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Stintzing S, Klein-Scory S, Fischer von Weikersthal L, Fuchs M, Kaiser F, Heinrich K, Modest DP, Hofheinz RD, Decker T, Gerger A, Angermeier S, Rumpold H, Dickhut A, Öhler L, Gruenberger B, Niedersuess-Beke D, Sandmann M, Winder T, Trojan J, Prager G, Held S, Kumbrink J, Schmiegel W, Baraniskin A, Heinemann V. Baseline Liquid Biopsy in Relation to Tissue-Based Parameters in Metastatic Colorectal Cancer: Results From the Randomized FIRE-4 (AIO-KRK-0114) Study. J Clin Oncol 2025; 43:1463-1473. [PMID: 39903881 DOI: 10.1200/jco.24.01174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/13/2024] [Accepted: 12/04/2024] [Indexed: 02/06/2025] Open
Abstract
PURPOSE The FIRE-4 study randomly assigned patients with first-line RAS wild-type (RASwt) metastatic colorectal cancer to either flourouracil (FU), folinic acid, and irinotecan (FOLFIRI) plus cetuximab until progression or intolerable toxicity (standard arm) or to FOLFIRI plus cetuximab followed by a switch maintenance treatment using FU plus bevacizumab (experimental arm). Here, we investigate the relevance of liquid biopsy (LB) RAS and BRAF testing compared with tissue-based analyses. PATIENTS AND METHODS LBs were taken at baseline and during treatment and were analyzed for RAS and BRAFV600E mutations using the in vitro diagnostics-certified ONCOBEAM RAS procedure (Sysmex Inostics) and digital-droplet polymerase chain reaction technology. RESULTS Six hundred seventy-two RASwt patients were randomly assigned. LBs of 540 patients were evaluable at baseline. Of those, 70 (13%) were RAS mutant (RASmut) and 38 (7%) BRAFV600E mutant. RASmut patients had significantly shorter survival compared with RASwt patients (progression-free survival [PFS], 9.0 months v 11.5 months; P < .001; hazard ratio [HR], 1.66; overall survival [OS], 22.1 months v 33.6 months; P < .001; HR, 1.85). RASmut patients had a numerically greater benefit from early switch maintenance compared with continuation of FOLFIRI/cetuximab (PFS, 10.1 months v 6.4 months; HR, 0.82; OS, 24.9 months v 16.3 months; HR, 0.57). Patients with a BRAFV600E mutation in LB showed poor outcome (PFS, 5.4 months; OS, 12.0 months). On the basis of serial LB analyses, the conversion rate from RASwt to RASmut at disease progression was significantly higher in the arm with continuous cetuximab administration than in the switch maintenance arm. CONCLUSION LB allows the detection of RAS and BRAF mutations in patients deemed RASwt on the basis of tissue analyses. These patients show outcome characteristics expected for RAS- and BRAF-mutant patients in tissue. The study thus confirms the high clinical relevance of LB performed at baseline before the start of therapy.
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Affiliation(s)
- Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology (CCM), Charité-Universtätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- DKTK Heidelberg, Partner Site, Berlin, Germany
| | - Susanne Klein-Scory
- Department of Internal Medicine, UK Knappschaftskrankenhaus Bochum GmbH, Ruhr University Bochum, Bochum, Germany
| | | | - Martin Fuchs
- Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, München Klinik Bogenhausen, Munich, Germany
| | | | - Kathrin Heinrich
- Department of Medicine III and Comprehensive Cancer Center (CCC Munich LMU), University Hospital, LMU Munich, Munich, Germany
| | - Dominik Paul Modest
- Department of Hematology, Oncology and Cancer Immunology (CCM), Charité-Universtätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | | | | | | | | | | | | | - Leopold Öhler
- Department of Internal Medicine/Oncology, St Joseph Hospital, Vienna, Austria
| | | | | | | | | | - Joerg Trojan
- Klinikum der Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt, Germany
| | | | | | - Jörg Kumbrink
- Faculty of Medicine, Institute of Pathology, LMU Munich, Munich, Germany
| | - Wolff Schmiegel
- Department of Internal Medicine, UK Knappschaftskrankenhaus Bochum GmbH, Ruhr University Bochum, Bochum, Germany
| | - Alexander Baraniskin
- Department of Hematology, Oncology and Palliative Care, Evangelisches Krankenhaus Hamm gGmbH, Hamm, Germany
| | - Volker Heinemann
- Department of Medicine III and Comprehensive Cancer Center (CCC Munich LMU), University Hospital, LMU Munich, Munich, Germany
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2
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Schillinger G. [Genetic tumour diagnostics and personalised medicine from a systems perspective]. ZEITSCHRIFT FUR EVIDENZ, FORTBILDUNG UND QUALITAT IM GESUNDHEITSWESEN 2023; 179:91-94. [PMID: 37183116 DOI: 10.1016/j.zefq.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/16/2023]
Abstract
High-quality studies are necessary and feasible in personalised medicine in order to evaluate the benefits across the entire treatment chain of biomarker tests and resulting treatments in regard to patient-relevant endpoints. With the introduction of genome sequencing in oncology, a considerable number of new treatment concepts with mostly low-quality evidence can be expected. High quality requirements, interdisciplinary cooperation structures, knowledge-generating care and the connection of patient care at the expense of the statutory health insurance funds, with research at the expense of the manufacturers or public funding, are necessary.
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3
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Tang YL, Li DD, Duan JY, Sheng LM, Wang X. Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments. World J Gastroenterol 2023; 29:926-948. [PMID: 36844139 PMCID: PMC9950860 DOI: 10.3748/wjg.v29.i6.926] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/24/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.
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Affiliation(s)
- Yuan-Ling Tang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dan-Dan Li
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Duan
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei-Ming Sheng
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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4
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Karan C, Tan E, Sarfraz H, Knepper TC, Walko CM, Felder S, Kim R, Sahin IH. Human Epidermal Growth Factor Receptor 2-Targeting Approaches for Colorectal Cancer: Clinical Implications of Novel Treatments and Future Therapeutic Avenues. JCO Oncol Pract 2022; 18:545-554. [PMID: 35613416 DOI: 10.1200/op.21.00904] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The treatment paradigm for colorectal cancer (CRC) has changed significantly over the past decade with targeted therapeutics. Human epidermal growth factor receptor 2 (HER2) amplification is seen among 3%-4% of patients with metastatic CRC (mCRC). The biological discovery of HER2 amplification in cancer cells has led to practice-changing drug development for several solid tumors, including breast, gastric, and esophageal cancers. HER2 amplification is now highly actionable in CRC with distinct therapeutic combinations, including the combination of monoclonal antibodies and HER2 receptor-specific tyrosine kinase inhibitors, as well as antibody-drug conjugates, that delivers targeted cytotoxic agents. However, it is essential to define the therapeutic role and sequence of these different combinations, some of which are already part of standard clinical practice. In this review article, we discuss recent clinical studies demonstrating the clinical benefits of each distinct therapeutic approach and their impacts on the current management of HER2-amplified mCRC. We also review ongoing clinical trials targeting the HER2 pathway in mCRC and elaborate on novel therapeutic opportunities in this space that may further define the changing paradigm of HER2-targeted therapy for CRC.
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Affiliation(s)
- Canan Karan
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Elaine Tan
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Humaira Sarfraz
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Todd C Knepper
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Christine M Walko
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Seth Felder
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Ibrahim Halil Sahin
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
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5
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Tabernero J, Velez L, Trevino TL, Grothey A, Yaeger R, Van Cutsem E, Wasan H, Desai J, Ciardiello F, Yoshino T, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study. ESMO Open 2021; 6:100328. [PMID: 34896698 PMCID: PMC8666642 DOI: 10.1016/j.esmoop.2021.100328] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/03/2021] [Accepted: 11/04/2021] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.
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Affiliation(s)
- J Tabernero
- Medical Oncology Department, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), UVIC-UCC, IOB-Quiron, Barcelona, Spain.
| | - L Velez
- Medical Oncology Department, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), UVIC-UCC, IOB-Quiron, Barcelona, Spain
| | - T L Trevino
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA
| | - A Grothey
- West Cancer Center and Research Institute, OneOncology, Germantown, USA
| | - R Yaeger
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - E Van Cutsem
- Digestive Oncology Department, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - H Wasan
- Department of Cancer Medicine, Hammersmith Hospital, London, UK
| | - J Desai
- Department of Medical Oncology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Walter and Aliza Hall Institute, Parkville, Australia
| | - F Ciardiello
- Department of Precision Medicine, University of Campania, Naples, Italy
| | - T Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | | | | | - S Kopetz
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA
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Giordano G, Parcesepe P, Bruno G, Piscazzi A, Lizzi V, Remo A, Pancione M, D’Andrea MR, De Santis E, Coppola L, Pietrafesa M, Fersini A, Ambrosi A, Landriscina M. Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era. Int J Mol Sci 2021; 22:7717. [PMID: 34299337 PMCID: PMC8307359 DOI: 10.3390/ijms22147717] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/05/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023] Open
Abstract
Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.
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Affiliation(s)
- Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
| | - Pietro Parcesepe
- Department of Diagnostics and Public Health—Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy;
| | - Giuseppina Bruno
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
| | - Annamaria Piscazzi
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
| | - Vincenzo Lizzi
- General Surgey Unit, Policlinico Riuniti, 71122 Foggia, Italy;
| | - Andrea Remo
- Pathology Unit “Mater Salutis” Hospital, ULSS9, Legnago, 37045 Verona, Italy;
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy;
| | | | - Elena De Santis
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Luigi Coppola
- UOC Anatomia ed Istologia Patologica e Citologia Diagnostica, Dipartimento dei Servizi Diagnostici e della Farmaceutica, Ospedale Sandro Pertini, ASL Roma 2, 00157 Roma, Italy;
| | - Michele Pietrafesa
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, 85028 Potenza, Italy;
| | - Alberto Fersini
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (A.F.); (A.A.)
| | - Antonio Ambrosi
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (A.F.); (A.A.)
| | - Matteo Landriscina
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, 85028 Potenza, Italy;
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Al-Salama ZT. Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. Drugs 2021; 81:849-856. [PMID: 33914242 DOI: 10.1007/s40265-021-01501-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2021] [Indexed: 11/26/2022]
Abstract
Encorafenib (Braftovi®) is an oral small molecule BRAF inhibitor used in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, who have received prior systemic therapy. In a clinical trial in adults with BRAF V600E-mutated mCRC who had disease progression after one or two previous regimens (BEACON CRC), encorafenib plus cetuximab was associated with a significantly longer median overall survival (OS), a higher objective response rate (ORR) and longer median progression-free survival (PFS), compared with standard therapy. Encorafenib plus cetuximab had a manageable tolerability profile in BEACON CRC. Current evidence suggests that encorafenib plus cetuximab combination therapy is an important targeted regimen for patients with mCRC and a BRAF V600E mutation who have received prior therapy.
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Affiliation(s)
- Zaina T Al-Salama
- Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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8
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Grothey A, Fakih M, Tabernero J. Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines. Ann Oncol 2021; 32:959-967. [PMID: 33836264 DOI: 10.1016/j.annonc.2021.03.206] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis. DESIGN Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting. RESULTS The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab. CONCLUSIONS The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration.
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Affiliation(s)
- A Grothey
- West Cancer Center and Research Institute, OneOncology, Germantown, USA
| | - M Fakih
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA
| | - J Tabernero
- Vall d'Hebron Hospital Campus, Vall d'Hebron Institute of Oncology, UVIC-UCC, IOB-Quiron, Barcelona, Spain.
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Henry JT, Coker O, Chowdhury S, Shen JP, Morris VK, Dasari A, Raghav K, Nusrat M, Kee B, Parseghian C, Pant S, Jeyakumar N, Zhu L, Nishioka Y, Fogelman D, Wolff RA, Hong D, Overman MJ, Vauthey J, Kopetz S, Johnson B. Comprehensive Clinical and Molecular Characterization of KRAS G12C-Mutant Colorectal Cancer. JCO Precis Oncol 2021; 5:PO.20.00256. [PMID: 34250391 PMCID: PMC8232253 DOI: 10.1200/po.20.00256] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/21/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023] Open
Abstract
PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.
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Affiliation(s)
- Jason T. Henry
- Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Oluwadara Coker
- Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Saikat Chowdhury
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Van K. Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maliha Nusrat
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bryan Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Christine Parseghian
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shubham Pant
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nikeshan Jeyakumar
- Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Limin Zhu
- Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yujiro Nishioka
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - David Fogelman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Robert A. Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - David Hong
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael J. Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - JeanNicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Benny Johnson
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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10
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Kam AE, Eng C. BRAF V600E mutated metastatic colorectal cancer: current progress and future directions. Expert Opin Biol Ther 2021; 21:1311-1313. [PMID: 33761808 DOI: 10.1080/14712598.2021.1908994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Audrey E Kam
- Department of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Cathy Eng
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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Cheng ML, Pectasides E, Hanna GJ, Parsons HA, Choudhury AD, Oxnard GR. Circulating tumor DNA in advanced solid tumors: Clinical relevance and future directions. CA Cancer J Clin 2021; 71:176-190. [PMID: 33165928 DOI: 10.3322/caac.21650] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/21/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
The application of genomic profiling assays using plasma circulating tumor DNA (ctDNA) is rapidly evolving in the management of patients with advanced solid tumors. Diverse plasma ctDNA technologies in both commercial and academic laboratories are in routine or emerging use. The increasing integration of such testing to inform treatment decision making by oncology clinicians has complexities and challenges but holds significant potential to substantially improve patient outcomes. In this review, the authors discuss the current role of plasma ctDNA assays in oncology care and provide an overview of ongoing research that may inform real-world clinical applications in the near future.
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Affiliation(s)
- Michael L Cheng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Eirini Pectasides
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Glenn J Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Heather A Parsons
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Atish D Choudhury
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Geoffrey R Oxnard
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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12
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Lisby AN, Flickinger JC, Bashir B, Weindorfer M, Shelukar S, Crutcher M, Snook AE, Waldman SA. GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021; 6:117-129. [PMID: 34027103 DOI: 10.1080/23808993.2021.1876518] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction Colorectal cancer (CRC) is one of the most-deadly malignancies worldwide. Current therapeutic regimens for CRC patients are relatively generic, based primarily on disease type and stage, with little variation. As the field of molecular oncology advances, so too must therapeutic management of CRC. Understanding molecular heterogeneity has led to a new-found promotion for precision therapy in CRC; underlining the diversity of molecularly targeted therapies based on individual tumor characteristics. Areas covered We review current approaches for the treatment of CRC and discuss the potential of precision therapy in advanced CRC. We highlight the utility of the intestinal protein guanylyl cyclase C (GUCY2C), as a multi-purpose biomarker and unique therapeutic target in CRC. Here, we summarize current GUCY2C-targeted approaches for treatment of CRC. Expert opinion The GUCY2C biomarker has multi-faceted utility in medicine. Developmental investment of GUCY2C as a diagnostic and therapeutic biomarker offers a variety of options taking the molecular characteristics of cancer into account. From GUCY2C-targeted therapies, namely cancer vaccines, CAR-T cells, and monoclonal antibodies, to GUCY2C agonists for chemoprevention in those who are at high risk for developing colorectal cancer, the utility of this protein provides many avenues for exploration with significance in the field of precision medicine.
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Affiliation(s)
- Amanda N Lisby
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - John C Flickinger
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Babar Bashir
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Megan Weindorfer
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Sanjna Shelukar
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Madison Crutcher
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Adam E Snook
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Scott A Waldman
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
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13
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Treatments after first progression in metastatic colorectal cancer. A literature review and evidence-based algorithm. Cancer Treat Rev 2020; 92:102135. [PMID: 33307331 DOI: 10.1016/j.ctrv.2020.102135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/23/2022]
Abstract
Prolonging survival, achieving symptoms palliation and preserving quality of life are the primary therapeutic goals of treatments administered after disease progression in mCRC. Even if the impact of these therapies on the prognosis of affected patients is less relevant than the impact of the upfront treatment, tailoring the optimal second-line therapy is increasingly important. Several therapeutic options are available, and different factors including not only patient- and disease-related characteristics, but also the first-line treatment received (i.e., type, timing of disease progression, observed outcome and reported toxicities) may drive this choice. Herein, we describe the current state of the art in the landscape of treatments after progression in mCRC. Based on a critical review of the literature, we built a patient-oriented therapeutic algorithm, aiming to guide clinicians in their daily decision-making.
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14
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Kanat O, Ertas H, Caner B. Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations. World J Gastrointest Oncol 2020; 12:1080-1090. [PMID: 33133378 PMCID: PMC7579731 DOI: 10.4251/wjgo.v12.i10.1080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/07/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Acıbadem Bursa Hospital, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Bursa City Hospital, Bursa 16059, Turkey
| | - Burcu Caner
- Department of Medical Oncoloy, Balıkesir Ataturk City Hospital, Bursa 16059, Turkey
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15
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[New drug approval: Encorafenib-metastatic colorectal cancers with BRAF V600E mutation after systemic chemotherapy]. Bull Cancer 2020; 107:1086-1088. [PMID: 33046237 DOI: 10.1016/j.bulcan.2020.08.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/03/2020] [Accepted: 08/20/2020] [Indexed: 11/24/2022]
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16
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Roviello G, D'Angelo A, Petrioli R, Roviello F, Cianchi F, Nobili S, Mini E, Lavacchi D. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. Transl Oncol 2020; 13:100795. [PMID: 32470910 PMCID: PMC7260582 DOI: 10.1016/j.tranon.2020.100795] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023] Open
Abstract
BRAFV600-mutated colorectal cancer (CRC) accounts for 8% to 12% of all CRC diagnoses. These tumors are often associated with specific patient features, including right-sided primary tumor location, peritoneal and non-regional lymph node involvement, and poor prognosis. In approximately 30% of cases, a simultaneous mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype is identified. The prognostic impact of the BRAF mutation appears to be less marked in patients with MSI-H CRC than in patients with microsatellite stable (MSS) tumor. The treatment of BRAFV600-mutated CRC is still a challenge for the clinicians, mainly due to the poor survival outcomes obtained with traditional chemotherapy regimens. In recent years, two novel treatment strategies have offered remarkable changes in the treatment of this specific patient subgroup. The first approach has included targeted therapies directed against BRAF and MEK, with support from the epidermal growth factor receptor (EGFR) blockade. The second approach has included immunotherapeutic agents that have been shown to be particularly promising for patients with simultaneous dMMR/MSI-H phenotype. Here we review the clinical trials that specifically enrolled patients with BRAF-mutated CRC, from the phase I/II studies to the phase III trial BEACON CRC. We also examine the future directions towards a molecularly guided therapy for patients with BRAF-mutated CRC and the crucial role of a molecularly and clinically based algorithm in order to offer the best choice of treatment for these patients.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy.
| | - Alberto D'Angelo
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom
| | - Roberto Petrioli
- Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Franco Roviello
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Bracci - Policlinico "Le Scotte", 53100, Siena, Italy
| | - Fabio Cianchi
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Stefania Nobili
- Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy
| | - Daniele Lavacchi
- Azienda Ospedaliera Careggi University Hospital of Florence and University of Florence, 50134 Florence, Italy
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Cohen R, Pudlarz T, Delattre JF, Colle R, André T. Molecular Targets for the Treatment of Metastatic Colorectal Cancer. Cancers (Basel) 2020; 12:E2350. [PMID: 32825275 PMCID: PMC7563268 DOI: 10.3390/cancers12092350] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/06/2020] [Accepted: 08/10/2020] [Indexed: 12/14/2022] Open
Abstract
Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).
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Affiliation(s)
- Romain Cohen
- Department of Medical Oncology, Hôpital Saint-Antoine, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75012 Paris, France; (T.P.); (J.-F.D.); (R.C.); (T.A.)
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18
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The Curcumin Analogue, MS13 (1,5-Bis(4-hydroxy-3- methoxyphenyl)-1,4-pentadiene-3-one), Inhibits Cell Proliferation and Induces Apoptosis in Primary and Metastatic Human Colon Cancer Cells. Molecules 2020; 25:molecules25173798. [PMID: 32825505 PMCID: PMC7504349 DOI: 10.3390/molecules25173798] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/26/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to identify the anti-cancer properties of curcumin analogue-MS13, a diarylpentanoid on the cytotoxicity, anti-proliferative and apoptotic activity of primary (SW480) and metastatic (SW620) human colon cancer cells. A cell viability assay showed that MS13 has greater cytotoxicity effect on SW480 (EC50: 7.5 ± 2.8 µM) and SW620 (EC50: 5.7 ± 2.4 µM) compared to curcumin (SW480, EC50: 30.6 ± 1.4 µM) and SW620, EC50: 26.8 ± 2.1 µM). Treatment with MS13 at two different doses 1X EC50 and 2X EC50 suppressed the colon cancer cells growth with lower cytotoxicity against normal cells. A greater anti-proliferative effect was also observed in MS13 treated colon cancer cells compared to curcumin at 48 and 72 h. Subsequent analysis on the induction of apoptosis showed that MS13 treated cells exhibited morphological features associated with apoptosis. The findings are also consistent with cellular apoptotic activities shown by increased caspase-3 activity and decreased Bcl-2 protein level in both colon cancer cell lines. In conclusion, MS13 able to suppress colon cancer cell growth by inhibiting cell proliferation and induce apoptosis in primary and metastatic human colon cancer cells.
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19
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Lièvre A, de la Fouchardière C, Samalin E, Benoist S, Phelip JM, André T, Lledo G. [BRAF V600E-mutant colorectal cancers: Where are we?]. Bull Cancer 2020; 107:881-895. [PMID: 32674932 DOI: 10.1016/j.bulcan.2020.04.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/14/2022]
Abstract
The BRAFV600E mutation, observed in 8 % of colorectal cancers (CRC), introduces a particular phenotype and a poor prognosis at the localized or metastatic stage. BRAF mutant CRCs are more often localized in the right colon, poorly differentiated and mucinous. They affect an older population (more often female) and are associated with a more frequent metastatic lymph node and peritoneal evolution. The BRAFV600E mutation is associated with a sporadic microsatellite instability (MSI) status in 20 to 40% of cases. In localized colon cancer, it does not imply any modification of the adjuvant treatment. In metastatic CRC, the first action must be the systematic search for an MSI phenotype, given its frequent association with the presence of a BRAF mutation, in order to propose immunotherapy that has been demonstrated to be very effective in MSI metastatic CRC. In non-MSI CRC, a first-line trichimiotherapy associated with bevacizumab is an option to be favored in patients in good general condition but the association with an anti-EGFR can be discussed, especially when the objective is tumor response. At the same time, surgical resection must be systematically discussed in the case of resectable hepatic metastases since the presence of a BRAFV600E mutation is not a risk factor for recurrence and that prolonged survival may be observed after surgery. In the second or third line, the triplet encorafenib, binimetinib and cetuximab, as well as the doublet encorafenib and cetuximab are superior to the association of irinotecan plus cetuximab in terms of response and survival (phase III study BEACON) and represent a new therapeutic standard. Their use on the front line is under study.
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Affiliation(s)
- Astrid Lièvre
- Service des maladies de l'appareil digestif, CHU Pontchaillou, université Rennes 1, Rennes, France.
| | | | - Emmanuelle Samalin
- Département d'oncologie, institut du cancer de Montpellier (ICM), University Montpellier, Montpellier et institut de génomique fonctionnelle, CNRS, inserm, university Montpellier, Montpellier, France
| | - Stéphane Benoist
- service de chirurgie digestive et oncologique, CHU Bicêtre, AP-HP, université Paris-Saclay, Le Kremlin Bicêtre, France
| | - Jean-Marc Phelip
- Service de gastroentérologie, CHU Saint-Étienne, Saint-Etienne, France
| | - Thierry André
- Département d'oncologie médicale, Sorbonne université, hôpital Saint-Antoine, AP-HP, 7512 Paris, France
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20
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Sahin IH. Precision medicine for gastrointestinal cancers: a conference report. Future Sci OA 2020; 6:FSO478. [PMID: 32670606 PMCID: PMC7351088 DOI: 10.2144/fsoa-2020-0061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 01/06/2023] Open
Abstract
As cancer management evolves into precision medicine national/international cancer meetings bring novel therapeutic approaches and potentially practice-changing results of clinical studies are presented. This year, the ASCO GI Symposium 2020 had also several updates from ongoing and finalized clinical trials. Although there were no groundbreaking results that impact the daily practice directly, several highly important data from ongoing studies were shared with the audience. In this report, the highlights of the ASCO GI Symposium 2020 are presented with a future perspective.
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Affiliation(s)
- Ibrahim Halil Sahin
- Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA
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21
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Lai E, Liscia N, Donisi C, Mariani S, Tolu S, Pretta A, Persano M, Pinna G, Balconi F, Pireddu A, Impera V, Dubois M, Migliari M, Spanu D, Saba G, Camera S, Musio F, Ziranu P, Puzzoni M, Demurtas L, Pusceddu V, Dettori M, Massa E, Atzori F, Dessì M, Astara G, Madeddu C, Scartozzi M. Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer. Cancers (Basel) 2020; 12:E1214. [PMID: 32413973 PMCID: PMC7281737 DOI: 10.3390/cancers12051214] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/03/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. METHODS A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. RESULTS RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. CONCLUSION Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Nicole Liscia
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
- Medical Oncology Unit, Sapienza University of Rome, 00161 Rome, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Simona Tolu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
- Medical Oncology Unit, Sapienza University of Rome, 00161 Rome, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
- Medical Oncology Unit, Sapienza University of Rome, 00161 Rome, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Annagrazia Pireddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
- Medical Oncology Unit, Sapienza University of Rome, 00161 Rome, Italy
| | - Valentino Impera
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
- Medical Oncology Unit, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Silvia Camera
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
- Medical Oncology Unit, Sapienza University of Rome, 00161 Rome, Italy
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Manuela Dettori
- Medical Oncology Unit, Azienda Ospedaliera Brotzu, Ospedale Businco, 09134 Cagliari, Italy
| | - Elena Massa
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Francesco Atzori
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Mariele Dessì
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (N.L.); (C.D.); (S.M.); (S.T.); (A.P.); (M.P.); (G.P.); (F.B.); (A.P.); (V.I.); (M.D.); (M.M.); (D.S.); (G.S.); (S.C.); (F.M.); (P.Z.); (M.P.); (L.D.); (V.P.); (E.M.); (F.A.); (M.D.); (G.A.); (C.M.)
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22
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C. Huynh J, Schwab E, Ji J, Kim E, Joseph A, Hendifar A, Cho M, Gong J. Recent Advances in Targeted Therapies for Advanced Gastrointestinal Malignancies. Cancers (Basel) 2020; 12:E1168. [PMID: 32384640 PMCID: PMC7281439 DOI: 10.3390/cancers12051168] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/20/2020] [Accepted: 04/30/2020] [Indexed: 12/19/2022] Open
Abstract
The treatment of advanced gastrointestinal (GI) cancers has become increasingly molecularly driven. Molecular profiling for HER2 and PD-L1 status is standard for metastatic gastroesophageal (GEJ) cancers to predict benefits from trastuzumab (HER2-targeted therapy) and pembrolizumab (anti-PD-1 therapy), while extended RAS and BRAF testing is standard in metastatic colorectal cancer to predict benefits from epidermal growth factor receptor (EGFR)-targeted therapies. Mismatch repair (MMR) or microsatellite instability (MSI) testing is standard for all advanced GI cancers to predict benefits from pembrolizumab and in metastatic colorectal cancer, nivolumab with or without ipilimumab. Here we review recent seminal trials that have further advanced targeted therapies in these cancers including Poly (adenosine diphosphate-ribose) polymerases (PARP) inhibition in pancreas cancer, BRAF inhibition in colon cancer, and isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) inhibition in biliary tract cancer. Targeted therapies in GI malignancies constitute an integral component of the treatment paradigm in these advanced cancers and have widely established the need for standard molecular profiling to identify candidates.
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Affiliation(s)
- Jasmine C. Huynh
- Hematology Oncology, University of California, Davis, Sacramento, CA 95817, USA; (E.K.); (A.J.); (M.C.)
| | - Erin Schwab
- Hematology Oncology, University of California, Davis, Sacramento, CA 95817, USA; (E.K.); (A.J.); (M.C.)
| | - Jingran Ji
- Internal Medicine, University of California, Davis, Sacramento, CA 95817, USA;
| | - Edward Kim
- Hematology Oncology, University of California, Davis, Sacramento, CA 95817, USA; (E.K.); (A.J.); (M.C.)
| | - Anjali Joseph
- Hematology Oncology, University of California, Davis, Sacramento, CA 95817, USA; (E.K.); (A.J.); (M.C.)
| | - Andrew Hendifar
- Hematology Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.H.); (J.G.)
| | - May Cho
- Hematology Oncology, University of California, Davis, Sacramento, CA 95817, USA; (E.K.); (A.J.); (M.C.)
| | - Jun Gong
- Hematology Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.H.); (J.G.)
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23
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Morris VK, Bekaii-Saab T. Improvements in Clinical Outcomes for BRAFV600E -Mutant Metastatic Colorectal Cancer. Clin Cancer Res 2020; 26:4435-4441. [PMID: 32253230 DOI: 10.1158/1078-0432.ccr-19-3809] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/25/2020] [Accepted: 04/02/2020] [Indexed: 11/16/2022]
Abstract
Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their colorectal cancer. Consequently, many patients present with metastatic colorectal cancer, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of colorectal cancer tumors and are associated with uninhibited cell proliferation, reduced apoptosis, and resistance to standard therapeutic options. In colorectal cancer, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared with tumors with wild-type BRAF Success in treating other BRAFV600E -mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic colorectal cancer. Consequently, combination therapy with inhibitors of BRAF, MEK, and EGFR, which overcomes the innate treatment-resistant characteristics of BRAF V600E-mutant colorectal cancer, is now recommended by treatment guidelines.
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Affiliation(s)
- Van K Morris
- University of Texas MD Anderson Cancer Center, Houston, Texas
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