chi-square and Fischer's exact tests. A p -value ≤ 0.05 was considered statistically significant for all the analyses. RESULTS Out of 127 CRC patients, the mean(SD) age of MSI cases was 55.6(16.9) years and of MSS cases was 55.4(15.5) years. The majority were MSS, 75(59.06%) followed by MSI, 52(40.9%). There were 14(11.02%) MLH-1 mutations, 30(23.62%) MSH2 mutations, and 26(20.47%) MSH6 mutations. BRAF mutational analysis showed only 5(3.9%) having pathologic missense BRAF V600 mutations. KRAS mutations consisted of only 8(6.3%) having pathologic missense KRAS mutations. CONCLUSIONS The high rate of MSI in Ugandan colorectal tumours was mainly associated with a lack of BRAF mutations and a high frequency of MSH2 and MSH6 MMR gene mutations. In CRC patients, identification of the causative mutation is recommended, however in a resource-limited setting, MSI testing and immunohistochemistry is more cost effective. In Ugandan CRC patients who meet at least one of the Bethesda criteria, MSI testing and immunohistochemistry may therefore be offered to obtain the MSI status of the tumour.
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Affiliation(s)
- Richard Wismayer
- Department of Surgery, Masaka Regional Referral Hospital, Masaka, Uganda.
- Department of Surgery, Faculty of Health Sciences, Equator University of Science and Technology, Masaka, Uganda.
- Department of Surgery, Faculty of Health Sciences, Habib Medical School, IUIU University, Kampala, Uganda.
- Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda.
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
| | - Rosie Matthews
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Celina Whalley
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Julius Kiwanuka
- Department of Epidemiology and Biostatistics, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Fredrick Elishama Kakembo
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
- African Centre of Excellence in Bioinformatics and Data Intensive Sciences, Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - Steve Thorn
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Henry Wabinga
- Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Michael Odida
- Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
- Department of Pathology, Faculty of Medicine, Gulu University, Gulu, Uganda
| | - Ian Tomlinson
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
- Department of Oncology, University of Oxford, Oxford, UK
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Vincken R, Armendáriz-Martínez U, Ruiz-Sáenz A. ADCC: the rock band led by therapeutic antibodies, tumor and immune cells. Front Immunol 2025; 16:1548292. [PMID: 40308580 PMCID: PMC12040827 DOI: 10.3389/fimmu.2025.1548292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Antibody-dependent cellular cytotoxicity (ADCC) is a critical mechanism by which therapeutic antibodies leverage the immune system to target and eliminate cancer cells. The key agents of ADCC are natural killer (NK) cells, specifically targeting antibody-covered cancer cells through the CD16 receptor. While other immune cells and Fc receptors can contribute and enhance ADCC, NK cells and the CD16 receptor are crucial for the efficacy of cancer therapies such as trastuzumab, cetuximab and rituximab. Co-culture assays are essential for understanding the mechanisms of these therapies, overcoming resistance and optimizing novel therapeutic antibodies. This review highlights the importance of measuring ADCC to assess the efficacy of therapeutic antibodies. Here we also present the various in vitro models and assay methodologies available for studying ADCC, comparing the strengths and limitations of approaches like using PBMCs to better reflect real-life conditions or NK cell lines for standardization. It also covers different readouts for ADCC, either focusing on effector cells activation, including reporter and degranulation assays or in the target cell killing, including different molecule release assays, flow cytometry and immunofluorescence techniques. Selecting the best model for studying ADCC is crucial for the translational significance of therapeutic antibody research.
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Affiliation(s)
- Roos Vincken
- Department of Cell Biology, Erasmus University Medical Center Rotterdam, CN, Rotterdam, Netherlands
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
| | - Uxue Armendáriz-Martínez
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
| | - Ana Ruiz-Sáenz
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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Yildirim ME, Karadurmuş N, Ökten İN, Türk HM, Urakçı Z, Arslan Ç, Çelik S, Dane F, Şendur MAN, Bilir C, Karabulut B, Cicin İ, Çubukçu E, Karaca M, Ozcelik M, Artaç M, Tanrikulu E, Alacacioglu A, Açıkgöz Ö, Öven B, Geredeli Ç, Çil T, Harputluoğlu H, Kefeli U, Bozkurt O, Tural D, Sakin A, Yalçın Ş, Gumus M. Real-world treatment outcomes from nationwide Onco-colon Turkey registry in RAS wild-type patients treated with biologics second-line mCRC. J Oncol Pharm Pract 2025; 31:404-411. [PMID: 38613329 DOI: 10.1177/10781552241241004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2024]
Abstract
Backgrounds and ObjectivesColorectal cancer is one of the leading causes of mortality both globally and in our country. In Turkey, we conducted a multicenter investigation into the effectiveness of second-line treatments and real-life data for patients with RAS wild-type metastatic colorectal cancer (NCT04757311).Materials and MethodsIn this retrospective analysis, records from 28 centers were collected, and histopathological, molecular, and clinical characteristics were documented. Patients were categorized into groups based on their second-line biological treatments: anti-EGFR (Group A and Group B, panitumumab and cetuximab) and anti-VEGF (Group C, bevacizumab and aflibercept). They were then compared within these groups.ResultsA total of 588 patients with documented RAS wild-type status were evaluated. The median OS was 15.7, 14.3 and 14.7 months in Group A, Group B and Group C, respectively (p = 0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/aflibercept were 7.8, 6.6 and 7.4 months, respectively (p = 0.848).ConclusionAccording to the results of our real-life data study, there is no significant difference in efficiency between the combination of biological agent and chemotherapy used in the second-line treatments.
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Affiliation(s)
- Mahmut Emre Yildirim
- Medical Oncology Department, İstanbul Dr. Lütfi Kırdar Kartal City Hospital, Istanbu, Türkiye
| | - Nuri Karadurmuş
- Medical Oncology Department, Gulhane Training and Research Hospital, Ankara, Türkiye
| | - İlker Nihat Ökten
- Medical Oncology Department, Medeniyet University Goztepe Training and Research Hospital, Istanbul, Türkiye
| | - Hacı Mehmet Türk
- Department of Medical Oncology, Bezmialem Vakif University Faculty of Medicine, Istanbul, Türkiye
| | - Zuhat Urakçı
- Department of Medical Oncology, Dicle University Medical Faculty, Diyarbakir, Türkiye
| | - Çağatay Arslan
- Medical Oncology, Bahcesehir Universitesi Tip Fakultesi, Istanbul, Türkiye
| | - Sinemis Çelik
- Medical Oncology Department, Istanbul Oncology Hospital, Istanbul, Türkiye
| | - Faysal Dane
- Department of Internal Medicine, Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Türkiye
| | | | - Cemil Bilir
- Medical Oncology Department, Sakarya University Training and Research Hospital, Sakarya, Türkiye
| | - Bülent Karabulut
- Medical Oncology, Ege University Faculty of Medicine, Izmir, Türkiye
| | - İrfan Cicin
- Department of Internal Medicine, Division of Oncology, Trakya University Faculty of Medicine, Edirne, Türkiye
| | - Erdem Çubukçu
- Faculty of Medicine, Medical Oncology, Uludag University, Bursa, Türkiye
| | - Mustafa Karaca
- Medical Oncology Department, Antalya Training and Research Hospital, Antalya, Türkiye
| | - Melike Ozcelik
- Department of Oncology, Umraniye Training and Research Hospital, Istanbul, Türkiye
| | - Mehmet Artaç
- Department of Medical Oncology, Necmettin Erbakan University Medical Faculty, Konya, Türkiye
| | - Eda Tanrikulu
- Medical Oncology, Istanbul Haydarpasa Numune Training and Research Hospital, Istanbul, Türkiye
| | - Ahmet Alacacioglu
- Medical Oncology Department, Ministry of Health İzmir Katip Çelebi University Atatürk Education and Research Hospital, Izmir, Türkiye
| | - Özgür Açıkgöz
- Medical Oncology Department, Istanbul Medipol University, İstanbul, Türkiye
| | - Başak Öven
- Medical Oncology Department, Yeditepe University Hospital, Istanbul, Türkiye
| | - Çağlayan Geredeli
- Department of Medical Oncology, Okmeydani Training and Research Hospital, Istanbul, Türkiye
| | - Timucin Çil
- Department of Medical Oncology, University of Health Sciences, Adana City Education and Research Hospital, Adana, Türkiye
| | | | - Umut Kefeli
- Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Türkiye
| | - Oktay Bozkurt
- Medical Oncology Department, Erciyes Universitesi, Kayseri, Türkiye
| | - Deniz Tural
- Medical Oncology, Istanbul Bakirkoy Dr Sadi Konuk Training and Research Hospital, Istanbul, Türkiye
| | - Abdullah Sakin
- Department of Medical Oncology, Yuzuncu Yil University, Van, Türkiye
| | - Şuayip Yalçın
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Mahmut Gumus
- Department of Medical Oncology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Türkiye
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Liu W, Niu J, Huo Y, Zhang L, Han L, Zhang N, Yang M. Role of circular RNAs in cancer therapy resistance. Mol Cancer 2025; 24:55. [PMID: 39994791 PMCID: PMC11854110 DOI: 10.1186/s12943-025-02254-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 01/30/2025] [Indexed: 02/26/2025] Open
Abstract
Over the past decade, circular RNAs (circRNAs) have gained recognition as a novel class of genetic molecules, many of which are implicated in cancer pathogenesis via different mechanisms, including drug resistance, immune escape, and radio-resistance. ExosomalcircRNAs, in particular, facilitatecommunication between tumour cells and micro-environmental cells, including immune cells, fibroblasts, and other components. Notably, micro-environmental cells can reportedly influence tumour progression and treatment resistance by releasing exosomalcircRNAs. circRNAs often exhibit tissue- and cancer-specific expression patterns, and growing evidence highlights their potential clinical relevance and utility. These molecules show strong promise as potential biomarkers and therapeutic targets for cancer diagnosis and treatment. Therefore, this review aimed to briefly discuss the latest findings on the roles and resistance mechanisms of key circRNAs in the treatment of various malignancies, including lung, breast, liver, colorectal, and gastric cancers, as well as haematological malignancies and neuroblastoma.This review will contribute to the identification of new circRNA biomarkers for the early diagnosis as well as therapeutic targets for the treatment of cancer.
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Affiliation(s)
- Wenjuan Liu
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Jiling Niu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Yanfei Huo
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Long Zhang
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
- School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong Province, China.
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Airoldi M, Bartolini M, Fazio R, Farinatti S, Daprà V, Santoro A, Puccini A. First-Line Therapy in Metastatic, RAS Wild-Type, Left-Sided Colorectal Cancer: Should Everyone Receive Anti-EGFR Therapy? Curr Oncol Rep 2024; 26:1489-1501. [PMID: 39392559 DOI: 10.1007/s11912-024-01601-x] [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: 08/23/2024] [Indexed: 10/12/2024]
Abstract
PURPOSE OF REVIEW This narrative review explores the efficacy and applicability of anti-EGFR therapy as the first-line treatment for patients with RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC). It critically examines current guidelines, along with recent evidence in the literature, to assess whether it should be universally applied. RECENT FINDINGS Recent evidences highlight the variability of the response to anti-EGFR therapies due to molecular diversity and several clinical factors, such as RAS mutational status and primary tumor location. Anti-EGFR plus chemotherapy is the standard first-line treatment for most patients with MSS, RAS-WT, left-sided mCRC. Whether this combination is the best treatment for these patients remains an open question. This review delves into the role of EGFR inhibition in mCRC, focusing on clinical factors and the knowledge of biology, molecular targets, and biomarkers. It underscores the crucial role of a personalized approach, empowering healthcare providers and equipping them with the confidence to make informed decisions.
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Affiliation(s)
- Marco Airoldi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy
| | - Michela Bartolini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy
| | - Roberta Fazio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy
| | - Sara Farinatti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy
| | - Valentina Daprà
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy
| | - Alberto Puccini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy.
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56Rozzano, 20089, Milan, Italy.
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Tinsley N, O'Dwyer ST, Nagaraju R, Chakrabarty B, Braun M, Mullamitha S, Kamposioras K, Marti Marti FE, Saunders M, Clouston H, Selvasekar C, Wild J, Wilson M, Renehan A, Aziz O, Barriuso J. Preoperative chemotherapy response and survival in patients with colorectal cancer peritoneal metastases. J Surg Oncol 2024; 130:1422-1432. [PMID: 39011877 PMCID: PMC11826003 DOI: 10.1002/jso.27776] [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: 05/13/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 07/17/2024]
Abstract
Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy (HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial response on preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versus NR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected by peritoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM.
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Affiliation(s)
- Nadina Tinsley
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Sarah T. O'Dwyer
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Raghavendar Nagaraju
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Bipasha Chakrabarty
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Michael Braun
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Saifee Mullamitha
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | | | - F. E. Marti Marti
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Mark Saunders
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Hamish Clouston
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Chelliah Selvasekar
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Jonathan Wild
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Malcolm Wilson
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Andrew Renehan
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Omer Aziz
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
| | - Jorge Barriuso
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Christie Peritoneal Oncology Centre (CPOC) at The Christie NHS Foundation TrustManchesterUK
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Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
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Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
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9
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Mattos D, Rocha M, Tessmann J, Ferreira L, Gimba E. Overexpression of Osteopontin-a and Osteopontin-c Splice Variants Are Worse Prognostic Features in Colorectal Cancer. Diagnostics (Basel) 2024; 14:2108. [PMID: 39410512 PMCID: PMC11475046 DOI: 10.3390/diagnostics14192108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Osteopontin (OPN) is a glycoprotein involved in various physiological and pathological processes, and its aberrant expression in cancer cells is closely linked to tumor progression. In colorectal cancer (CRC), OPN is overexpressed, but the roles of its splice variants (OPN-SVs), OPNa, OPNb, and OPNc, are not well understood. This study aimed to characterize the expression patterns of OPN-SVs and their potential diagnostic and prognostic implications in CRC using transcriptomic data deposited in TSVdb and TCGA. Methods: The expression patterns of each OPN-SV were analyzed using transcriptomic data deposited in TSVdb and TCGA, which were correlated to patient data available at cBioPortal. Results: Bioinformatic analysis revealed that OPNa, OPNb, and OPNc are overexpressed in CRC samples compared to non-tumor samples. Notably, OPNa and OPNc are overexpressed in CRC stages (II, III, and IV) compared to stage I. Higher levels of OPNa and OPNc transcripts are associated with worse overall survival (OS) and shorter progression-free survival (PFS) in CRC patients. Additionally, the expression of OPNa, OPNb, and OPNc is correlated with BRAFV600E mutations in CRC samples. Conclusions: These findings suggest that OPNa and OPNc, in particular, have potential as diagnostic and prognostic biomarkers, paving the way for their further evaluation in CRC diagnosis and prognosis.
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Affiliation(s)
- Daniella Mattos
- Hemato-Oncology Molecular Program, National Institute of Cancer, 23rd Red Cross Square, 6th Floor, Rio de Janeiro 20230-130, RJ, Brazil;
- Biomedical Science Graduation Program, Fluminense Federal University, Rua Professor Hernani Pires de Melo, 101, Niterói 24210-130, RJ, Brazil
| | - Murilo Rocha
- Cellular and Molecular Oncobiology Program, National Institute of Cancer, Rio de Janeiro 20231-050, RJ, Brazil; (M.R.); (J.T.)
| | - Josiane Tessmann
- Cellular and Molecular Oncobiology Program, National Institute of Cancer, Rio de Janeiro 20231-050, RJ, Brazil; (M.R.); (J.T.)
| | - Luciana Ferreira
- Hemato-Oncology Molecular Program, National Institute of Cancer, 23rd Red Cross Square, 6th Floor, Rio de Janeiro 20230-130, RJ, Brazil;
- Departamento de Genética, Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, BR-465, Km 07, Seropédica, Rio de Janeiro 23897-000, RJ, Brazil
| | - Etel Gimba
- Hemato-Oncology Molecular Program, National Institute of Cancer, 23rd Red Cross Square, 6th Floor, Rio de Janeiro 20230-130, RJ, Brazil;
- Biomedical Science Graduation Program, Fluminense Federal University, Rua Professor Hernani Pires de Melo, 101, Niterói 24210-130, RJ, Brazil
- Departamento de Ciências da Natureza, Humanities and Healthy Institute, Fluminense Federal University, Recife Street, Bela Vista, Rio das Ostras 28895-532, RJ, Brazil
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10
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Petrelli F, Antista M, Dottorini L, Russo A, Arru M, Invernizzi R, Manzoni M, Cremolini C, Zaniboni A, Garrone O, Tomasello G, Ghidini M. First line therapy in stage IV BRAF mutated colorectal cancer. Heliyon 2024; 10:e36497. [PMID: 39263130 PMCID: PMC11388748 DOI: 10.1016/j.heliyon.2024.e36497] [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: 02/09/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/13/2024] Open
Abstract
Introduction The molecular profile of colorectal cancer (CRC) plays a crucial role in understanding patient prognosis and treatment response. Within CRC, a distinct subgroup can be identified by the presence of the BRAF V600E mutation. This specific mutation, classified as Class I of BRAF mutations, is known to be associated with a poor prognosis and resistance to standard therapy. To determine the most effective treatment approach for this specific subgroup of CRC, we conducted a network meta-analysis (NMA) to compare various pharmacological interventions and evaluate their relative effectiveness in BRAF-mutated CRCs. Materials and methods On July 31, 2023, we conducted a systematic search of PubMed, Cochrane Central Register of Controlled Trials, and Embase. The inclusion criteria were as follows: 1) reporting of outcomes in patients with BRAF-mutated CRC who underwent first-line chemotherapy; 2) reporting of survival information as hazard ratios (HR); and 3) publication in English. The data were combined using HRs for overall and progression-free survival (OS and PFS) using random-effects models. NMA was performed under the Bayesian framework, utilizing the GeMTC package. The relative rankings of the treatments were determined using SUCRA scores. Results A total of 16 studies were included. When compared to standard chemotherapy (CT) doublets (such as FOLFOX or FOLFIRI), none of the comparison arms demonstrated a gain in OS. CT doublet + bevacizumab did not show significant superiority over either CT doublet alone or 5FU/capecitabine + bevacizumab. FOLFOXIRI and FOLFOXIRI + bevacizumab did not show superiority over any other treatment schedule that was compared. CT doublets + bevacizumab had the highest SUCRA score (0.87), followed by single-agent fluoropyrimidines + bevacizumab (0.61), and FOLFOXIRI (0.56). Regarding PFS, no regimen was found to be superior to the combination of CT doublet plus bevacizumab. However, FOLFOXIRI + bevacizumab + atezolizumab showed a tendency towards better results (HR = 0.26, 95 % CI 0.05-1.1). Conclusions Our review suggests that a CT doublet with bevacizumab is the most favorable option for OS. However, a reasonable alternative could be a triplet CT without bevacizumab.
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Affiliation(s)
| | | | | | | | - Marcella Arru
- Surgery Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| | | | | | - Chiara Cremolini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | - Ornella Garrone
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | | | - Michele Ghidini
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
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11
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Ouchi K, Takahashi S, Sasaki K, Yoshida Y, Taniguchi S, Kasahara Y, Komine K, Imai H, Saijo K, Shirota H, Takahashi M, Ishioka C. Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer: Translational research of the EPIC trial. Int J Colorectal Dis 2024; 39:89. [PMID: 38862615 PMCID: PMC11166830 DOI: 10.1007/s00384-024-04659-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/26/2024] [Indexed: 06/13/2024]
Abstract
PURPOSE The genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. METHODS Clinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups. RESULTS Of the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm. CONCLUSIONS GWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer.
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Affiliation(s)
- Kota Ouchi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Shin Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Keiju Sasaki
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Yuya Yoshida
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Sakura Taniguchi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Yuki Kasahara
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Keigo Komine
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Hiroo Imai
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Ken Saijo
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Hidekazu Shirota
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Masanobu Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Chikashi Ishioka
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
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12
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McDonald HG, Kerekes DM, Kim J, Khan SA. Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery. Surg Oncol Clin N Am 2024; 33:321-341. [PMID: 38401913 DOI: 10.1016/j.soc.2023.12.007] [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: 02/26/2024]
Abstract
Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.
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Affiliation(s)
- Hannah G McDonald
- Department of General Surgery, Division of Surgical Oncology, The University of Kentucky, 800 Rose Street, Lexington, KY 40508, USA
| | - Daniel M Kerekes
- Department of General Surgery, Division of Surgical Oncology, Yale University, 15 York Street, New Haven, CT 06510, USA
| | - Joseph Kim
- Department of General Surgery, Division of Surgical Oncology, The University of Kentucky, 800 Rose Street, Lexington, KY 40508, USA
| | - Sajid A Khan
- Department of Surgery, Yale University, 15 York Street, New Haven, CT 06510, USA.
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13
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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14
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [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: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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15
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Mohapatra L, Tripathi AS, Mishra D, Yasir M, Maurya RK, Prajapati BG, Alka. Colorectal cancer: understanding of disease. COLORECTAL CANCER 2024:1-27. [DOI: 10.1016/b978-0-443-13870-6.00010-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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16
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Yang TS, Chen HH, Bo-Wen L, Kim TW, Kim JG, Ahn JB, Lee MA, Lin J, Ho GF, Anh LT, Temraz S, Burge M, Chua C, Huang J, Park YS. Prospective, open-label, and observational study of cetuximab for metastatic colorectal carcinoma: The OPTIM1SE study. Asia Pac J Clin Oncol 2023; 19:672-680. [PMID: 36855017 DOI: 10.1111/ajco.13920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 12/13/2022] [Accepted: 12/26/2022] [Indexed: 03/02/2023]
Abstract
AIM The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice. METHODS OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). RESULTS From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab. CONCLUSION Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only.
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Affiliation(s)
- Tsai-Sheng Yang
- Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Hong-Hwa Chen
- Department of Colorectal Surgery, Chang Gung Memorial Hospital, Kaohsiung City, Taiwan
| | - Lin Bo-Wen
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tae Won Kim
- Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Jong Gwang Kim
- Kyungpook National University Medical Center, Daegu, South Korea
| | - Joong Bae Ahn
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Myung-Ah Lee
- The Catholic University of Korea, Seoul St Mary's Hospital, Seoul, South Korea
| | - Johnson Lin
- Division of Hematology and Oncology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Gwo Fuang Ho
- Department of Oncology, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Le Tuan Anh
- Department of Medical and Radiation Oncology, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Sally Temraz
- Division of Hematology and Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Matthew Burge
- Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Clarinda Chua
- Division of Medical Oncology, National Cancer Centre, Singapore
| | - Jason Huang
- Merck Pte. Ltd., Singapore, an affiliate of Merck KGaA, Darmstadt, Germany
| | - Young Suk Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Lu X, Li Y, Li Y, Zhang X, Shi J, Feng H, Yu Z, Gao Y. Prognostic and predictive biomarkers for anti-EGFR monoclonal antibody therapy in RAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer 2023; 23:1117. [PMID: 37974093 PMCID: PMC10655341 DOI: 10.1186/s12885-023-11600-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial. METHODS We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups. RESULTS Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain. CONCLUSIONS In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
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Affiliation(s)
- Xiaona Lu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yuyao Li
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yue Li
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xuemei Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jia Shi
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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18
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Doleschal B, Kirchweger P, Schwendinger S, Kupferthaler A, Burghofer J, Webersinke G, Jukic E, Wundsam H, Biebl M, Petzer A, Rumpold H. Response prediction by mutation- or methylation-specific detection of ctDNA dynamics in pretreated metastatic colorectal cancer. Ther Adv Med Oncol 2023; 15:17588359231200462. [PMID: 37786537 PMCID: PMC10541738 DOI: 10.1177/17588359231200462] [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: 01/16/2023] [Accepted: 08/25/2023] [Indexed: 10/04/2023] Open
Abstract
Background Serial analysis of circulating tumor DNA (ctDNA) levels is a promising tool for both relapse prediction in the curative setting, as well as predicting clinical benefit from systemic treatment in metastasic colorectal cancer (mCRC). Most data in this context are derived from treatment naive patients. Objective To predict progressive disease (PD) as early as possible through monitoring of changes in ctDNA levels during systemic treatment in pretreated patients with mCRC. Design A prospective, single-center, observational study. Methods Patients treated beyond first-line were prospectively included between February 2020 and September 2021. Blood for ctDNA detection was taken before every treatment cycle from start of treatment until first restaging by CT-scan. ctDNA was detected by mutation- (mut-ctDNA) and methylation-specific ddPCR. Receiver Operating Characteristic (ROC)-analysis was used to describe sensitivity and specificity for prediction of PD at restaging for all time points. Results A total of 42 patients were included who all carried a mutation in tumor tissue. Detection rate of mut-ctDNA was 88.1% and 74.4% for meth-ctDNA. Absolute ctDNA levels before treatment were prognostic in terms of overall survival. Levels of ctDNA were significantly higher in patients with PD at restaging. Median time from start of treatment to restaging was 93 days (95% CI 88.8-96). After a median of 19 days of treatment (95% CI 16.1-20.2), a decline of either mutation- or methylation-specific ctDNA levels of ⩽58% predicted PD at restaging with a sensitivity/specificity of 92.9/85.7% and 85.7/100%, respectively. Median time to restaging was 66 days (95% CI 56.8-75.2). There was no significant increase of sensitivity/specificity at later time points of ctDNA measurements. Conclusion Monitoring early changes of ctDNA levels either by mut- or meth-ctDNA allows for early prediction of PD in pretreated patients with mCRC. This has the potential to complement RECIST-based treatment assessment with the aim to switch potentially insufficient treatments as early as possible, which is of particular interest in higher treatment lines.
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Affiliation(s)
- Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Oberösterreich, Austria
| | - Patrick Kirchweger
- Department of Surgery, Ordensklinikum Linz, Linz, Oberösterreich, Austria
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | | | - Alexander Kupferthaler
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
- Department of Diagnostic and Interventional Radiology, Ordensklinikum Linz, Linz, Austria
| | - Jonathan Burghofer
- Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria
| | - Gerald Webersinke
- Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria
| | - Emina Jukic
- Institute of Human Genetics, Medical University of Innsbruck, Austria
| | - Helwig Wundsam
- Department of Surgery, Ordensklinikum Linz, Linz, Austria
| | - Matthias Biebl
- Department of Surgery, Ordensklinikum Linz, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Oberösterreich, Austria
| | - Holger Rumpold
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Seilerstaette 4, Linz 4010, Austria
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Qunaj L, May MS, Neugut AI, Herzberg BO. Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. Front Oncol 2023; 13:1252516. [PMID: 37790760 PMCID: PMC10543081 DOI: 10.3389/fonc.2023.1252516] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/28/2023] [Indexed: 10/05/2023] Open
Abstract
KRAS G12C mutations are critical in the pathogenesis of multiple cancer types, including non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal (CRC) cancers. As such, they have increasingly become a target of novel therapies in the management of these malignancies. However, the therapeutic success of KRAS G12C inhibitors to date has been far more limited in CRC and PDAC than NSCLC. In this review, we briefly summarize the biochemistry of KRAS targeting and treatment resistance, highlight differences in the epidemiology of various G12C-mutated cancers, and provide an overview of the published data on KRAS G12C inhibitors for various indications. We conclude with a summary of ongoing clinical trials in G12C-mutant CRC and a discussion of future directions in the management of this disease. KRAS G12C mutation, targeted therapies, colorectal cancer, non-small cell lung cancer, pancreatic cancer, drug development.
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Affiliation(s)
- Lindor Qunaj
- Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY, United States
| | - Michael S. May
- Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY, United States
| | - Alfred I. Neugut
- Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY, United States
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, United States
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Benjamin O. Herzberg
- Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY, United States
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, United States
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20
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Kobayashi S, Bando H, Taketomi A, Takamoto T, Shinozaki E, Shiozawa M, Hara H, Yamazaki K, Komori K, Matsuhashi N, Kato T, Kagawa Y, Yokota M, Oki E, Komine K, Takahashi S, Wakabayashi M, Yoshino T. NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases. BMC Cancer 2023; 23:779. [PMID: 37605122 PMCID: PMC10440878 DOI: 10.1186/s12885-023-11311-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION jRCT2031220025, April. 16, 2022.
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Affiliation(s)
- Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 2770882, Japan.
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Eiji Shinozaki
- Gastrointestinal Oncology Department, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroki Hara
- Gastroenterological Department, Saitama Cancer Center, Ina, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Koji Komori
- Department of Gastroenterological Surgery Aichi Cancer Center Hospital, Nagoya, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery, Pediatric Surgery, Gifu University Hospital, Gifu, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yoshinori Kagawa
- Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan
| | - Mitsuru Yokota
- Department of General Surgery, Kurashiki Central Hospital, Kurashiki, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keigo Komine
- Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Shinichiro Takahashi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Masashi Wakabayashi
- Division for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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21
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Putri S, Saldi SRF, Khoe LC, Setiawan E, Megraini A, Santatiwongchai B, Nugraha RR, Permanasari VY, Nadjib M, Sastroasmoro S, Armansyah A. Cetuximab as first-line treatment for metastatic colorectal cancer (mCRC): a model-based economic evaluation in Indonesia setting. BMC Cancer 2023; 23:731. [PMID: 37553566 PMCID: PMC10408081 DOI: 10.1186/s12885-023-11253-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 08/03/2023] [Indexed: 08/10/2023] Open
Abstract
OBJECTIVES To assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia. METHODS A cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model's uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage. RESULTS There was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1-3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years. CONCLUSIONS The combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.
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Affiliation(s)
- Septiara Putri
- Health Policy and Administration Department, Faculty of Public Health, University of Indonesia, Depok, West Java, 16424, Indonesia.
- Center for Health Economics and Policy Studies (CHEPS), University of Indonesia, Depok, West Java, 16424, Indonesia.
| | - Siti Rizny F Saldi
- Center for Clinical Epidemiology and Evidence-Based Medicine (CEEBM), Cipto Mangunkusomo Hospital, Jakarta, 10430, Indonesia
| | - Levina Chandra Khoe
- Department of Community Medicine, Faculty of Medicine, University of Indonesia, Jakarta, 10430, Indonesia
| | - Ery Setiawan
- Center for Health Economics and Policy Studies (CHEPS), University of Indonesia, Depok, West Java, 16424, Indonesia
| | - Amila Megraini
- Center for Health Economics and Policy Studies (CHEPS), University of Indonesia, Depok, West Java, 16424, Indonesia
| | - Benjarin Santatiwongchai
- Health Intervention and Technology Assessment Program (HITAP), Ministry of Public Health, Nonthaburi, 11000, Thailand
| | - Ryan R Nugraha
- Center for Population, Family, and Health, Department of Family Medicine and Population Health, University of Antwerp, Antwerp, 2610, Belgium
| | - Vetty Y Permanasari
- Health Policy and Administration Department, Faculty of Public Health, University of Indonesia, Depok, West Java, 16424, Indonesia
| | - Mardiati Nadjib
- Health Policy and Administration Department, Faculty of Public Health, University of Indonesia, Depok, West Java, 16424, Indonesia
- Indonesian Health Technology Assessment Committee, Jakarta, 12950, Indonesia
| | - Sudigdo Sastroasmoro
- Indonesian Health Technology Assessment Committee, Jakarta, 12950, Indonesia
- Department of Pediatrics, Faculty of Medicine, University of Indonesia, Jakarta, 10430, Indonesia
| | - Armansyah Armansyah
- Center for Health Financing and Insurance, Ministry of Health Republic of Indonesia, Jakarta, 12950, Indonesia
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22
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Van Cutsem E, Taieb J, Yaeger R, Yoshino T, Grothey A, Maiello E, Elez E, Dekervel J, Ross P, Ruiz-Casado A, Graham J, Kato T, Ruffinelli JC, André T, Carrière Roussel E, Klauck I, Groc M, Vedovato JC, Tabernero J. ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer. J Clin Oncol 2023; 41:2628-2637. [PMID: 36763936 PMCID: PMC10414717 DOI: 10.1200/jco.22.01693] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/12/2022] [Accepted: 12/27/2022] [Indexed: 02/12/2023] Open
Abstract
PURPOSE The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC. METHODS In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on day 1 of cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).
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Affiliation(s)
| | - Julien Taieb
- Department of Hepatogastroenterology and Gastrointestinal Oncology, University Paris-cité (Paris Descartes), SIRIC CARPEM, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Axel Grothey
- West Cancer Center and Research Institute, Germantown, TN
| | - Evaristo Maiello
- Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Elena Elez
- Department of Medical Oncology, Vall d’Hebron Barcelona Hospital Campus, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Paul Ross
- Department of Oncology, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Ana Ruiz-Casado
- Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, Madrid, Spain
| | - Janet Graham
- Dept of Medical Oncology, Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK
| | - Takeshi Kato
- Department of Colorectal Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan
| | - Jose C. Ruffinelli
- Institut Català dˊOncologia LˊHospitalet–Hospital, Duran i Reynals, Barcelona, Spain
| | - Thierry André
- Sorbonne University; Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
| | | | - Isabelle Klauck
- Pierre Fabre, Medical & Patient/Consumer Division, Boulogne, France
| | - Mélanie Groc
- Pierre Fabre, Medical & Patient/Consumer Division, Langlade, France
| | | | - Josep Tabernero
- Department of Medical Oncology, Vall d’Hebron Barcelona Hospital, Vall d’Hebron Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
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23
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Piringer G, Decker J, Trommet V, Kühr T, Heibl S, Dörfler K, Thaler J. Ongoing complete response after treatment cessation with dabrafenib, trametinib, and cetuximab as third-line treatment in a patient with advanced BRAF V600E mutated, microsatellite-stable colon cancer: A case report and literature review. Front Oncol 2023; 13:1166545. [PMID: 37213293 PMCID: PMC10196488 DOI: 10.3389/fonc.2023.1166545] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/28/2023] [Indexed: 05/23/2023] Open
Abstract
Metastatic BRAFV600E mutated colorectal cancer is associated with poor overall survival and modest effectiveness to standard therapies. Furthermore, survival is influenced by the microsatellite status. Patients with microsatellite-stable and BRAFV600E mutated colorectal cancer have the worst prognosis under the wide range of genetic subgroups in colorectal cancer. Herein, we present a patient case of an impressive therapeutic efficacy of dabrafenib, trametinib, and cetuximab as later-line therapy in a 52-year-old woman with advanced BRAFV600E mutated, microsatellite-stable colon cancer. This patient achieved a complete response after 1 year of triple therapy. Due to skin toxicity grade 3 and recurrent urinary tract infections due to mucosal toxicity, a therapy de-escalation to dabrafenib and trametinib was performed, and the double therapy was administered for further 41 months with ongoing complete response. For 1 year, the patient was off therapy and is still in complete remission.
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Affiliation(s)
- Gudrun Piringer
- Department of Internal Medicine IV, Wels-Grieskirchen Medical Hospital, Wels, Austria
- Department of Hematology and Oncology, Kepler University Hospital, Linz, Austria
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Jörn Decker
- Department of Internal Medicine, Klinikum Rohrbach, Rohrbach, Austria
| | - Vera Trommet
- Department of Internal Medicine IV, Wels-Grieskirchen Medical Hospital, Wels, Austria
| | - Thomas Kühr
- Department of Internal Medicine IV, Wels-Grieskirchen Medical Hospital, Wels, Austria
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Sonja Heibl
- Department of Internal Medicine IV, Wels-Grieskirchen Medical Hospital, Wels, Austria
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Konrad Dörfler
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Josef Thaler
- Department of Internal Medicine IV, Wels-Grieskirchen Medical Hospital, Wels, Austria
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
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24
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Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World J Gastrointest Surg 2023; 15:495-519. [PMID: 37206081 PMCID: PMC10190721 DOI: 10.4240/wjgs.v15.i4.495] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/11/2023] [Accepted: 03/03/2023] [Indexed: 04/22/2023] Open
Abstract
Colorectal cancer (CRC) affects 1 in 23 males and 1 in 25 females, making it the third most common cancer. With roughly 608000 deaths worldwide, CRC accounts for 8% of all cancer-related deaths, making it the second most common cause of death due to cancer. Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy, chemotherapy, immunotherapy, and their combinational regimen for non-resectable CRC. Despite these tactics, nearly half of patients develop incurable recurring CRC. Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways, including drug inactivation, drug influx and efflux modifications, and ATP-binding cassette transporter overexpression. These constraints necessitate the development of new target-specific therapeutic strategies. Emerging therapeutic approaches, such as targeted immune boosting therapies, non-coding RNA-based therapies, probiotics, natural products, oncolytic viral therapies, and biomarker-driven therapies, have shown promising results in preclinical and clinical studies. We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.
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Affiliation(s)
- Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Vipasha Gautam
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Arushi Sandhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Kajal Rawat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Ibrahimi AK, Al-Hussaini M, Laban DA, Ammarin R, Wehbeh L, Al-Mousa A. Cetuximab plus XELOX show efficacy against brain metastasis from colorectal cancer: a case report. CNS Oncol 2023; 12:CNS97. [PMID: 37129184 PMCID: PMC10171034 DOI: 10.2217/cns-2023-0004] [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: 05/03/2023] Open
Abstract
Brain metastasis (BM) from colorectal cancer (CRC) is rare and associated with poor prognosis. The mainstay of treatment for BM from CRC is radiotherapy, systemic treatment options for CRC can include novel targeted agents, conventional chemotherapy or a combination of both. Nevertheless, the efficacy of these systemic treatment options against BM from CRC is not yet fully established. Cetuximab, a monoclonal antibody, has been shown to be effective in patients with KRAS wild-type metastatic CRC. The combination of cetuximab with oxaliplatin-based chemotherapy is commonly utilized as a systemic treatment for metastatic CRC. Hereby, we report a case of BM from CRC with significant response after capecitabine and oxaliplatin (XELOX) combined with cetuximab.
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Affiliation(s)
- Ahmad Kh Ibrahimi
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, 11941, Jordan
| | - Maysa Al-Hussaini
- Department of Pathology & Laboratory Medicine, King Hussein Cancer Center, Amman, 11941, Jordan
| | - Dima Abu Laban
- Department of Radiology, King Hussein Cancer Center, Amman, 11941, Jordan
| | - Rula Ammarin
- Department of Internal Medicine, King Hussein Cancer Center, Amman, 11941, Jordan
| | - Lina Wehbeh
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, 11941, Jordan
| | - Abdelatif Al-Mousa
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, 11941, Jordan
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Yu Q, Jiang H, Su X, Jiang Z, Liang X, Zhang C, Shang W, Zhang Y, Chen H, Yang Z, Shen M, Huang F, Chen X, Yang Y, Pan B, Wang B, Lu D, Guo W. Development of multiplex drop-off digital PCR assays for hotspot mutation detection of KRAS, NRAS, BRAF and PIK3CA in the plasma of colorectal cancer patients. J Mol Diagn 2023; 25:388-402. [PMID: 36963484 DOI: 10.1016/j.jmoldx.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/30/2022] [Accepted: 03/08/2023] [Indexed: 03/26/2023] Open
Abstract
The detection of mutations in KRAS, NRAS, BRAF and PIK3CA has become essential in treatment management of metastatic colorectal cancer (mCRC), with the approval of new targeted therapies. We developed novel multiplex drop-off digital PCR (MDO-dPCR) assays, by combining amplitude-/ratio-based multiplexing with drop-off/double drop-off strategies, which allow for detection of at least 69 most frequent hotspot mutations in all four genes with only three reactions. We assessed the analytical performance of the assays using synthetic oligonucleotides, further validated on plasma cfDNA samples from a large cohort of CRC patients and compared with next generation sequencing (NGS) data. The MDO-dPCR assays showed a high sensitivity with a limit of detection (LOD) ranging from 0.084 to 0.182% in mutant allelic frequency (MAF). The screening of plasma cfDNAs from 106 CRC patients identified mutations in 42.45% of them, with a sensitivity of 95.24%, a specificity of 98.53% and an accuracy of 96.98% for mutation detection and a strong correlation of measured MAFs as compared to NGS results. The high sensitivity and comprehensive mutation coverage of the MDO-dPCR assays make them suitable for rapid and cost-effective detection of KRAS, NRAS, BRAF and PIK3CA mutations in the plasma of CRC patients, and could be useful in early response assessment and longitudinal disease monitoring.
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Affiliation(s)
- Qian Yu
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Huiqin Jiang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xi Su
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | - Xue Liang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Chunyan Zhang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Wu Shang
- Nanjing Pregene Biotechnology, Nanjing, China
| | | | - Hao Chen
- Nanjing Pregene Biotechnology, Nanjing, China
| | - Zhijie Yang
- Nanjing Pregene Biotechnology, Nanjing, China
| | - Minna Shen
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fei Huang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xinning Chen
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yihui Yang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Baishen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Beili Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Daru Lu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
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Mirzapoor Abbasabadi Z, Hamedi Asl D, Rahmani B, Shahbadori R, Karami S, Peymani A, Taghizadeh S, Samiee Rad F. KRAS, NRAS, BRAF, and PIK3CA mutation rates, clinicopathological association, and their prognostic value in Iranian colorectal cancer patients. J Clin Lab Anal 2023; 37:e24868. [PMID: 36930789 PMCID: PMC10098058 DOI: 10.1002/jcla.24868] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/13/2023] [Accepted: 03/01/2023] [Indexed: 03/19/2023] Open
Abstract
AIM Mutations in KRAS, NRAS, BRAF, and PIK3CA genes are critical factors in clinical evaluation of colorectal cancer (CRC) development and progression. In Iran, however, the data regarding genetic profile of CRC patients is limited except for KRAS exon2 and BRAF V600F mutations. This study aimed to investigate the mutational spectrum and prognostic effects of these genes and explore the relationship between these mutations and clinicopathological features of CRC. METHOD To achieve these objectives, mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), PIK3CA (exons 9 and 20), and BRAF (exon 15) was determined using PCR and pyrosequencing in a total of 151 patients with colorectal cancer. RESULTS KRAS, BRAF, NRAS, and PIK3CA mutations were identified in 41%, 5.96%, 3.97%, and 13.24% of the cases, respectively. There were some significant correlations between clinicopathological features and KRAS, PIK3CA, BRAF, and NRAS mutations. Mutations in KRAS and PIK3CA were shown to be independent risk factors for poor survival of the patients at stage I-IV (p < 0.0001 and p = 0.001, respectively). No significant impact on prognosis was observed in patients with BRAF mutations. CONCLUSION Our study revealed the prevalence of CRC biomarkers mutations in Iranian patients and emphasized the role of KRAS and PIK3CA on shorter overall survival rates in this population.
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Affiliation(s)
- Zohreh Mirzapoor Abbasabadi
- Department of Molecular Medicine, Faculty of Medical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran.,Department of Pathology and Molecular Medicine, Behsotun Lab, Alborz University of Medical Sciences, Karaj, Iran
| | - Dariush Hamedi Asl
- Department of Pathology and Molecular Medicine, Mehr Lab, Alborz University of Medical Sciences, Hashtgerd, Iran
| | - Babak Rahmani
- Department of Molecular Medicine, Faculty of Medical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Rozhin Shahbadori
- Department of Pathology and Molecular Medicine, Mehr Lab, Alborz University of Medical Sciences, Hashtgerd, Iran
| | - Sara Karami
- Department of Pathology and Molecular Medicine, Behsotun Lab, Alborz University of Medical Sciences, Karaj, Iran
| | - Amir Peymani
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sara Taghizadeh
- Translational Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Samiee Rad
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.,Department of Pathology, Qazvin University of Medical Sciences, Qazvin, Iran
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Meng Q, Zhao J, Yu Y, Wang K, Ren J, Xu C, Wang Y, Wang G. Survival comparison of first-line treatment regimens in patients with braf-mutated advanced colorectal cancer: a multicenter retrospective study. BMC Cancer 2023; 23:191. [PMID: 36849918 PMCID: PMC9969634 DOI: 10.1186/s12885-023-10640-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 02/13/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Patients with V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated advanced colorectal cancer (CRC) have a poor prognosis, and treatment options that can improve outcome are still under investigation. The purpose of this study was to discuss the differences of overall survival (OS) and progression-free survival (PFS) between patients with BRAF V600E-mutated advanced CRC who were treated with chemotherapy alone and chemotherapy combined with targeted therapy in advanced first-line therapy. METHODS Grouping of 61 patients according to first-line treatment regimen (chemotherapy alone/chemotherapy combined with bevacizumab). Kaplan-Meier method and log-rank test were used to compare OS and PFS. Cox proportional hazards regression model was used to measure the risk of first-line medication therapies while correcting for confounding factors that may affect PFS and OS. RESULTS There was no significant difference in OS between patients treated with chemotherapy alone and those treated with chemotherapy combined with bevacizumab (P = 0.93; HR, 1.027; 95% CI, 0.555-1.901). Likewise, there was no significant difference in PFS between the two groups (P = 0.29; HR, 0.734; 95% CI, 0.413-1.304). Subgroup analysis showed that OS and PFS of different treatment regimens were not significantly different among subgroups. Multivariate analysis suggested that surgical treatment of primary tumor (P = 0.001; HR, 0.326; 95% CI, 0.169-0.631) and presence of liver metastasis (P = 0.009; HR, 2.399; 95% CI, 1.242-4.635) may serve as independent prognostic indicators in patients with BRAF-mutated advanced CRC. Surgical treatment of the primary tumor (P = 0.041; HR, 0.523; 95% CI, 0.280-0.974) was significantly associated with PFS too. CONCLUSION For patients with BRAF V600E-mutated advanced CRC, chemotherapy alone did not differ significantly in OS and PFS compared with chemotherapy + bevacizumab for advanced first-line therapy. Chemotherapy combined with targeted therapy did not render a survival benefit to these patients, demonstrating that the importance of developing new treatment options for this population.
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Affiliation(s)
- Qianhao Meng
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Jian Zhao
- grid.263452.40000 0004 1798 4018Department of Digestive, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi 030013 People’s Republic of China
| | - Yuanyuan Yu
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Ke Wang
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Jing Ren
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Chang Xu
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Yusheng Wang
- Department of Digestive, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People's Republic of China.
| | - Guangyu Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, People's Republic of China.
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Saibu OA, Singh G, Olugbodi SA, Oluwafemi AT, Ajayi TM, Hammed SO, Oladipo OO, Odunitan TT, Omoboyowa DA. Identification of HER2 inhibitors from curcumin derivatives using combination of in silico screening and molecular dynamics simulation. J Biomol Struct Dyn 2023; 41:12328-12337. [PMID: 36752338 DOI: 10.1080/07391102.2023.2175260] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/01/2023] [Indexed: 02/09/2023]
Abstract
Breast cancer remains a major world health challenge in women. Some Breast cancers are human epidermal growth factor receptor 2 (HER2) positive. Since this protein promotes the growth of cancer cells, it remains a therapeutic target for novel drugs. This study uses in silico model to predict HER2 inhibitors from curcumin derivatives via QSAR, e-pharmacophore, ADMET as well as structure-based virtual screening using Schrodinger suite. The molecular dynamics simulation of lead compounds, reference ligand and co-crystalized ligand was performed using GROMACS. At the end, eight active curcumin derivatives were predicted as inhibitors of HER2 with high binding affinity and better interaction compared with the reference drug (Neratinib) but lower binding affinity compared with the co-crystalized ligand (TAK-285). After prediction of the bioactivity of the molecules using AutoQSAR, the hit compounds showed appreciable inhibitory pIC50 compared with the reference and co-crystalized ligands against HER2. The pharmacokinetics profile predicted the eight hit compounds as drug-like and drug candidates. The MD simulation predicted the stability of the two top-scored compounds (10763284 and 78321412) in complex with HER2 for the final 80 ns of the trajectory period after initial equilibration with higher H-bond interactions in the protein-reference drug complex compared to the hit compounds-HER2 complexes. This study revealed that curcumin derivatives especially (1E,6E)-1,8-bis(4-hydroxy-3-methoxyphenyl)octa-1,6-diene-3,5-dione and (1E,6E)-4-ethyl-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione were identified to demonstrate inhibitory activity against HER2 which is comparable to neratinib. Conclusively, the lead compounds require further in vitro and in vivo experimental validation for the discovery of new HER2 antagonists for breast cancer management.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Oluwatosin A Saibu
- Department of Environmental Toxicology, Universitat Duisburg-Essen, North Rhine-Westphalia, Germany
| | - Gagandeep Singh
- Section of Microbiology, Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, India
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India
| | - Sunday A Olugbodi
- Department of Environmental Toxicology, Universitat Duisburg-Essen, North Rhine-Westphalia, Germany
| | - Adenrele T Oluwafemi
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Temitope M Ajayi
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Sodiq O Hammed
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Oladapo O Oladipo
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Tope T Odunitan
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
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Ducreux M, Tabernero J, Grothey A, Arnold D, O'Dwyer PJ, Gilberg F, Abbas A, Thakur MD, Prizant H, Irahara N, Tahiri A, Schmoll HJ, Van Cutsem E, de Gramont A. Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer. Eur J Cancer 2023; 184:137-150. [PMID: 36921494 DOI: 10.1016/j.ejca.2023.01.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
PURPOSE MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). METHODS Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). RESULTS Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50-1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90-2.29; P = 0.128). CONCLUSIONS Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. TRIAL REGISTRATION ClinicalTrials.gov: NCT02291289.
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Affiliation(s)
- Michel Ducreux
- Université Paris-Saclay, Gustave Roussy, Villejuif, France.
| | - Josep Tabernero
- Vall D'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain.
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, Germany.
| | - Peter J O'Dwyer
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
| | | | | | | | - Hen Prizant
- F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | | | | | | | - Eric Van Cutsem
- University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium.
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Aggarwal H, Han Y, Sheffield KM, Cui ZL. Real-world comparison between weekly versus biweekly dosing of cetuximab for metastatic colorectal cancer. J Comp Eff Res 2023; 12:e220143. [PMID: 36705061 PMCID: PMC10288952 DOI: 10.2217/cer-2022-0143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 01/09/2023] [Indexed: 01/28/2023] Open
Abstract
Aim: This real-world study aims to compare overall survival (OS) associated with biweekly (Q2W) versus weekly (Q1W) cetuximab dosing regimens for metastatic colorectal cancer (mCRC) treatment in the US. Methods: Adult patients with KRAS wild-type mCRC who received cetuximab ± chemotherapy from 2013 to 2019 were selected using Flatiron Health's electronic health records database. Propensity score matching was used to balance Q2W and Q1W cohorts on baseline patient characteristics. The Kaplan-Meier method was used for survival analyses. Several sensitivity analyses were conducted to assess the robustness of findings from the main analysis. Results: Of 1075 patients in the study, 60.7% received cetuximab Q1W and 39.3% Q2W. Median OS (95% confidence interval) in months was 17.2 (15.3, 18.8) for Q2W versus 14.3 (12.8, 16.0) for Q1W; p = 0.246. Similar OS between the dosing cohorts was observed in sensitivity analyses. Conclusion: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study.
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Affiliation(s)
- Himani Aggarwal
- Eli Lilly and Company, 893 S Delaware St., Indianapolis, IN 46225, USA
| | - Yimei Han
- Eli Lilly and Company, 893 S Delaware St., Indianapolis, IN 46225, USA
| | | | - Zhanglin Lin Cui
- Eli Lilly and Company, 893 S Delaware St., Indianapolis, IN 46225, USA
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Zhang Q, Zheng Y, Liu J, Tang X, Wang Y, Li X, Li H, Zhou X, Tang S, Tang Y, Wang X, He H, Li T. CircIFNGR2 enhances proliferation and migration of CRC and induces cetuximab resistance by indirectly targeting KRAS via sponging to MiR-30b. Cell Death Dis 2023; 14:24. [PMID: 36639711 PMCID: PMC9839739 DOI: 10.1038/s41419-022-05536-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 12/18/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023]
Abstract
Currently the clinical efficacy of colorectal cancer (CRC) which is the most common malignant tumors over the world has not reached an ideal level. Cetuximab, the monoclonal antibody targeting the extracellular domain of EGFR, has shown its great efficacy in the promotion of apoptosis and the inhibition of tumor cells-like characteristics in numerous cancers. However certain KRAS wild-type CRC patients unexpectedly show cetuximab resistance and the specific mechanism remains unclear. Circular RNAs (circRNAs) as the promising novel type of biomarkers in the cancer diagnosis and therapy, have been reported to be related with the drug resistance. In this study, with wondering the mechanism of cetuximab resistance in KRAS wild-type CRC patients, we evaluate the impact of circIFNGR2 on CRC and detect the association among circIFNGR2, miR-30b and KRAS via various experiments such as RT-qPCR, immunohistochemistry, luciferase assays, cell functional experiments and xenograft model. We conclude that circIFNGR2 induces cetuximab resistance in colorectal cancer cells by indirectly regulating target gene KRAS by sponging miR-30b at the post-transcriptional level. It is thus suggested that inhibition of circIFNGR2 can be a promising therapeutic strategy for malignant CRC patients with cetuximab resistance.
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Affiliation(s)
- Qi Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yifeng Zheng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Jiajia Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xiaoxiao Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yuan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xianzheng Li
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Huibin Li
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Xiaoying Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Shiru Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yitao Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xiaoyan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
| | - Han He
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Tingting Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
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Guerrero RM, Labajos VA, Ballena SL, Macha CA, Lezama MS, Roman CP, Beltran PM, Torrejon AF. Targeting BRAF V600E in metastatic colorectal cancer: where are we today? Ecancermedicalscience 2022; 16:1489. [PMID: 36819812 PMCID: PMC9934973 DOI: 10.3332/ecancer.2022.1489] [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: 09/05/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the second most frequent cause of direct cancer death worldwide. The study of the molecular state of oncogenes has predictive and prognostic value in metastatic CRC (mCRC). The B-raf proto-oncogene (BRAF) gene mutation represents the 8%-12% of all mutations in mCRC. The BRAF V600E mutation, considered the most common alteration of BRAF, corresponds to a constitutive kinase with a high activating capacity of the RAS/RAF/MEK/ERK pathway after a cascade of successive phosphorylations in the transcription of genes. BRAF V600E mutation is more prevalent in women, elderly, right-sided colon cancer and Caucasian population. Unfortunately, it is considered a poor predictive and prognosis biomarker. Patients with mCRC BRAF V600E mutated (BRAFm) are generally associated with poor response to chemotherapy and short progression-free survival and overall survival. Recently, randomised clinical trials have studied the combination of different chemotherapy regimens with angiogenic inhibitors in mCRC BRAFm. In addition, new anti-BRAF and immunotherapy agents have also been studied in this population, with positive results. The objective of this review is to acknowledge the biology and molecular pathway of BRAF, critically analyse the clinical trials and the therapy options published until today and evaluate the options of treatment according to the patient's clinical presentation.
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Affiliation(s)
- Rodrigo Motta Guerrero
- Instituto Nacional de Enfermedades Neoplásicas, Surquillo 15038, Peru
- https://orcid.org/0000-0002-8086-3513
| | - Veronica Arnao Labajos
- Instituto Nacional de Enfermedades Neoplásicas, Surquillo 15038, Peru
- https://orcid.org/0000-0001-7079-1010
| | - Sophia Lozano Ballena
- Hospital Almanzor Aguinaga Asenjo, Chiclayo 14001, Peru
- https://orcid.org/0000-0002-7868-6802
| | - Carlos Aliaga Macha
- Centro Oncológico ALIADA, San Isidro 15036, Peru
- https://orcid.org/0000-0003-0237-7058
| | - Miguel Sotelo Lezama
- Centro Oncológico ALIADA, San Isidro 15036, Peru
- https://orcid.org/0000-0002-8861-9355
| | - Cristian Pacheco Roman
- Instituto Nacional de Enfermedades Neoplásicas, Surquillo 15038, Peru
- https://orcid.org/0000-0003-2359-5126
| | - Paola Montenegro Beltran
- Instituto Nacional de Enfermedades Neoplásicas, Surquillo 15038, Peru
- https://orcid.org/0000-0002-1484-9537
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O'Riordan E, Bennett MW, Daly L, Power DG. The implication of BRAF mutation in advanced colorectal cancer. Ir J Med Sci 2022; 191:2467-2474. [PMID: 34877621 PMCID: PMC9672001 DOI: 10.1007/s11845-021-02689-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/09/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND Advanced colorectal cancer (CRC) is frequently a lethal disease. Mutations in the BRAF gene is a key driver in CRC pathogenesis and confers a poor prognosis. To date, Irish data on this molecular subtype of CRC is lacking. AIMS Our aim was to compare the natural history of Irish patients with BRAF (BRAFMUT) metastatic CRC with a control group of metastatic CRC patients without BRAF mutation (BRAFWT wild- type). METHOD A retrospective observational analysis of advanced CRC patients with known BRAFMUT was conducted by chart review. BRAFMUT patients were identified from the Cork University Hospital (CUH) histopathology database. Controls with known BRAFWT were randomly selected from the database. Demographic characteristics and clinicopathological data were recorded. Survival was assessed with Kaplan-Meier curve/Cox proportional hazard models. RESULTS Twenty patients with BRAFMUT and 36 with BRAFWT were studied. BRAFMUT were more likely female (75% vs 33%, p = 0.007) and right-sided (65% vs 31.4%, p = 0.033). Median overall survival was lower in BRAFMUT group (17.3 months (95% CI 0-40.8)) compared to patients with BRAFWT (median survival not reached, log rank p = 0.001). On multivariate analysis, BRAFMUT was independently associated with an increased risk of mortality (HR 12.76 (95% CI 3.15-51.7), p < 0.001). CONCLUSION BRAFMUT advanced colorectal cancer was associated with significantly reduced overall survival in this Irish CRC population. Knowledge of mutation status should now be considered standard of care and should dictate management. Surgeons should be aware of this genetic signature as the natural history of the disease may mitigate against an aggressive surgical strategy. A prospective study should be conducted to further corroborate these findings.
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Affiliation(s)
- Emma O'Riordan
- School of Medicine, University College Cork, Cork, Republic of Ireland.
| | | | - Louise Daly
- School of Food & Nutritional Sciences, University College Cork, Cork, Republic of Ireland
| | - Derek G Power
- Department of Medical Oncology, Mercy & Cork University Hospitals, Cork, Republic of Ireland
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Rosati G, Montrone M, Pacilio C, Colombo A, Cicero G, Paragliola F, Vaia A, Annunziata L, Bilancia D. An Update on the Role of Anti-EGFR in the Treatment of Older Patients with Metastatic Colorectal Cancer. J Clin Med 2022; 11:jcm11237108. [PMID: 36498683 PMCID: PMC9739901 DOI: 10.3390/jcm11237108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/10/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
Although colorectal cancer is increasingly being diagnosed in older patients, their number is largely underrepresented in phase II or III clinical trials. Consequently, guidelines and the SIOG recommendations are not sufficiently clear regarding the treatment of these patients, particularly when chemotherapy is combined with monoclonal antibodies (bevacizumab, cetuximab, and panitumumab). Targeted therapy based on the use of anti-epidermal growth factor receptors (EGFRs) is conditioned by the potential for increased toxicity, making it more difficult to treat an older, rat sarcoma virus (RAS) and B rapidly accelerated fibrosarcoma (BRAF) wild-type patient. In light of a more detailed characterization of the older population, modernly differentiable between fit, vulnerable, or frail patients on the basis of the comprehensive geriatric assessment, and of the analysis of more recent studies, this review fully collects data from the literature, differentiating the results on functional status patients.
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Affiliation(s)
- Gerardo Rosati
- Medical Oncology Unit, “San Carlo” Hospital, 85100 Potenza, Italy
- Correspondence: ; Tel.: +39-0971-612273
| | - Michele Montrone
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
| | - Carmen Pacilio
- Medical Breast Cancer Department, IRCCS Istituto Tumori “G. Pascale”, 80131 Napoli, Italy
| | - Alfredo Colombo
- Medical Oncology Unit, CDC Macchiarella, 90138 Palermo, Italy
| | - Giuseppe Cicero
- Medical Oncology, Università degli Studi di Palermo, 90133 Palermo, Italy
| | | | - Angelo Vaia
- Medical Oncology Unit, “San Carlo” Hospital, 85100 Potenza, Italy
| | - Luigi Annunziata
- Medical Oncology Unit, “San Carlo” Hospital, 85100 Potenza, Italy
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36
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Doleschal B, Petzer A, Rumpold H. Current concepts of anti-EGFR targeting in metastatic colorectal cancer. Front Oncol 2022; 12:1048166. [PMID: 36465407 PMCID: PMC9714621 DOI: 10.3389/fonc.2022.1048166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/26/2022] [Indexed: 11/07/2023] Open
Abstract
Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
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Affiliation(s)
- Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
- Johannes Kepler University Linz, Medical Faculty, Linz, Austria
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Lote H, Starling N, Pihlak R, Gerlinger M. Advances in immunotherapy for MMR proficient colorectal cancer. Cancer Treat Rev 2022; 111:102480. [DOI: 10.1016/j.ctrv.2022.102480] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/23/2022] [Accepted: 10/26/2022] [Indexed: 11/02/2022]
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Javid H, Hashemian P, Yazdani S, Sharbaf Mashhad A, Karimi-Shahri M. The role of heat shock proteins in metastatic colorectal cancer: A review. J Cell Biochem 2022; 123:1704-1735. [PMID: 36063530 DOI: 10.1002/jcb.30326] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/20/2022] [Accepted: 08/24/2022] [Indexed: 01/18/2023]
Abstract
Heat shock proteins (HSPs) are a large molecular chaperone family classified by their molecular weights, including HSP27, HSP40, HSP60, HSP70, HSP90, and HSP110. HSPs are likely to have antiapoptotic properties and participate actively in various processes such as tumor cell proliferation, invasion, metastases, and death. In this review, we discuss comprehensively the functions of HSPs associated with the progression of colorectal cancer (CRC) and metastasis and resistance to cancer therapy. Taken together, HSPs have numerous clinical applications as biomarkers for cancer diagnosis and prognosis and potential therapeutic targets for CRC and its related metastases.
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Affiliation(s)
- Hossein Javid
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
| | - Pedram Hashemian
- Jahad Daneshgahi Research Committee, Jahad Daneshgahi Institute, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Laboratory Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
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Ciombor KK, Strickler JH, Bekaii-Saab TS, Yaeger R. BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape. J Clin Oncol 2022; 40:2706-2715. [PMID: 35649231 PMCID: PMC9390817 DOI: 10.1200/jco.21.02541] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/07/2022] [Accepted: 03/07/2022] [Indexed: 12/13/2022] Open
Abstract
BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAFV600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAFV600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAFV600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.
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Affiliation(s)
- Kristen K. Ciombor
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - John H. Strickler
- Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, Durham, NC
| | | | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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40
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Wu Q, Wang H, Zhang S, Zeng Y, Yang W, Pan W, Hong G, Gao W. Efficacy and safety of triplet chemotherapy plus anti-EGFR agents in metastatic colorectal cancer: a systematic review and meta-analysis. World J Surg Oncol 2022; 20:258. [PMID: 35965307 PMCID: PMC9377107 DOI: 10.1186/s12957-022-02707-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To date, the optimal treatment for potentially resectable metastatic colorectal cancer (mCRC) patients has yet to be determined. Encouraging results have been reported in studies exploring the efficacy of triplet chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) target agents. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of triplet chemotherapy plus anti-EGFR target agents. METHODS We systematically searched the PubMed, Embase, and Web of Science databases from December 2004 to October 2021 for studies examining the efficacy of triplet chemotherapy plus anti-EGFR target agents in mCRC patients. The primary outcomes were the objective response rate (ORR) and R0 resection rate (R0RR), and the secondary outcomes were median progression-free survival (mPFS), median overall survival (mOS), and toxicity. Data were analyzed with R software 4.1.2. RESULTS Fourteen studies comprising 762 patients with mCRC were included in this meta-analysis. Analysis with a random effects model revealed that after treatment with triplet chemotherapy plus anti-EGFR target agents, the pooled ORR was 82% (95% CI= 76-88%, I2= 76%), and the pooled R0RR of colorectal liver metastasis (CLM) was 59% (95% CI= 49-68%, I2= 60%). The mPFS ranged from 9.5 to 17.8 months, and the mOS ranged from 24.7 to 62.5 months. A total of 648 grade 3 or 4 adverse events were reported; the most commonly reported events were diarrhea (174/648), neutropenia (157/648), and skin toxicity (95/648), which had pooled prevalence rates of 29% (95% CI= 20-39%, I2= 84%), 28% (95% CI= 20-37%, I2= 77%), and 17% (95% CI= 11-24%, I2= 66%), respectively. CONCLUSIONS Triplet chemotherapy plus anti-EGFR agents therapy seems to be capable of increasing the ORR of mCRC patients and the R0RR of CLM patients. The toxicity of this treatment is manageable. High-quality randomized controlled trial (RCT) studies are required for further validation.
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Affiliation(s)
- Qian Wu
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Huan Wang
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Suqin Zhang
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Yifei Zeng
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Wei Yang
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Wenjun Pan
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Guodai Hong
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China
| | - Wenbin Gao
- Department of Oncology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, 518000, People's Republic of China.
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Yu IS, Aubin F, Goodwin R, Loree JM, Mather C, Sheffield BS, Snow S, Gill S. Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline. Ther Adv Med Oncol 2022; 14:17588359221111705. [PMID: 35898967 PMCID: PMC9310231 DOI: 10.1177/17588359221111705] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/17/2022] [Indexed: 11/17/2022] Open
Abstract
The systemic therapy management of metastatic colorectal cancer (mCRC) has evolved from primarily cytotoxic chemotherapies to now include targeted agents given alone or in combination with chemotherapy, and immune checkpoint inhibitors. A better understanding of the pathogenesis and molecular drivers of colorectal cancer not only aided the development of novel targeted therapies but led to the discovery of tumor mutations which act as predictive biomarkers for therapeutic response. Mutational status of the KRAS gene became the first genomic biomarker to be established as part of standard of care molecular testing, where KRAS mutations within exons 2, 3, and 4 predict a lack of response to anti- epidermal growth factor receptor therapies. Since then, several other biomarkers have become relevant to inform mCRC treatment; however, there are no published Canadian guidelines which reflect the current standards for biomarker testing. This guideline was developed by a pan-Canadian advisory group to provide contemporary, evidence-based recommendations on the minimum acceptable standards for biomarker testing in mCRC, and to describe additional biomarkers for consideration.
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Affiliation(s)
- Irene S. Yu
- Department of Medical Oncology, BC Cancer
Surrey, Surrey, BC, Canada
| | - Francine Aubin
- Division of Hematology and Oncology, Department
of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, QC,
Canada
| | - Rachel Goodwin
- Division of Medical Oncology, Department of
Medicine, Ottawa Hospital Cancer Centre, Ottawa, ON, Canada
| | - Jonathan M. Loree
- Department of Medical Oncology, BC Cancer
Agency - Vancouver Centre, Vancouver, BC, Canada
| | - Cheryl Mather
- Department of Laboratory Medicine and
Pathology, University of Alberta, Edmonton, AB, Canada
| | - Brandon S. Sheffield
- Division of Advanced Diagnostics, William Osler
Health System, Brampton, ON, Canada
| | - Stephanie Snow
- Department of Medicine, Queen Elizabeth II
Health Sciences Centre, Halifax, NS, Canada
| | - Sharlene Gill
- Department of Medical Oncology, BC Cancer
Agency – Vancouver Centre, 600 W 10th Ave, Vancouver, BC, V5Z 4E6,
Canada
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From Intestinal Epithelial Homeostasis to Colorectal Cancer: Autophagy Regulation in Cellular Stress. Antioxidants (Basel) 2022; 11:antiox11071308. [PMID: 35883800 PMCID: PMC9311735 DOI: 10.3390/antiox11071308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 02/01/2023] Open
Abstract
The intestinal epithelium is continuously exposed to abundant stress stimuli, which relies on an evolutionarily conserved process, autophagy, to maintain its homeostasis by degrading and recycling unwanted and damaged intracellular substances. Otherwise, disruption of this balance will result in the development of a wide range of disorders, including colorectal cancer (CRC). Dysregulated autophagy is implicated in the regulation of cellular responses to stress during the development, progression, and treatment of CRC. However, experimental investigations addressing the impact of autophagy in different phases of CRC have generated conflicting results, showing that autophagy is context-dependently related to CRC. Thus, both inhibition and activation of autophagy have been proposed as therapeutic strategies against CRC. Here, we will discuss the multifaceted role of autophagy in intestinal homeostasis and CRC, which may provide insights for future research directions.
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Hafliger E, Boccaccino A, Lapeyre-Prost A, Perret A, Gallois C, Antista M, Pilla L, Lecomte T, Scartozzi M, Soularue E, Salvatore L, Bourgeois V, Salati M, Tougeron D, Evesque L, Vaillant JN, El-Khoury R, Lonardi S, Cremolini C, Taieb J. Encorafenib plus cetuximab treatment in BRAF V600E-mutated metastatic colorectal cancer patients pre-treated with an anti-EGFR: An AGEO-GONO case series. Eur J Cancer 2022; 168:34-40. [PMID: 35436675 DOI: 10.1016/j.ejca.2022.03.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/25/2022] [Accepted: 03/13/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAFV600E mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent. METHODS We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1). RESULTS Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01-7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event. CONCLUSIONS Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options.
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Affiliation(s)
- Emilie Hafliger
- Department of Gastroenterology and Digestive Oncology, SIRIC CARPEM, Georges-Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP-Paris Centre), Université de Paris, Paris France
| | - Alessandra Boccaccino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | | | - Audrey Perret
- Department of Medical Oncology, Institut Gustave Roussy, Paris, France
| | - Claire Gallois
- Department of Gastroenterology and Digestive Oncology, SIRIC CARPEM, Georges-Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP-Paris Centre), Université de Paris, Paris France
| | - Maria Antista
- Department of Oncology and Hemato-oncology, Universita' Degli Studi di Milano, Milan, Italy; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Lorenzo Pilla
- Department of Gastroenterology and Digestive Oncology, SIRIC CARPEM, Georges-Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP-Paris Centre), Université de Paris, Paris France
| | - Thierry Lecomte
- Department of Gastroenterology and Digestive Oncology, Centre Hospitalier Universitaire de Tours, Tours, France
| | - Mario Scartozzi
- Medical Oncology, University of Cagliari, University Hospital, Cagliari, Italy
| | - Emilie Soularue
- Department of Oncology, Institut Mutualiste Montsouris, Paris, France
| | - Lisa Salvatore
- Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS, Rome, Italy
| | - Vincent Bourgeois
- Department of Digestive Oncology, Centre Hospitalier de Boulogne sur Mer, France
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - David Tougeron
- Department of Gastroenterology and Digestive Oncology, Centre Hospitalier Universitaire de Poitiers, Université de Poitiers, Poitiers, France
| | - Ludovic Evesque
- Department of Digestive Oncology, Centre Antoine Lacassagne, Nice, France
| | - Jean-Nicolas Vaillant
- Department of Medical Oncology, Centre de Cancérologie de La Porte de Saint-Cloud, Paris, France
| | - Reem El-Khoury
- Department of Gastroenterology and Digestive Oncology, SIRIC CARPEM, Georges-Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP-Paris Centre), Université de Paris, Paris France
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV and IRCCS, Padua, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, SIRIC CARPEM, Georges-Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP-Paris Centre), Université de Paris, Paris France.
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Immune Profile of BRAF-Mutated Metastatic Colorectal Tumors with Good Prognosis after Palliative Chemotherapy. Cancers (Basel) 2022; 14:cancers14102383. [PMID: 35625987 PMCID: PMC9139363 DOI: 10.3390/cancers14102383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/04/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
Background: BRAF-mutated colorectal cancers (BRAF-MT CRCs) are known to have poor prognoses. BRAF-MT CRC was reported to be possibly related to the immune-activated phenotype. Objectives: This study aimed to investigate the association between the immune microenvironment and prognosis of BRAF-MT CRC. Methods: We evaluated clinical outcomes and investigated the immune profile of the BRAF-MT CRC tumors using the multiplex immunohistochemistry of immune-related markers: cytokeratin, programmed death ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and a cluster of differentiation 8 (CD8). Results: Out of 2313 tumors, 123 were BRAF-MT tumors. Among them, 86 tumors with available tissue were included. Out of 86 patients, 75 patients were non-good responders (GR), whereas 11 patients were GR. Median progression-free survival after first-line chemotherapy (4.6 vs. 12.4 months, p = 0.008) and overall survival (11.8 vs. 45.0 months) were longer in the GR group (p < 0.001). Median CD8+ T cell (254.29 vs. 656.0, p = 0.092), PD-L1+ tumor cell (0.95 vs.15.56, p = 0.050), PD-L1+ stromal cell (3.17 vs. 72.38, p = 0.025), PD-L1+ tumor and stromal cell (5.08 vs. 74.92, p = 0.032), and PD-1+ stromal cell (45.08 vs. 325.40, p = 0.046) counts were greater in the GR group. Conclusion: The clinical outcomes of unselected patients with BRAF-MT CRC were generally similar to those in previous studies. Based on the immune profile analysis, higher PD-L1 expression and CD8-positive cell infiltration were observed in BRAF-MT tumors with a good prognosis.
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Saharti S. KRAS/NRAS/BRAF Mutation Rate in Saudi Academic Hospital Patients With Colorectal Cancer. Cureus 2022; 14:e24392. [PMID: 35619874 PMCID: PMC9124608 DOI: 10.7759/cureus.24392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2022] [Indexed: 12/13/2022] Open
Abstract
Background: KRAS/NRAS/BRAF mutations are prognostic and predictive molecular biomarkers for colorectal cancers (CRCs). CRC has different frequencies in the population for mutations such as KRAS, NRAS, and BRAF. The aim of this study is to verify the frequency of the somatic KRAS/NRAS/BRAF mutations in Saudi academic hospital patients diagnosed with CRC and compare it with those estimated at the local and national levels. Methods: Out of 280 colorectal carcinomas diagnosed between 2018 and 2021 (primary and secondary), 97 (34.6%) were evaluated by Next Generation Sequencing (NGS) for colorectal cancer molecular markers. Four of these failed the PCR amplification, while 93 were successfully tested. KRAS, NRAS, and BRAF mutation rates and clinical pathological characteristics were recorded. Results: In this retrospective study, almost half of the tested samples were reported to have a clinically significant mutation (46/93 positive calls, while others were triple-negative). We found that the most prevalent mutation in KRAS (45.2%) was followed by NRAS (2.2%) and BRAF (2.2%). KRAS p.G12D accounted for the most frequently resulting variant (17/42, 40.5%). Second in ranking is KRAS p. G12V (6/42, 14.3%). Conclusion: This study is the first to describe the frequency of triple mutations in the city of Jeddah. The findings are consistent with previous research conducted in the Middle East and other local Saudi centers.
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Gray S, Lamarca A, Edeline J, Klümpen HJ, Hubner RA, McNamara MG, Valle JW. Targeted Therapies for Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:1789. [PMID: 35406560 PMCID: PMC8997784 DOI: 10.3390/cancers14071789] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
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Affiliation(s)
- Simon Gray
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Julien Edeline
- Centre Eugène Marquis, Av. de la Bataille Flandres Dunkerque-CS 44229, CEDEX, 35042 Rennes, France;
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Center, P.O. Box 7057, 1081 HV Amsterdam, The Netherlands;
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
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Jin H, Amonkar M, Aguiar-Ibáñez R, Thosar M, Chase M, Keeping S. Systematic literature review and network meta-analysis of pembrolizumab versus other interventions for previously untreated, unresectable or metastatic, microsatellite instability-high or mismatch repair-deficient colorectal cancer. Future Oncol 2022; 18:2155-2171. [PMID: 35332802 DOI: 10.2217/fon-2021-1633] [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: 11/21/2022] Open
Abstract
Aim: To compare pembrolizumab with competing interventions for previously untreated, unresectable or metastatic microsatellite instability-high or mismatch repair-deficient colorectal cancer. Method: Trials were identified via a systematic literature review and synthesized using a Bayesian network meta-analysis with time-varying hazard ratios (HRs). Results: Using intention-to-treat data, HRs for overall survival were generally in favor of pembrolizumab but not statistically significant; however, statistical significance was reached versus all comparators by month 16 when accounting for crossover. Estimated HRs for progression-free survival significantly favored pembrolizumab versus all comparators by month 12. Pembrolizumab was also superior to all comparators in terms of grade ≥3 adverse events. Conclusion: These analyses suggest that pembrolizumab is a highly efficacious and safe treatment in this population.
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Affiliation(s)
- He Jin
- PRECISIONheor, New York, NY 10165, USA
| | | | | | | | | | - Sam Keeping
- PRECISIONheor, Vancouver, BC, V6H 3Y4, Canada
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Hou J, He Z, Liu T, Chen D, Wang B, Wen Q, Zheng X. Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening. Front Oncol 2022; 12:755053. [PMID: 35372044 PMCID: PMC8970599 DOI: 10.3389/fonc.2022.755053] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 02/17/2022] [Indexed: 12/14/2022] Open
Abstract
Molecular targeted therapy has revolutionized the landscape of cancer treatment due to better therapeutic responses and less systemic toxicity. However, therapeutic resistance is a major challenge in clinical settings that hinders continuous clinical benefits for cancer patients. In this regard, unraveling the mechanisms of drug resistance may identify new druggable genetic alterations for molecularly targeted therapies, thus contributing to improved therapeutic efficacies. The recent rapid development of novel methodologies including CRISPR-Cas9 screening technology and patient-derived models provides powerful tools to dissect the underlying mechanisms of resistance to targeted cancer therapies. In this review, we updated therapeutic targets undergoing preclinical and clinical evaluation for various cancer types. More importantly, we provided comprehensive elaboration of high throughput CRISPR-Cas9 screening in deciphering potential mechanisms of unresponsiveness to molecularly targeted therapies, which will shed light on the discovery of novel opportunities for designing next-generation anti-cancer drugs.
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Affiliation(s)
- Jue Hou
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zongsheng He
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Tian Liu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Dongfeng Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Bin Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xi Zheng
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China
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Allart M, Leroy F, Kim S, Sefrioui D, Nayeri M, Zaanan A, Rousseau B, Ben Abdelghani M, de la Fouchardière C, Cacheux W, Legros R, Louafi S, Tougeron D, Bouché O, Fares N, Roquin G, Bignon AL, Maillet M, Pozet A, Hautefeuille V. Metastatic colorectal carcinoma with signet-ring cells: Clinical, histological and molecular description from an Association des Gastro-Entérologues Oncologues (AGEO) French multicenter retrospective cohort. Dig Liver Dis 2022; 54:391-399. [PMID: 34384712 DOI: 10.1016/j.dld.2021.06.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/21/2021] [Accepted: 06/27/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Metastatic signet-ring cell colorectal carcinoma is rare. We analyzed its clinicopathological and molecular features, prognostic factors and chemosensitivity. METHODS Retrospective study from 2003 to 2017 in 31 French centers, divided into three groups: curative care (G1), chemotherapy alone (G2), and best supportive care (G3). RESULTS Tumors were most frequently in the proximal colon (46%), T4 (71%), and poorly differentiated (86%). The predominant metastatic site was peritoneum (69%). Microsatellite instability and BRAF mutation were found in 19% and 9% (mainly right-sided) of patients and RAS mutations in 23%. Median overall survival (mOS) of the patients (n = 204) was 10.1 months (95%CI: 7.9;12.8), 45.1 for G1 (n = 38), 10.9 for G2 (n = 112), and 1.8 months for G3 (n = 54). No difference in mOS was found when comparing tumor locations, percentage of signet-ring cell contingent and microsatellite status. In G1, relapse-free survival was 14 months (95%CI: 6.5-20.9). In G2, median progression-free survival (PFS) was 4.7 months (95%CI: 3.6;5.9]) with first-line treatment. Median PFS was higher with biological agents than without (5.0 vs 3.9 months, p = 0.016). CONCLUSIONS mSRCC has a poor prognosis with specific location and molecular alterations resulting in low chemosensitivity. Routine microsatellite analysis should be performed because of frequent MSI-high tumors in this population.
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Affiliation(s)
- Marion Allart
- Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Florence Leroy
- Department of Cancer Medicine, Gustave Roussy Institute, Villejuif, France
| | - Stephano Kim
- Department of Medical Oncology, Jean Minjoz University Hospital, Besançon, France
| | - David Sefrioui
- Department of Hepato-Gastroenterology, Rouen University Hospital, Rouen, France
| | - Mihane Nayeri
- Department of Digestive and Oncological Surgery, Lille University, Claude Huriez University Hospital, Lille, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, APHP, Univ. Paris, Paris, France
| | - Benoit Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital - Créteil, Memorial Sloan Kettering Cancer Center, New York, United States of America
| | | | | | - Wulfran Cacheux
- Department of Medical Oncology, Private Hospital Pays de Savoie, Annemasse, France
| | - Romain Legros
- Department of Gastroenterology, Limoges University Hospital, Limoges, France
| | - Samy Louafi
- Department of Medical Oncology, Oncology Federation of Essonne - Corbeil-Essonnes, France
| | - David Tougeron
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
| | - Olivier Bouché
- Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France
| | - Nadim Fares
- Department of Hepato-Gastroenterology, Toulouse University Hospital, Toulouse, France
| | - Guillaume Roquin
- Department of Gastroenterology and Digestive Oncology, Angers University Hospital, Angers, France
| | - Anne Laure Bignon
- Department of Hepato-Gastroenterology and Nutrition, Caen University Hospital, Caen, France
| | - Marianne Maillet
- Department of Gastroenterology, Saint Louis Hospital, APHP, Paris, France
| | - Astrid Pozet
- Methodology and Quality of Life in Oncology Unit, INSERM UMR 1098, Besançon University Hospital, Besançon, France
| | - Vincent Hautefeuille
- Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.
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Chen Y, Yang M, Meng F, Zhang Y, Wang M, Guo X, Yang J, Zhang H, Zhang H, Sun J, Wang W. SRSF3 Promotes Angiogenesis in Colorectal Cancer by Splicing SRF. Front Oncol 2022; 12:810610. [PMID: 35198444 PMCID: PMC8859257 DOI: 10.3389/fonc.2022.810610] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 01/17/2022] [Indexed: 12/14/2022] Open
Abstract
SRSF3, an important member of the serine/arginine-rich protein (SRp) family, is highly expressed in various tumors and plays an important role in tumor cell proliferation, migration and invasion. However, it is still unclear whether SRSF3 is involved in tumor angiogenesis. In this study, we first revealed that SRSF3 regulated the expression of numerous genes related to angiogenesis, including proangiogenic SRF. Then, we confirmed that SRSF3 was highly expressed in colorectal cancer (CRC) and was positively correlated with SRF. Mechanistic studies revealed that SRSF3 directly bound to the “CAUC” motif in exon 6 of SRF and induced the exclusion of introns. Knockdown of SRSF3 significantly reduced the secretion of VEGF from CRC cells. Conditioned medium from SRSF3-knockdown CRC cells significantly inhibited the migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, SRF silencing inhibited angiogenesis, while SRF overexpression reversed the antiangiogenic effects of SRSF3 knockdown on tube formation. These findings indicate that SRSF3 is involved in the splicing of SRF and thereby regulates the angiogenesis of CRC, which offers novel insight into antiangiogenic therapy in CRC.
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Affiliation(s)
- Yinshuang Chen
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Fanyi Meng
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Yawen Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Mengmeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Xuqin Guo
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Jie Yang
- Institute of Medical Technology, Suzhou Vocational Health College, Suzhou, China
| | - Hongjian Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Haiyang Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Jing Sun
- Institute of Medical Technology, Suzhou Vocational Health College, Suzhou, China
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
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