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Su J, Wang J, Chen W, Xu Y, Yang W, Liu W, Wang Z, Huang M. Unveiling MAGEA3: a novel predictive biomarker for bevacizumab resistance in colorectal cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:22. [PMID: 40342736 PMCID: PMC12059477 DOI: 10.20517/cdr.2025.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/21/2025] [Accepted: 04/21/2025] [Indexed: 05/11/2025]
Abstract
Aim: Bevacizumab has long been a cornerstone in the treatment of colorectal cancer (CRC), serving as a fundamental antiangiogenic therapeutic option. However, a significant proportion of patients exhibit insensitivity to bevacizumab, and no reliable biomarker has been established to predict treatment efficacy. Notably, while many angiogenic factors in tumors have been extensively studied, they have failed to consistently demonstrate reliable predictive value for patient survival outcomes in CRC. This study is designed to screen tumor biomarkers with predictive value for bevacizumab resistance in CRC. Methods: Online CRC databases with bevacizumab treatment were downloaded from the GEO datasets along with the TCGA database, which were then analyzed to generate genes overexpressed in bevacizumab non-responders. In vitro experiments using colorectal cancer cell lines were then performed to explore the underlying mechanism of the candidate gene that impacts bevacizumab efficacy. Finally, clinical samples of CRC were collected to validate the predictive effect of the candidate gene on bevacizumab efficacy. Results: We conducted comprehensive analyses of CRC patient datasets, identifying MAGEA3 as a pivotal gene that is not only highly upregulated in bevacizumab-resistant primary CRC but also strongly associated with poor overall survival prognosis. Our in vitro experiments revealed a novel mechanistic insight: MAGEA3 specifically inhibits the expression and secretion of VEGF through the mTOR signaling pathway in colorectal cancer cells, while exhibiting minimal impact on other key angiogenic factors such as PDGF, FGF, and ANGPT2. This selective regulation of VEGF provides a molecular basis for MAGEA3's role in bevacizumab resistance. Furthermore, we discovered that MAGEA3 significantly impairs mitochondrial function in cancer cells, suggesting an additional layer of complexity in its oncogenic role. Clinically, our findings demonstrated that high baseline levels of MAGEA3 in CRC patients were strongly associated with worse progression-free survival (PFS) following bevacizumab treatment. Conclusion: Collectively, these findings position MAGEA3 as a promising predictive biomarker for bevacizumab resistance in CRC, offering a potential solution to the longstanding challenge of treatment stratification.
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Affiliation(s)
- Juncheng Su
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jiahui Wang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weilin Chen
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yingjie Xu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wen Yang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiwei Liu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Masha Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Ruzzo A, Graziano F, Palladino S, Fischer NW, Catalano V, Giordani P, Malkin D, Tamburrano T, Patriti A, Petrelli F, Sarti D, Chiari R. Clinical impact of TP53 functional mutations in patients with metastatic colorectal cancer treated with bevacizumab and chemotherapy. Oncologist 2025; 30:oyae277. [PMID: 39436921 PMCID: PMC11954512 DOI: 10.1093/oncolo/oyae277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Clinical and experimental studies indicate that the tumor protein p53 (TP53) gene loss of function due to missense mutations (MMs) may confer sensitivity to anti-angiogenics. This effect seems to be linked to cross-talk mechanisms among TP53, vascular endothelial growth factor (VEGF), and VEGF receptors. We investigated whether specific TP53 MMs are associated with clinical outcomes of patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy plus Bevacizumab. The study focused on KRAS-mutated, liver-only mCRC cases as a homogeneous subgroup that may represent a relevant setting for exploring this association. MATERIALS AND METHODS MMs were identified on primary tumors. MMs were classified by mutant-specific residual transcriptional activity scores (TP53RTAS) as transcriptionally inactive (TP53inactive = TP53RTAS 0%) or active (TP53active = TP53RTAS ≥ 1%) and used for stratifying patients in progression-free survival (PFS), response rate, and overall survival (OS) analyses. RESULTS The study population consisted of 62 patients. MMs were found in 39 cases (62%) with 16 having TP53inactive and 23 TP53active MMs. Patients with TP53inactive MMs showed better PFS in comparison with the remaining groups (wild-type and TP53active). This effect was retained in the multivariate model. A similar clinical impact was observed in the OS analysis. There was a significant difference in the overall response rate and rate of post-treatment resection of liver metastases between the TP53inactive and the wild-type or TP53active MMs cases. CONCLUSIONS Specific TP53 MMs may identify sub-groups of patients who benefit from Bevacizumab-based systemic therapy and these findings could lead to novel tailored treatment strategies in this setting.
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Affiliation(s)
- Annamaria Ruzzo
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy
| | | | - Silvia Palladino
- Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy
| | - Nicholas W Fischer
- Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, M5G 0A4, Canada
| | | | | | - David Malkin
- Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, M5G 0A4, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 0A4, Canada
- Division of Hematology-Oncology, The Hospital for Sick Children, Toronto, M5G 0A4, Canada
- Department of Pediatrics, The Hospital for Sick Children, Toronto, M5G 0A4, Canada
| | | | | | | | | | - Rita Chiari
- Medical Oncology Unit, AST1, 61121 Pesaro, Italy
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Piercey O, Chantrill L, Hsu H, Ma B, Price T, Tan IB, Teng H, Tie J, Desai J. Expert consensus on the optimal management of BRAF V600E-mutant metastatic colorectal cancer in the Asia-Pacific region. Asia Pac J Clin Oncol 2025; 21:31-45. [PMID: 39456063 PMCID: PMC11733838 DOI: 10.1111/ajco.14132] [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: 05/15/2024] [Revised: 09/14/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024]
Abstract
The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.
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Affiliation(s)
| | - Lorraine Chantrill
- Illawarra Shoalhaven Local Health DistrictIllawarraNew South WalesAustralia
- Faculty of Science, Medicine and HealthUniversity of WollongongWollongongNew South WalesAustralia
| | - Hung‐Chih Hsu
- Division of Hematology OncologyChang Gung Memorial HospitalNew TaipeiTaiwan
- College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Brigette Ma
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer InstituteThe Chinese University of Hong KongHong Kong SARChina
| | - Timothy Price
- The Queen Elizabeth HospitalAdelaideSouth AustraliaAustralia
| | - Iain Beehuat Tan
- Division of Medical OncologyNational Cancer Centre SingaporeSingaporeSingapore
| | - Hao‐Wei Teng
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Jeanne Tie
- Peter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVictoriaAustralia
| | - Jayesh Desai
- Peter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVictoriaAustralia
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Piercey O, Tie J, Hollande F, Wong HL, Mariadason J, Desai J. BRAF V600E-Mutant Metastatic Colorectal Cancer: Current Evidence, Future Directions, and Research Priorities. Clin Colorectal Cancer 2024; 23:215-229. [PMID: 38816264 DOI: 10.1016/j.clcc.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 04/24/2024] [Indexed: 06/01/2024]
Abstract
BRAFV600E-mutant metastatic colorectal cancer represents a distinct molecular phenotype known for its aggressive biological behavior, resistance to standard therapies, and poor survival rates. Improved understanding of the biology of the BRAF oncogene has led to the development of targeted therapies that have paved the way for a paradigm shift in managing this disease. However, despite significant recent advancements, responses to targeted therapies are short-lived, and several challenges remain. In this review, we discuss how progress in treating BRAFV600E-mutant metastatic colorectal cancer has been made through a better understanding of its unique biological and clinical features. We provide an overview of the evidence to support current treatment approaches and discuss critical areas of need and future research strategies that hold the potential to refine clinical practice further. We also discuss some challenging aspects of managing this disease, particularly the complexity of acquired resistance mechanisms that develop under the selective pressure of targeted therapies and rational strategies being investigated to overcome them.
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Affiliation(s)
- Oliver Piercey
- Peter MacCallum Cancer Centre, Melbourne, Australia; Centre for Cancer Research, The University of Melbourne, Melbourne, Australia; Department of Clinical Pathology, The University of Melbourne, Australia.
| | - Jeanne Tie
- Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | - Frederic Hollande
- Centre for Cancer Research, The University of Melbourne, Melbourne, Australia; Department of Clinical Pathology, The University of Melbourne, Australia
| | - Hui-Li Wong
- Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | - John Mariadason
- Olivia Newton John Cancer Wellness and Research Centre, Heidelberg, Australia; School of Medicine, La Trobe University, Melbourne, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
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Gu R, Fang H, Wang R, Dai W, Cai G. A comprehensive overview of the molecular features and therapeutic targets in BRAF V600E-mutant colorectal cancer. Clin Transl Med 2024; 14:e1764. [PMID: 39073010 PMCID: PMC11283586 DOI: 10.1002/ctm2.1764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/23/2024] [Accepted: 07/03/2024] [Indexed: 07/30/2024] Open
Abstract
As one of the most prevalent digestive system tumours, colorectal cancer (CRC) poses a significant threat to global human health. With the emergence of immunotherapy and target therapy, the prognosis for the majority of CRC patients has notably improved. However, the subset of patients with BRAF exon 15 p.V600E mutation (BRAFV600E) has not experienced remarkable benefits from these therapeutic advancements. Hence, researchers have undertaken foundational investigations into the molecular pathology of this specific subtype and clinical effectiveness of diverse therapeutic drug combinations. This review comprehensively summarised the distinctive molecular features and recent clinical research advancements in BRAF-mutant CRC. To explore potential therapeutic targets, this article conducted a systematic review of ongoing clinical trials involving patients with BRAFV600E-mutant CRC.
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Affiliation(s)
- Ruiqi Gu
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Hongsheng Fang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Renjie Wang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Weixing Dai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Guoxiang Cai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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Latimer NR, Dewdney A, Campioni M. A cautionary tale: an evaluation of the performance of treatment switching adjustment methods in a real world case study. BMC Med Res Methodol 2024; 24:17. [PMID: 38253996 PMCID: PMC10802004 DOI: 10.1186/s12874-024-02140-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Treatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval [CI] 0.82-1.22) for all patients, and 0.99 (95% CI 0.75-1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus). METHODS We tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76-0.77 (95% CI 0.60-0.98) for all patients, and 0.55-0.73 (95% CI 0.41-0.93) for patients with wild-type KRAS. RESULTS Some applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals. CONCLUSIONS Adjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.
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Affiliation(s)
- Nicholas R Latimer
- Sheffield Centre for Health and Related Research (SCHARR), University of Sheffield, Regent Court, 30 Regent Street, Sheffield, South Yorkshire, S1 4DA, UK.
- Delta Hat Limited, Nottingham, UK.
| | - Alice Dewdney
- Weston Park Cancer Centre, Sheffield Teaching Hospital, Sheffield, UK
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Ros J, Rodríguez-Castells M, Saoudi N, Baraibar I, Salva F, Tabernero J, Élez E. Treatment of BRAF-V600E mutant metastatic colorectal cancer: new insights and biomarkers. Expert Rev Anticancer Ther 2023; 23:797-806. [PMID: 37482749 DOI: 10.1080/14737140.2023.2236794] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/11/2023] [Indexed: 07/25/2023]
Abstract
INTRODUCTION The presence of a BRAF-V600E mutation in metastatic colorectal cancer (mCRC) is observed in approximately 12% of cases and is associated with poor prognosis and aggressive disease. Unlike melanoma, the development of successful BRAF blockade in colorectal cancer has been complex. The phase III BEACON trial made significant progress in the development of BRAF inhibitors by establishing encorafenib-cetuximab as the new standard of care for patients with mCRC who have progressed to one or two previous lines of treatment. Nonetheless, not all patients respond to encorafenib-based combinations, and some responses are short-lived. Identifying new strategies to boost antitumor activity and improve survival is paramount. AREAS COVERED The development of targeted therapy for BRAF-V600E mCRC starting with BRAF inhibitors as monotherapy through novel combinations with anti-VEGF or anti-PD1 agents to enhance antitumor activity is reviewed, with a particular focus on the development of predictive and prognostic biomarkers. EXPERT OPINION There is a crucial need to better understand tumor biology and develop accurate and reliable biomarkers to enhance the antitumor activity of encorafenib-based combinations. The RNF43 mutation is an accurate and reliable predictive biomarker of response, and combinations that target crosstalk between the MAPK pathway, the immune system, and WNT pathways seem promising.
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Affiliation(s)
- Javier Ros
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Marta Rodríguez-Castells
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Nadia Saoudi
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Iosune Baraibar
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Francesc Salva
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Josep Tabernero
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Elena Élez
- Vall d'Hebron University Hospital, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain
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Sasaki K, Takahashi S, Ouchi K, Otsuki Y, Wakayama S, Ishioka C. Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types. Sci Rep 2023; 13:4868. [PMID: 36964217 PMCID: PMC10039000 DOI: 10.1038/s41598-023-32092-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/22/2023] [Indexed: 03/26/2023] Open
Abstract
Functional properties caused by TP53 mutations are involved in cancer development and progression. Although most of the mutations lose normal p53 functions, some of them, gain-of-function (GOF) mutations, exhibiting novel oncogenic functions. No reports have analyzed the impact of TP53 mutations on the gene expression profile of the p53 signaling pathway across cancer types. This study is a cross-cancer type analysis of the effects of TP53 mutations on gene expression. A hierarchical cluster analysis of the expression profile of the p53 signaling pathway classified 21 cancer types into two clusters (A1 and A2). Changes in the expression of cell cycle-related genes and MKI67 by TP53 mutations were greater in cluster A1 than in cluster A2. There was no distinct difference in the effects between GOF and non-GOF mutations on the gene expression profile of the p53 signaling pathway.
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Affiliation(s)
- Keiju Sasaki
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Shin Takahashi
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Kota Ouchi
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Yasufumi Otsuki
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Shonosuke Wakayama
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Chikashi Ishioka
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan.
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
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Martinelli E, Cremolini C, Mazard T, Vidal J, Virchow I, Tougeron D, Cuyle PJ, Chibaudel B, Kim S, Ghanem I, Asselain B, Castagné C, Zkik A, Khan S, Arnold D. Real-world first-line treatment of patients with BRAF V600E-mutant metastatic colorectal cancer: the CAPSTAN CRC study. ESMO Open 2022; 7:100603. [PMID: 36368253 PMCID: PMC9832736 DOI: 10.1016/j.esmoop.2022.100603] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND BRAFV600E mutations occur in 8%-12% of metastatic colorectal cancer (mCRC) cases and are associated with poor survival. European guidelines recommend combination (doublet or triplet) chemotherapy plus bevacizumab in first line. However, an unmet need remains for more effective treatments for these patients. PATIENTS AND METHODS CAPSTAN CRC is a European, retrospective, multicenter, observational study evaluating real-world treatment practices for patients with BRAFV600E-mutant mCRC treated between 1 January 2016 and 31 January 2020. The primary objective was to describe first-line treatment patterns. Secondary objectives included describing baseline demographics, mutational testing procedures, treatment effectiveness, and safety. RESULTS In total, 255 patients (median age 66.0 years; 58.4% female) with BRAFV600E-mutant unresectable mCRC from seven countries were included. Most had right-sided tumors (52.5%) and presented with synchronous disease at diagnosis (66.4%). Chemotherapy plus targeted therapy (68.7%) was preferred at first line over chemotherapy alone (31.3%). The main first-line treatments were FOLFOX plus bevacizumab (27.1%) and FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) with/without bevacizumab (27.1%/19.2%). Median duration of first-line treatment was 4.9 months. Overall, 52.5% received second-line treatment. Across all first-line regimens, progression-free survival (PFS) and overall survival were 6.0 [95% confidence interval (CI) 5.3-6.7] months and 12.9 (95% CI 11.6-14.1) months, respectively. Triplet plus targeted therapy was associated with more adverse events (75.0%) compared with triplet chemotherapy alone (50.0%) and doublet chemotherapy alone (36.1%). Multivariate analysis identified low body mass index and presence of three or more metastatic sites as significant prognostic factors for PFS. CONCLUSIONS This study is, to date, the largest real-world analysis of patients with BRAFV600E-mutant mCRC, providing valuable insights into routine first-line treatment practices for these patients. The data highlight the intrinsic aggressiveness of this disease subgroup, confirming results from previous real-world studies and clinical trials, and stressing the urgent need for more effective treatment options in this setting.
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Affiliation(s)
- E Martinelli
- Medical Oncology, Department of Precision Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy.
| | - C Cremolini
- Oncologia Medica, University of Pisa, Pisa, Italy
| | - T Mazard
- Institut de Recherche en Cancerologie de Montpellier, INSERM, Montpellier University, Institut du Cancer de Montpellier, Montpellier, France
| | - J Vidal
- Department of Medical Oncology, Hospital del Mar - IMIM, CIBERONC, Barcelona, Spain
| | - I Virchow
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - D Tougeron
- Department of Hepato-gastroenterology, Poitiers University Hospital and University of Poitiers, Poitiers, France
| | - P-J Cuyle
- Gastroenterology and Digestive Oncology Department, Imelda General Hospital, Bonheiden, Belgium
| | - B Chibaudel
- Department of Medical Oncology, Hôpital Franco-Britannique - Fondation Cognacq-Jay, Levallois-Perret, France
| | - S Kim
- Department of Medical Oncology, Centre Hospitalier Régional et Universitaire de Besançon, Besançon, France
| | - I Ghanem
- Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain
| | | | - C Castagné
- Pierre Fabre, Boulogne-Billancourt, France
| | - A Zkik
- Pierre Fabre, Boulogne-Billancourt, France
| | - S Khan
- Pierre Fabre, Boulogne-Billancourt, France
| | - D Arnold
- Asklepios Tumorzentrum Hamburg AK Altona, Hamburg, Germany
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Eskandarion MR, Tizmaghz Z, Andalib B, Parsa N, Emami SAH, Shahsiah R, Oghabian MA, Shirkoohi R. A case report of the sustained and rapid response of bevacizumab in a TP53-positive breast cancer and liver metastatic patient through personalized medicine. Front Oncol 2022; 12:940678. [PMID: 36119510 PMCID: PMC9479335 DOI: 10.3389/fonc.2022.940678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/08/2022] [Indexed: 11/28/2022] Open
Abstract
HER2-positive metastatic breast cancer is much less frequent than other subgroups of breast cancer. Treatment options for this cancer are mostly limited to systemic chemotherapy, which leads to moderate improvements. Targeted therapy against malignant breast cancer requires the identification of reliable biomarkers for personalized medicine to obtain the maximum benefit of this therapy. Any mutations in the TP53 signaling pathway can be considered as a significant causative factor of breast cancer, for which the identification of target genes plays an important role in selecting the appropriate treatment. The use of personalized gene expression profiling could be valuable to find the direct target of the treatment in this case. The present study assessed the genetic profile of an HER2-positive metastatic breast cancer patient (with a liver metastasis) and figured out a complete and sustained response to bevacizumab. According to the results of next-generation sequencing (NGS) analysis, the patient’s genetic profile showed an increased expression of p4EBP1 and PTEN and the activation of the mTOR signaling pathway with a mutation in the TP53 gene. Based on the common treatment of similar profiling, we administrated bevacizumab/Taxol/Gemzar chemotherapy up to six courses. Accordingly, as the response to treatment was revealed by reducing the volume of the liver metastasis from 4 to 1.4 cm, metastasectomy was performed as a complementary treatment. Hence, personalized gene expression profiling not only is useful for targeted therapy but also could be recommended to avoid prescription of non-responsive drugs.
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Affiliation(s)
- Mohammad Reza Eskandarion
- Cancer Research Center, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Tizmaghz
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Radiation Oncology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahram Andalib
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Radiation Oncology Central Clinic of Karaj (ROCK), Karaj, Iran
- *Correspondence: Reza Shirkoohi, ; Bahram Andalib,
| | - Nasser Parsa
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Iranian Cancer Association, Tehran, Iran
| | - Seyed Amir Hossein Emami
- Cancer Research Center, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Hematology and Medical Oncology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shahsiah
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Department of Anatomical and Clinical Pathology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Oghabian
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Medical Physics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shirkoohi
- Cancer Research Center, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- BESTforPM (Biomarker Evaluation and Supervision Team for Personalized Medicine), Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Reza Shirkoohi, ; Bahram Andalib,
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11
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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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12
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Qin BD, Jiao XD, Wang Y, Wu Y, Ling Y, Liu K, Zang YS. Effect of smoking habits on the efficacy of EGFR-TKI plus anti-angiogenic agent in advanced EGFR-mutant NSCLC. Lung Cancer 2022; 170:91-97. [PMID: 35728482 DOI: 10.1016/j.lungcan.2022.06.006] [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: 03/04/2022] [Revised: 05/20/2022] [Accepted: 06/08/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND The types of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients who could obtain significant clinical benefit from the dual inhibition of EGFR/vascular EGFR (VEGFR) pathways remain unclear. No consensus has been reached on the significance of smoking habits in clinical benefit obtained from EGFR-TKI plus anti-angiogenic agents. METHODS PubMed, EMBASE, and Cochrane databases for all phase II/III randomized clinical trials (RCTs) investigating the efficacy of EGFR-TKI combined with anti-angiogenic agents stratified by smoking habits (updated October 2021) were searched systematically. The primary outcomes were the pooled HRs for PFS/OS in smokers and non-smokers, and differences in efficacy of EGFR-TKI plus anti-angiogenic treatment between smokers and non-smokers, measured by difference in PFS and OS. RESULTS Seven phase II/III RCTs involving 1452 patients were identified. The pooled analysis demonstrated that EGFR-TKI plus anti-angiogenic agent could decrease the risk of progression by 40% (HR, 0.60; 95%CI 0.48-0.75) in smokers when compared with EGFR-TKI alone, but not in non-smokers (HR, 0.92; 95%CI 0.68-1.25). The comparison analysis further demonstrated that EGFR-mutated NSCLC patients who smoked obtained greater progression-free survival (PFS) benefit from treatment with EGFR-TKI plus anti-angiogenic agents (HR, 0.68; 95%CI 0.51-0.91). Consistent with the results for PFS, smokers receiving EGFR-TKI plus anti-angiogenic agents appeared to exhibit better overall survival (OS) than non-smokers but not to a statistically significant degree (HR, 0.60; 95%CI 0.23-1.52). Meta-regression analysis revealed no significant effect of the line of treatment (P = 0.52), trial phase (P = 0.52), EGFR-TKI type (P = 0.13), or anti-angiogenic agent type (P = 0.50) on PFS effect sizes under multivariate models. CONCLUSION Comprehensive analysis suggested that EGFR-TKI plus anti-angiogenic agents led to favorable PFS among smoking EGFR-mutant patients, comparable to nonsmokers, which might provide a useful guide for clinicians.
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Affiliation(s)
- Bao-Dong Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xiao-Dong Jiao
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yan Wang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Ying Wu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yan Ling
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Ke Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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13
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Cohen R, Liu H, Fiskum J, Adams R, Chibaudel B, Maughan TS, Van Cutsem E, Venook A, Douillard JY, Heinemann V, Punt CJ, Falcone A, Bokemeyer C, Kaplan R, Lenz HJ, Koopman M, Yoshino T, Zalcberg J, Grothey A, de Gramont A, Shi Q, André T. BRAF V600E Mutation in First-Line Metastatic Colorectal Cancer: An Analysis of Individual Patient Data From the ARCAD Database. J Natl Cancer Inst 2021; 113:1386-1395. [PMID: 33734401 PMCID: PMC7617278 DOI: 10.1093/jnci/djab042] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/06/2021] [Accepted: 03/15/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. METHODS Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. RESULTS A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). CONCLUSIONS Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.
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Affiliation(s)
- Romain Cohen
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
- Department of Medical Oncology, Sorbonne University, Saint-Antoine Hospital, Paris, France
| | - Heshan Liu
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Jack Fiskum
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, UK
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Timothy S. Maughan
- Cancer Research UK and the Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UK
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and University of Leuven, Belgium
| | - Alan Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany
| | - Cornelis Ja Punt
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Carsten Bokemeyer
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard Kaplan
- Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Heinz-Josef Lenz
- Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | | | | | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Qian Shi
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Thierry André
- Department of Medical Oncology, Sorbonne University, Saint-Antoine Hospital, Paris, France
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14
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Beypinar I, Demir H, Sakin A, Taskoylu BY, Sakalar T, Ergun Y, Korkmaz M, Ates O, Eren T, Turhal S, Artac M. The Real-Life Data of BRAF Mutation on the Treatment of Colorectal Cancer: a TOG Study. J Gastrointest Cancer 2021; 52:932-939. [PMID: 32914373 DOI: 10.1007/s12029-020-00514-9] [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] [Indexed: 10/23/2022]
Abstract
PURPOSE Colorectal cancer is the third leading diagnosis accounting for nearly 10% of all new cancers worldwide. The distinct features among BRAF mutant colorectal cancers make these tumor groups hard to treat for oncologists. The median overall survival (OS) of these types of cancers is reported to be 9 to 14 months. METHODS The study was declared on the Turkish Oncology Study Group Conference and approved. The patients' data was received from the centers who confirmed to participate. The BRAF-mutated patients were included in the study. The demographic features (age, gender, etc.), type of mutation, tumor localizations, histology, microsatellite instability (MSI) status, metastasis patterns chemotherapeutic agents and progression, and death times were recorded. RESULTS Thirty-nine patients were enrolled in the study. Sixteen patients had concurrent KRAS mutations, while 7 had NRAS mutations. Most of the patients received doublet chemotherapies in combination with anti-VEGF agents in the first and second line of the treatment. There was a significant difference in OS according to the stage which showed a decreased survival in stage IV patients at the time of diagnosis. Concurrent KRAS mutation resulted in increased OS. The median OS was 47 and 24 months favoring the KRAS mutant group. The patients whose primary tumor operated had better survival when compared with other patients. The median OS of the operated group was 47 months, while the non-operated group was 24 months. Liver metastasis was related to worse prognosis at the time of diagnosis in univariate analysis. CONCLUSION In our study we found a high concurrent RAS mutation ratio in a BRAF mutant patient group which was different from prior studies. The concurrent mutations resulted in a favorable outcome in terms of OS which is also different from the current knowledge. More prospective studies are needed especially BRAF-mutated patient population and especially with concurrent RAS mutations.
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Affiliation(s)
- Ismail Beypinar
- Department of Medical Oncology, Eskişehir City Hospital, Eskişehir, Turkey.
| | - Hacer Demir
- Department of Medical Oncology, Afyonkarahisar Health Sciences University, Afyon, Turkey
| | - Abdullah Sakin
- Department of Medical Oncology, Yüzüncü Yıl University, Van, Turkey
| | | | - Teoman Sakalar
- Department of Medical Oncology, Kahramanmaraş Necip Fazıl City Hospital, Kahramanmaraş, Turkey
| | - Yakup Ergun
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Mustafa Korkmaz
- Meram Medicine Faculty, Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey
| | - Ozturk Ates
- Department of Medical Oncology, Abdurrahman Yurtaslan Training and Research Hospital, Ankara, Turkey
| | - Tulay Eren
- Training and Research Hospital, Dışkapı Training and Research Hospital, Ankara, Turkey
| | - Serdar Turhal
- Department of Medical Oncology, Anadolu Health Center, Istanbul, Turkey
| | - Mehmet Artac
- Meram Medicine Faculty, Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey
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15
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Truelsen SLB, Mousavi N, Wei H, Harvey L, Stausholm R, Spillum E, Hagel G, Qvortrup K, Thastrup O, Harling H, Mellor H, Thastrup J. The cancer angiogenesis co-culture assay: In vitro quantification of the angiogenic potential of tumoroids. PLoS One 2021; 16:e0253258. [PMID: 34234354 PMCID: PMC8263287 DOI: 10.1371/journal.pone.0253258] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 06/01/2021] [Indexed: 01/07/2023] Open
Abstract
The treatment response to anti-angiogenic agents varies among cancer patients and predictive biomarkers are needed to identify patients with resistant cancer or guide the choice of anti-angiogenic treatment. We present “the Cancer Angiogenesis Co-Culture (CACC) assay”, an in vitro Functional Precision Medicine assay which enables the study of tumouroid induced angiogenesis. This assay can quantify the ability of a patient-derived tumouroid to induce vascularization by measuring the induction of tube formation in a co-culture of vascular cells and tumoroids established from the primary colorectal tumour or a metastasis. Furthermore, the assay can quantify the sensitivity of patient-derived tumoroids to anti-angiogenic therapies. We observed that tube formation increased in a dose-dependent manner upon treatment with the pro-angiogenic factor vascular endothelial growth factor A (VEGF-A). When investigating the angiogenic potential of tumoroids from 12 patients we found that 9 tumoroid cultures induced a significant increase in tube formation compared to controls without tumoroids. In these 9 angiogenic tumoroid cultures the tube formation could be abolished by treatment with one or more of the investigated anti-angiogenic agents. The 3 non-angiogenic tumoroid cultures secreted VEGF-A but we observed no correlation between the amount of tube formation and tumoroid-secreted VEGF-A. Our data suggests that the CACC assay recapitulates the complexity of tumour angiogenesis, and when clinically verified, could prove a valuable tool to quantify sensitivity towards different anti-angiogenic agents.
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Affiliation(s)
| | - Nabi Mousavi
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Haoche Wei
- School of Biochemistry, University of Bristol, Bristol, United Kingdom
| | - Lucy Harvey
- School of Biochemistry, University of Bristol, Bristol, United Kingdom
| | | | | | | | - Klaus Qvortrup
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Henrik Harling
- 2cureX, Symbion, Copenhagen, Denmark
- Department of Digestive Diseases, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Harry Mellor
- School of Biochemistry, University of Bristol, Bristol, United Kingdom
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16
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Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers (Basel) 2021; 13:2296. [PMID: 34064974 PMCID: PMC8150459 DOI: 10.3390/cancers13102296] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.
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Affiliation(s)
- Maurice Michel
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, 55131 Mainz, Germany
| | - Annett Maderer
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Peter R. Galle
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Markus Moehler
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
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17
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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: 127] [Impact Index Per Article: 31.8] [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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18
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Takeda H, Sunakawa Y. Management of BRAF Gene Alterations in Metastatic Colorectal Cancer: From Current Therapeutic Strategies to Future Perspectives. Front Oncol 2021; 11:602194. [PMID: 33842313 PMCID: PMC8027060 DOI: 10.3389/fonc.2021.602194] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 03/09/2021] [Indexed: 12/24/2022] Open
Abstract
BRAF mutations constitute an important poor prognostic factor in metastatic colorectal cancer (mCRC) and the development of treatments in this context is of great necessity to prolong patient survival. Although the association between BRAF mutations and microsatellite instability (MSI) has been known for several years, previous clinical trials have revealed that the former has a limited prognostic impact and that immune checkpoint inhibitors offer a significant survival benefit to mCRC patients with both characteristics. Furthermore, the genomic classification of BRAF mutations according to their molecular functions enables greater understanding of the characteristics of mCRC patients with BRAF mutations, with therapeutic strategies based on this classification made more ideal to improve poor prognosis through the delivery of targeted therapies. Recently, a phase III trial was conducted in previously treated mCRC patients with BRAF V600E-mutated tumors and revealed that the combination therapy approach of BRAF inhibition and anti-epidermal growth factor receptor antibody therapy with or without MEK inhibition was more efficacious than standard chemotherapy alone. This review discusses current treatment strategies and future perspectives in BRAF-mutated mCRC.
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Affiliation(s)
| | - Yu Sunakawa
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan
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19
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Mauri G, Bonazzina E, Amatu A, Tosi F, Bencardino K, Gori V, Massihnia D, Cipani T, Spina F, Ghezzi S, Siena S, Sartore-Bianchi A. The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer. Cancers (Basel) 2021; 13:E137. [PMID: 33406649 PMCID: PMC7795863 DOI: 10.3390/cancers13010137] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 12/20/2022] Open
Abstract
The BRAFV600E mutation is found in 8-10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.
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Affiliation(s)
- Gianluca Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Erica Bonazzina
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Viviana Gori
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Daniela Massihnia
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Tiziana Cipani
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Francesco Spina
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Silvia Ghezzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; (G.M.); (E.B.); (A.A.); (F.T.); (K.B.); (V.G.); (D.M.); (T.C.); (F.S.); (S.G.); (S.S.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
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20
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Novel Genetic and Epigenetic Biomarkers of Prognostic and Predictive Significance in Stage II/III Colorectal Cancer. Mol Ther 2020; 29:587-596. [PMID: 33333293 DOI: 10.1016/j.ymthe.2020.12.017] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/15/2020] [Accepted: 12/09/2020] [Indexed: 12/18/2022] Open
Abstract
The therapeutic strategies of stage II/III colorectal cancer (CRC) patients after curative surgery remain controversial. In the clinical decision-making process, oncologists need to answer questions such as whether adjuvant chemotherapy is necessary or which therapeutic regimen should be given to each patient. At present, whether adjuvant chemotherapy should be applied is primarily based on histopathological features and clinical risk factors. However, only a fraction of patients can benefit from it. More rigorous stratifying biomarkers are urgently needed to help further distinguishing these populations of patients. Recent progress in next-generation sequencing and high-throughput technologies has greatly promoted biomarker discovery as well as our understanding of the underlying mechanisms in CRC. Novel genetic and epigenetic biomarkers that are associated with prognosis or therapeutic responses have emerged. In this review, we discuss the strategies of biomarker discovery and summarize the status and assess the utility of previously published biomarkers in CRC.
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21
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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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22
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Molina-Cerrillo J, San Román M, Pozas J, Alonso-Gordoa T, Pozas M, Conde E, Rosas M, Grande E, García-Bermejo ML, Carrato A. BRAF Mutated Colorectal Cancer: New Treatment Approaches. Cancers (Basel) 2020; 12:cancers12061571. [PMID: 32545884 PMCID: PMC7353017 DOI: 10.3390/cancers12061571] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022] Open
Abstract
Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.
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Affiliation(s)
- Javier Molina-Cerrillo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
- Correspondence: or
| | - María San Román
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Javier Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
| | - Miguel Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Elisa Conde
- Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain; (E.C.); (M.L.G.-B.)
| | - Marta Rosas
- Pathology department, University Hospital Ramon y Cajal, 28034 Madrid, Spain;
| | - Enrique Grande
- Department of Medical Oncology, MD Anderson Cancer Center, 28033 Madrid, Spain;
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain; (E.C.); (M.L.G.-B.)
| | - Alfredo Carrato
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
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23
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The Role of Anti-Angiogenics in Pre-Treated Metastatic BRAF-Mutant Colorectal Cancer: A Pooled Analysis. Cancers (Basel) 2020; 12:cancers12041022. [PMID: 32326305 PMCID: PMC7226019 DOI: 10.3390/cancers12041022] [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: 03/25/2020] [Revised: 04/10/2020] [Accepted: 04/20/2020] [Indexed: 12/22/2022] Open
Abstract
Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF-mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF-mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results. Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29-0.85) (p = 0.01). Conclusions. Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF-mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option.
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24
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Lau DK, Burge M, Roy A, Chau I, Haller DG, Shapiro JD, Peeters M, Pavlakis N, Karapetis CS, Tebbutt NC, Segelov E, Price TJ. Update on optimal treatment for metastatic colorectal cancer from the AGITG expert meeting: ESMO congress 2019. Expert Rev Anticancer Ther 2020; 20:251-270. [PMID: 32186929 DOI: 10.1080/14737140.2020.1744439] [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] [Indexed: 02/07/2023]
Abstract
Introduction: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype.Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping.Expert opinion: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended RAS wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor RAS, BRAF, HER2 and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with KRAS G12 C mutation and gene TRK fusion defects.
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Affiliation(s)
- David K Lau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | - Matthew Burge
- Medical Oncology, Royal Brisbane Hospital, Brisbane, Australia.,University of Queensland, Brisbane, Australia
| | - Amitesh Roy
- Medical Oncology, Flinders Centre for Innovation in Cancer, Bedford Park, Australia
| | - Ian Chau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | - Daniel G Haller
- Abramson Cancer Center at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeremy D Shapiro
- Monash University, Melbourne, Australia.,Medical Oncology, Cabrini Medical Centre, Melbourne, Australia
| | - Marc Peeters
- Medical Oncology, University Hospital Antwerp, Edegem, Belgium
| | - Nick Pavlakis
- Medical Oncology, Royal North Shore Hospital, St Leonards, Australia.,Sydney University, Camperdown, Sydney, Australia
| | | | - Niall C Tebbutt
- Medical Oncology, Austin Health, Heidelberg, Australia.,Department of Surgery, University of Melbourne, Melbourne, Australia
| | - Eva Segelov
- Monash University, Melbourne, Australia.,Medical Oncology, Monash Medical Centre, Clayton, Australia
| | - Timothy J Price
- Medical Oncology, The Queen Elizabeth Hospital, Woodville, Australia
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25
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Xie H, Lafky JM, Morlan BW, Stella PJ, Dakhil SR, Gross GG, Loui WS, Hubbard JM, Alberts SR, Grothey A. Dual VEGF inhibition with sorafenib and bevacizumab as salvage therapy in metastatic colorectal cancer: results of the phase II North Central Cancer Treatment Group study N054C (Alliance). Ther Adv Med Oncol 2020; 12:1758835920910913. [PMID: 32201506 PMCID: PMC7066587 DOI: 10.1177/1758835920910913] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 01/20/2020] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. METHODS mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1-5 and 8-12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. RESULTS Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progression-free at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). CONCLUSIONS The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity. CLINICALTRIALSGOV IDENTIFIER NCT00826540, URL:http://clinicaltrials.gov/ct2/show/NCT00826540.
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Affiliation(s)
- Hao Xie
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Jacqueline M. Lafky
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA Department of Biostatistics, Mayo Clinic, Rochester, MN, USA
| | - Bruce W. Morlan
- Department of Biostatistics, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | | | | | - Axel Grothey
- Medical Oncology, West Cancer Center, 9745 Wolf River Blvd, Germantown, TN 38138-1762, USA
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26
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Fridman WH, Miller I, Sautès-Fridman C, Byrne AT. Therapeutic Targeting of the Colorectal Tumor Stroma. Gastroenterology 2020; 158:303-321. [PMID: 31622621 DOI: 10.1053/j.gastro.2019.09.045] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 09/05/2019] [Accepted: 09/08/2019] [Indexed: 02/07/2023]
Abstract
Colorectal tumors have been classified based on histologic factors, genetic factors, and consensus molecular subtypes, all of which affect the tumor microenvironment. Elements of the tumor microenvironment serve as therapeutic targets and might be used as prognostic factors. For example, immune checkpoint inhibitors are used to treat tumors with microsatellite instability, and anti-angiogenic agents may be used in combination with other drugs to slow or inhibit tumor growth. We review the features of the colorectal tumor stroma that are associated with patient outcomes and discuss potential therapeutic agents that target these features.
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Affiliation(s)
- Wolf H Fridman
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Inflammation, Complement and Cancer Team, Paris, France.
| | - Ian Miller
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Catherine Sautès-Fridman
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Inflammation, Complement and Cancer Team, Paris, France
| | - Annette T Byrne
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
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27
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Udar N, Iyer A, Porter M, Haigis R, Smith S, Dhillon S, Meier K, Ward D, Lu J, Wenz P, Buchner L, Dunn T, Wise A, Mueller A, Gutekunst K. Development and Analytical Validation of a DNA Dual-Strand Approach for the US Food and Drug Administration-Approved Next-Generation Sequencing-Based Praxis Extended RAS Panel for Metastatic Colorectal Cancer Samples. J Mol Diagn 2019; 22:159-178. [PMID: 31837434 DOI: 10.1016/j.jmoldx.2019.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 09/03/2019] [Accepted: 09/27/2019] [Indexed: 12/28/2022] Open
Abstract
A next-generation sequencing method was developed that can distinguish single-stranded modifications from low-frequency somatic mutations present on both strands of DNA in formalin-fixed paraffin-embedded colorectal cancer samples. We applied this method for analytical validation of the Praxis Extended RAS Panel, a US Food and Drug Administration-approved companion diagnostic for panitumumab, on the Illumina MiSeqDx platform. With the use of the TruSeq amplicon workflow, both strands of DNA from the starting material were interrogated independently. Mutations were reported only if found on both strands; artifacts usually present on only one strand would not be reported. A total of 56 mutations were targeted within the KRAS and NRAS genes. A minimum read depth of 1800× per amplicon is required per sample but averaged >30,000× at maximum multiplexing levels. Analytical validation studies were performed to determine the simultaneous detection of mutations on both strands, reproducibility, assay detection level, precision of the assay across various factors, and the impact of interfering substances. In conclusion, this assay can clearly distinguish single-stranded artifacts from low-frequency mutations. Furthermore, the assay is accurate, precise, and reproducible, can achieve consistent detection of a mutation at 5% mutation frequency, exhibits minimal impact from tested interfering substances, and can simultaneously detect 56 mutations in a single run using 10 samples plus controls.
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Affiliation(s)
- Nitin Udar
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California
| | - Anita Iyer
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California.
| | - Margaret Porter
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California
| | - Robert Haigis
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California
| | - Shannon Smith
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California
| | - Shivani Dhillon
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California
| | - Kristen Meier
- Department of Biostatistics, Illumina, Inc., San Diego, California
| | - Diane Ward
- Department of Biostatistics, Illumina, Inc., San Diego, California
| | - Jing Lu
- Department of Biostatistics, Illumina, Inc., San Diego, California
| | - Paul Wenz
- Department of Biostatistics, Illumina, Inc., San Diego, California
| | - Leonard Buchner
- Department of Biostatistics, Illumina, Inc., San Diego, California
| | - Tamsen Dunn
- Department of Bioinformatics, Illumina, Inc., San Diego, California
| | - Aaron Wise
- Department of Bioinformatics, Illumina, Inc., San Diego, California
| | - Amy Mueller
- Department of Medical Affairs, Illumina, Inc., San Diego, California
| | - Karen Gutekunst
- Department of Clinical Genomics Assay Development and Oncology, Illumina, Inc., San Diego, California
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28
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Liang X, Shen J. Impact of KRAS mutation status on outcomes of metastatic colorectal cancer treated with anti-angiogenic agents: a meta-analysis. J Chemother 2019; 32:41-48. [PMID: 31838964 DOI: 10.1080/1120009x.2019.1692282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Xiaojun Liang
- Department of ICU, Jinshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Jie Shen
- Department of ICU, Jinshan Hospital Affiliated to Fudan University, Shanghai, China
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29
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Procopio F, Viganò L, Cimino M, Donadon M, Del Fabbro D, Torzilli G. Does KRAS mutation status impact the risk of local recurrence after R1 vascular resection for colorectal liver metastasis? An observational cohort study. Eur J Surg Oncol 2019; 46:818-824. [PMID: 31839435 DOI: 10.1016/j.ejso.2019.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 11/26/2019] [Accepted: 12/02/2019] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION R0 margin is the standard in the surgical treatment of colorectal liver metastases (CLM). Recently R1 surgery, at least that enabling CLM vessel-detachment (R1vasc), seems comparable to R0. As a possible background of that biologic factors could play some role. Among them, KRAS has been investigated in the present study. METHODS Patients who underwent curative surgery for CLM between 2008 and 2016 were identified. R0, R1vasc and parenchymal R1 (R1par; tumor exposure once dissected from the parenchyma) resections with known KRAS status were analyzed. RESULTS Of 1000 resection areas in 340 patients, 654 (65%) R0, 98 (10%) R1vasc and 248 (25%) R1par. In mutated KRAS (mKRAS), local recurrence (LR) was similar between R0 and R1vasc (per-patient 4,8% vs. 2%, p = 0.628; per-area 2,1% vs. 1,9%, p = 0.940), while higher in R1par (per-patient 25,4% and per-area 19,5%; p < 0.001 for both). In wild-type KRAS (wtKRAS), R0 had less LR compared to R1vasc (per-patient 7,6% vs 14,6%, p = 0.335; per-area 3,1% vs 13,3%, p = 0.012) and R1par (per-patient 18,3%, p = 0.060; per-area 9,9%, p = 0.013). KRAS did not impact LR in R0 (per-patient 7,6% vs. 4,8%, p = 0.491; per-area 3,1% vs. 2,1%, p = 0.555), while wtKRAS R1par had less LR compared to mKRAS R1par (per-patient 18,3% vs 25,4%, p = 0.404; per-area 9,9% vs 19,5%, p = 0.048). Inversely, LR was increased in wtKRAS R1vasc compared to mKRAS R1vasc (per-patient 14,6% vs 2%, p = 0.043; per-area 13,3% vs 1,9%, p = 0.046). CONCLUSION KRAS status does not impact LR risk in R0 resection. Inversely, R1vasc vs R1par LR risk is reduced in mKRAS, and increased in wtKRAS. If confirmed these results are of note.
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Affiliation(s)
- Fabio Procopio
- Division of Hepatobiliary & General Surgery, Department of Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy
| | - Luca Viganò
- Division of Hepatobiliary & General Surgery, Department of Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy
| | - Matteo Cimino
- Division of Hepatobiliary & General Surgery, Department of Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy
| | - Matteo Donadon
- Division of Hepatobiliary & General Surgery, Department of Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy
| | - Daniele Del Fabbro
- Division of Hepatobiliary & General Surgery, Department of Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy
| | - Guido Torzilli
- Division of Hepatobiliary & General Surgery, Department of Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy.
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Papachristos A, Kemos P, Katsila T, Panoilia E, Patrinos GP, Kalofonos H, Sivolapenko GB. VEGF-A and ICAM-1 Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer. Int J Mol Sci 2019; 20:ijms20225791. [PMID: 31752122 PMCID: PMC6888109 DOI: 10.3390/ijms20225791] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 11/10/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022] Open
Abstract
Bevacizumab is used to treat metastatic colorectal cancer (mCRC). However, there are still no available predictors of clinical outcomes. We investigated selected single nucleotide polymorphisms (SNPs) in the genes involved in VEGF-dependent and -independent angiogenesis pathways and other major intracellular signaling pathways involved in the pathogenesis of mCRC as an attempt to find predictors of clinical outcome. Forty-six patients treated with first-line bevacizumab-based chemotherapy were included in this study with a 5 year follow up. Genomic DNA was isolated from whole blood for the analysis of VEGF-A (rs2010963, 1570360, rs699947), ICAM-1 (rs5498, rs1799969) SNPs and from tumor tissue for the detection of genomic variants in KRAS, NRAS, BRAF genes. PCR and next generation sequencing were used for the analysis. The endpoints of the study were progression-free survival (PFS) and overall survival (OS). The VEGF-A rs699947 A/A allele was associated with increased PFS (p = 0.006) and OS (p = 0.043). The ICAM-1 rs1799969 G/A allele was associated with prolonged OS (p = 0.036). Finally, BRAF wild type was associated with increased OS (p = 0.027). We identified VEGF-A and ICAM-1 variants in angiogenesis and other major intracellular signaling pathways, such as BRAF, that can predict clinical outcome upon bevacizumab administration. These identified biomarkers could be used to select patients with mCRC who may achieve long-term responses and benefit from bevacizumab-based therapies.
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Affiliation(s)
- Apostolos Papachristos
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (A.P.); (E.P.)
- Division of Cancer, University College London Hospital NHS Foundation Trust, London NW12BU, UK
| | - Polychronis Kemos
- Centre for Immunobiology, Blizard institute, Queen Mary University of London, London E12AT, UK;
| | - Theodora Katsila
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (T.K.); (G.P.P.)
- Institute of Chemical Biology, National Hellenic Research Centre, Athens 11635, Greece
| | - Eirini Panoilia
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (A.P.); (E.P.)
| | - George P. Patrinos
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (T.K.); (G.P.P.)
| | - Haralabos Kalofonos
- Division of Medical Oncology, University Hospital of Patras, Patra 26504, Greece;
| | - Gregory B. Sivolapenko
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patra 26504, Greece; (A.P.); (E.P.)
- Correspondence: ; Tel.: +30-26-1096-2324
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Caputo F, Santini C, Bardasi C, Cerma K, Casadei-Gardini A, Spallanzani A, Andrikou K, Cascinu S, Gelsomino F. BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights. Int J Mol Sci 2019; 20:E5369. [PMID: 31661924 PMCID: PMC6861966 DOI: 10.3390/ijms20215369] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view.
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Affiliation(s)
- Francesco Caputo
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Chiara Santini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Camilla Bardasi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Krisida Cerma
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Stefano Cascinu
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
- IRCCS San Raffaele Scientific Institute Hospital, 20019 Milan, Italy.
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
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Ghimessy AK, Gellert A, Schlegl E, Hegedus B, Raso E, Barbai T, Timar J, Ostoros G, Megyesfalvi Z, Gieszer B, Moldvay J, Renyi-Vamos F, Lohinai Z, Hoda MA, Klikovits T, Klepetko W, Laszlo V, Dome B. KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy. Cancers (Basel) 2019; 11:E1514. [PMID: 31600989 PMCID: PMC6827133 DOI: 10.3390/cancers11101514] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/23/2019] [Accepted: 10/03/2019] [Indexed: 01/09/2023] Open
Abstract
Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.
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Affiliation(s)
- Aron Kristof Ghimessy
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.
| | - Aron Gellert
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.
| | - Erzsebet Schlegl
- Department of Tumor Biology, National Koranyi Institute of Pulmonology-Semmelweis University, 1122 Budapest, Hungary.
| | - Balazs Hegedus
- Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, 45239 Essen, Germany.
- nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary.
- Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary.
| | - Erzsebet Raso
- nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary.
- Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary.
| | - Tamas Barbai
- nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary.
- Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary.
| | - Jozsef Timar
- nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary.
- Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary.
| | - Gyula Ostoros
- th Department of Pulmonology, National Koranyi Institute of Pulmonology, 1122 Budapest, Hungary.
| | - Zsolt Megyesfalvi
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.
- Department of Tumor Biology, National Koranyi Institute of Pulmonology-Semmelweis University, 1122 Budapest, Hungary.
| | - Balazs Gieszer
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.
| | - Judit Moldvay
- Department of Tumor Biology, National Koranyi Institute of Pulmonology-Semmelweis University, 1122 Budapest, Hungary.
- nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary.
- MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, 1091 Budapest, Hungary.
| | - Ferenc Renyi-Vamos
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.
| | - Zoltan Lohinai
- Department of Tumor Biology, National Koranyi Institute of Pulmonology-Semmelweis University, 1122 Budapest, Hungary.
| | - Mir Alireza Hoda
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, A-1090 Vienna, Austria.
| | - Thomas Klikovits
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, A-1090 Vienna, Austria.
| | - Walter Klepetko
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, A-1090 Vienna, Austria.
| | - Viktoria Laszlo
- Department of Tumor Biology, National Koranyi Institute of Pulmonology-Semmelweis University, 1122 Budapest, Hungary.
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, A-1090 Vienna, Austria.
| | - Balazs Dome
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.
- Department of Tumor Biology, National Koranyi Institute of Pulmonology-Semmelweis University, 1122 Budapest, Hungary.
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, A-1090 Vienna, Austria.
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Taieb J, Lapeyre-Prost A, Laurent Puig P, Zaanan A. Exploring the best treatment options for BRAF-mutant metastatic colon cancer. Br J Cancer 2019; 121:434-442. [PMID: 31353365 PMCID: PMC6738120 DOI: 10.1038/s41416-019-0526-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 06/05/2019] [Accepted: 06/19/2019] [Indexed: 12/18/2022] Open
Abstract
The BRAFV600E mutation is a well-accepted poor prognostic factor in patients with metastatic colorectal cancer (mCRC), as it confers Ras-independent stimulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway involved in proliferation, migration, angiogenesis and the suppression of apoptosis. Analysis of the potential predictive value of BRAF for treatment efficacy is inherently confounded by this known prognostic impact. Currently, approved therapeutic strategies for patients with BRAF-mutant (BRAF-mt) mCRC are suboptimal, and uncertainty exists regarding how to best treat these patients. Based on the available evidence, it is currently not possible to confirm the superiority of any available treatment options cited in European Society for Medical Oncology and National Comprehensive Cancer Network guidelines (that is, doublet or triplet chemotherapy regimens plus anti-vascular endothelial growth factor or anti-epidermal growth factor receptors), even if triplet chemotherapy plus bevacizumab is the most accepted standard regimen. In this review, we highlight still-emerging strategies that could be deployed to combat BRAF-mt mCRC, including triplet chemotherapy plus available biologic agents, rationally derived combinations of targeted agents and immunotherapy. While it is clear that the needs of patients with BRAF-mt mCRC are currently unmet, we are cautiously optimistic that the recently renewed research interest in these patients will yield clinically relevant insights and therapeutic strategies.
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Affiliation(s)
- Julien Taieb
- Sorbonne Paris-Cité, Paris Descartes University, Assistance Publique Hôpitaux de Paris (APHP), Gastro-enterology and GI Oncology Department, Georges Pompidou European Hospital, Paris, France.
- INSERM UMR-S1138, CNRS SNC5014, Paris Descartes University, Equipe labellisée Ligue Nationale contre le Cancer, Paris, France.
| | - Alexandra Lapeyre-Prost
- Sorbonne Paris-Cité, Paris Descartes University, Assistance Publique Hôpitaux de Paris (APHP), Gastro-enterology and GI Oncology Department, Georges Pompidou European Hospital, Paris, France
| | - Pierre Laurent Puig
- INSERM UMR-S1138, CNRS SNC5014, Paris Descartes University, Equipe labellisée Ligue Nationale contre le Cancer, Paris, France
- Sorbonne Paris Cité, Paris Descartes University, Assistance Publique Hôpitaux de Paris, Department of Biology, Georges Pompidou European Hospital, Paris, France
| | - Aziz Zaanan
- Sorbonne Paris-Cité, Paris Descartes University, Assistance Publique Hôpitaux de Paris (APHP), Gastro-enterology and GI Oncology Department, Georges Pompidou European Hospital, Paris, France
- INSERM UMR-S1138, CNRS SNC5014, Paris Descartes University, Equipe labellisée Ligue Nationale contre le Cancer, Paris, France
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TP53 DNA Binding Domain Mutations Predict Progression-Free Survival of Bevacizumab Therapy in Metastatic Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11081079. [PMID: 31366114 PMCID: PMC6721375 DOI: 10.3390/cancers11081079] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/22/2019] [Accepted: 07/26/2019] [Indexed: 12/21/2022] Open
Abstract
(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, TP53 DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13−0.65; p = 0.005). In contrast, TP53 truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45−27.50; p = 0.017). Importantly, neither TP53 mutation subtype was associated with overall response rate. In multivariate analysis, TP53 DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13–0.77; p = 0.011). The other genetic factor independently associated with PFS were PTPRT/PTPRD deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: TP53 DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of TP53 mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.
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Ducreux M, Chamseddine A, Laurent-Puig P, Smolenschi C, Hollebecque A, Dartigues P, Samallin E, Boige V, Malka D, Gelli M. Molecular targeted therapy of BRAF-mutant colorectal cancer. Ther Adv Med Oncol 2019; 11:1758835919856494. [PMID: 31244912 PMCID: PMC6582307 DOI: 10.1177/1758835919856494] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/16/2019] [Indexed: 12/11/2022] Open
Abstract
Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF-V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.
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Affiliation(s)
- Michel Ducreux
- Département d’Oncologie Médicale, Université Paris-Saclay, Gustave Roussy Cancer Campus Grand Paris, 114 rue Edouard Vaillant, Villejuif Cedex, 94805, France
| | - Ali Chamseddine
- Département d’Oncologie Médicale, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - Pierre Laurent-Puig
- Département de Biologie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
- Université Paris-Descartes, Paris, France; INSERM UMRS-1147, Paris, France
| | - Cristina Smolenschi
- Département d’Oncologie Médicale, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - Antoine Hollebecque
- Département d’Oncologie Médicale, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
- Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - Peggy Dartigues
- Département de Biopathologie, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - Emmanuelle Samallin
- Département d’Oncologie Digestive, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Valérie Boige
- Département d’Oncologie Médicale, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - David Malka
- Département d’Oncologie Médicale, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - Maximiliano Gelli
- Département de Chirurgie Viscérale, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
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Chen Z, Jiang L. The clinical application of fruquintinib on colorectal cancer. Expert Rev Clin Pharmacol 2019; 12:713-721. [PMID: 31177854 DOI: 10.1080/17512433.2019.1630272] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Zhongguang Chen
- Department of Pharmaceutical, Central Hospital of Linyi City, Yishui, Shandong, China
| | - Lili Jiang
- Ultrasound Medical Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
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Chun YS, Passot G, Yamashita S, Nusrat M, Katsonis PP, Loree JM, Conrad C, Tzeng CWD, Xiao L, Aloia TA, Eng C, Kopetz SE, Lichtarge O, Vauthey JN. Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases. Ann Surg 2019; 269:917-923. [PMID: 28767562 PMCID: PMC7462436 DOI: 10.1097/sla.0000000000002450] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM). BACKGROUND Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery. METHODS Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection. Missense TP53 mutations were classified by the evolutionary action score (EAp53)-a novel approach that dichotomizes mutations as low or high risk. RESULTS The most frequent somatic gene mutations were TP53 (65.6%), followed by KRAS (48.1%) and APC (47.4%). Double mutation in RAS/TP53, identified in 31.4% of patients, was correlated with primary tumor location in the right colon (P = 0.006). On multivariable analysis, RAS/TP53 double mutation was an independent predictor of shorter overall survival (hazard ratio 2.62, 95% confidence interval 1.41-4.87, P = 0.002). In patients with co-mutated RAS, EAp53 high-risk mutations were associated with shorter 5-year overall survival of 12.2%, compared with 55.7% for TP53 wild type (P < 0.001). The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes. CONCLUSIONS Concomitant RAS and TP53 mutations are associated with decreased survival after CLM resection. A high EAp53 predicts a subset of patients with worse prognosis. These preliminary analyses suggest that surgical resection of liver metastases should be carefully considered in this subset of patients.
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Affiliation(s)
- Yun Shin Chun
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Guillaume Passot
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suguru Yamashita
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maliha Nusrat
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Jonathan M. Loree
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Claudius Conrad
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ching-Wei D. Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lianchun Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Thomas A. Aloia
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott E. Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olivier Lichtarge
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Debeuckelaere C, Murgioni S, Lonardi S, Girardi N, Alberti G, Fano C, Gallimberti S, Magro C, Ahcene-Djaballah S, Daniel F, Fassan M, Prenen H, Loupakis F. Ramucirumab: the long and winding road toward being an option for mCRC treatment. Expert Opin Biol Ther 2019; 19:399-409. [PMID: 30917706 DOI: 10.1080/14712598.2019.1600505] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 03/25/2019] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is one of the main causes of cancer-related morbidity and mortality worldwide. Mortality is most often attributable to metastatic disease. Despite the progress achieved so far, life expectancy continues to be limited in most patients. Ramucirumab, a most recent antiangiogenic drug, is vying in the race to metastatic CRC (mCRC) treatment since its approval by the Food and Drug Administration (FDA), based on the results of the RAISE study. AREAS COVERED This article reviews the role of ramucirumab in mCRC, including clinical indication, safety issues, and future perspectives. EXPERT OPINION The use of Ramucirumab in clinical practice is still limited, probably due to economic burden and the lack of specific biomarkers. Future efforts will be addressed to improve our knowledge in the use of this drug and better guide us in patients' care.
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Affiliation(s)
| | - Sabina Murgioni
- b Department of Oncology, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
| | - Sara Lonardi
- b Department of Oncology, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
| | - Noemi Girardi
- c Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Giulia Alberti
- b Department of Oncology, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
- c Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Carolina Fano
- d Research Nurses Coordinating Center, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
| | - Sara Gallimberti
- d Research Nurses Coordinating Center, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
| | - Cristina Magro
- d Research Nurses Coordinating Center, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
| | - Selma Ahcene-Djaballah
- b Department of Oncology, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
| | - Francesca Daniel
- b Department of Oncology, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
- e Clinical Oncology, Department of Morphology, Surgery and Experimental Medicine , S. Anna University Hospital , Ferrara , Italy
| | - Matteo Fassan
- f Department of Medicine, Pathology and Cytopathology Unit , Padua University Hospital , Padua , Italy
| | - Hans Prenen
- a Department of Oncology , University Hospital Antwerp , Edegem , Belgium
- g Center for Oncological Research , Antwerp University , Edegem , Belgium
| | - Fotios Loupakis
- b Department of Oncology, Unit of Oncology 1 , Veneto Institute of Oncology, Scientific Institute for Research and Healthcare (IRCCS) , Padua , Italy
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Bruera G, Pepe F, Malapelle U, Pisapia P, Mas AD, Di Giacomo D, Calvisi G, Troncone G, Ricevuto E. KRAS, NRAS and BRAF mutations detected by next generation sequencing, and differential clinical outcome in metastatic colorectal cancer (MCRC) patients treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy. Oncotarget 2018; 9:26279-26290. [PMID: 29899858 PMCID: PMC5995185 DOI: 10.18632/oncotarget.25180] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 04/05/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND First line triplet chemotherapy/BEV significantly improved clinical outcome of MCRC. KRAS/NRAS/BRAF mutations were evaluated by next generation sequencing (NGS) in MCRC patients treated with first line FIr-B/FOx. METHODS KRAS exons 2-4 (KRAS2-4 ), NRAS2-4 , BRAF15 were evaluated in 67 tumours by ION Torrent platform. Mutation detection criteria: >500×sequence coverage (cov); >1% mutant allelic fraction (AF). Clinical outcomes were compared by log-rank. RESULTS In 63 samples, KRAS2-4 /NRAS2-4 /BRAF15 wild-type (wt) were 14 (22.2%), mutant (mut) 49 (77.8%): KRAS2-4 42 (66.7%); NRAS2-4 11 (16.4%); BRAF15 5 (7.5%). Sixty mutations were detected, range 1-3 mut: 43 (71.7%) >1000×cov/>5% AF; 9 (15%) >500×cov/>5% AF; 8 (13.3%) >1000×cov/<5% AF. Mut distribution in KRAS2-4 /NRAS2-4 /BRAF15 : 40 (63.5%) >1000×cov/>5% AF, 8 (12.7%) >500×cov/>5% AF, 1 (1.6%) >1000×cov/<5% AF; BRAF15 1 (1.5%) >500×cov/>5% AF, 4 (6%) >1000×cov/<5% AF. Prevalence of ≥2 mut samples: KRAS2-4 /NRAS2-4 /BRAF15 8 (12.7%); KRAS2-4 7 (11.1%); NRAS2-4 5 (7.5%). BRAF15 mutant were all ≥2 mut (7.5%), atypical and associated to KRAS and/or NRAS mut: c.1405 G>A; c.1406 G>C; c.1756 G>A, 2 samples; c.1796 C>T. At 21 months (m) follow-up, clinical outcome wt compared to mut was not significantly different: in KRAS2-4 /NRAS2-4 /BRAF15 , progression-free survival (PFS) 18/12 m, overall survival (OS) 28/22 m; 1/≥2 mutations, PFS 14/11, OS 37/22. PFS was trendy worse in RAS/BRAF wt vs ≥2 mut genes (P 0.059). CONCLUSIONS Most MCRC harboured KRAS2-4 /NRAS2-4 /BRAF15 mutations by NGS, often multiple and affecting few tumoral clones; 22% were triple wt. Clinical outcome is not significantly affected by KRAS2-4 /NRAS2-4 /BRAF15 genotype, trendy different in triple wt, compared with KRAS2-4 /NRAS2-4 /BRAF15 ≥2 mut.
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Affiliation(s)
- Gemma Bruera
- Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Francesco Pepe
- Department of Public Health, University Federico II, Napoli, Italy
| | | | - Pasquale Pisapia
- Department of Public Health, University Federico II, Napoli, Italy
| | - Antonella Dal Mas
- Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy
| | - Daniela Di Giacomo
- Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Giuseppe Calvisi
- Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy
| | | | - Enrico Ricevuto
- Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
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Varol U, Yildiz I, Salman T, Karabulut B, Uslu R. Markers to Predict the Efficacy of Bevacizumab in the Treatment of Metastatic Colorectal Cancer. TUMORI JOURNAL 2018. [DOI: 10.1177/1636.17888] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Umut Varol
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Ibrahim Yildiz
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Tarik Salman
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Bulent Karabulut
- Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey
| | - Ruchan Uslu
- Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey
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Huemer F, Thaler J, Piringer G, Hackl H, Pleyer L, Hufnagl C, Weiss L, Greil R. Sidedness and TP53 mutations impact OS in anti-EGFR but not anti-VEGF treated mCRC - an analysis of the KRAS registry of the AGMT (Arbeitsgemeinschaft Medikamentöse Tumortherapie). BMC Cancer 2018; 18:11. [PMID: 29298682 PMCID: PMC5753540 DOI: 10.1186/s12885-017-3955-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 12/21/2017] [Indexed: 01/05/2023] Open
Abstract
Background In metastatic colorectal cancer (mCRC), the localization of the primary tumour has been shown to be of prognostic as well as predictive relevance. Methods With the aim to investigate clinical and molecular disease characteristics with respect to sidedness in a real-world cohort, we analyzed 161 mCRC patients included in the KRAS Registry of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) between January 2006 and October 2013. Results Right-sided mCRC displayed a worse median overall survival (OS) in comparison to left-sided disease (18.1 months [95%-CI: 14.3–40.7] versus 32.3 months [95%-CI: 25.5–38.6]; HR: 1.63 [95%-CI: 1.13–2.84]; p = 0.013). The choice of the biological agent in front-line therapy had a statistically significant impact on median OS in patients with right-sided tumours (anti-epidermal growth factor receptor (EGFR): 10.6 months [95%-CI: 5.2-NA]; anti-vascular endothelial growth factor (VEGF): 26.2 months [95%-CI: 17.9-NA]; HR: 2.69 [95%-CI: 1.30–12.28]; p = 0.015) but not in patients with left-sided tumours (anti-EGFR: 37.0 months [95%-CI: 20.2–56.6]; anti-VEGF: 32.3 months [95%-CI: 23.6–41.1]; HR: 0.97 [95%-CI: 0.56–1.66]; p = 0.905). When evaluating molecular characteristics of tumour samples, we found a clinically meaningful trend towards an inferior OS in TP53 mutant mCRC treated with anti-EGFR based therapy compared to anti-VEGF based therapy (17.1 months [95%-CI: 8.7-NA] versus 38.3 months [95%-CI: 23.6–48.0], HR = 1.95 [95%-CI: 0.95–5.88]; p = 0.066), which was not significantly dependent on sidedness. This was not the case in patients with TP53 wild-type tumours. Therefore we evaluated the combined impact of sidedness and TP53 mutation status in the anti-EGFR treated cohort and patients with left-sided/TP53 wild-type mCRC showed the longest median OS (38.9 months) of all groups (right-sided/TP53 mutant: 12.1 months; right-sided/TP53 wild-type: 8.9 months; left-sided/TP53 mutant: 18.4 months; p = 0.020). Conclusions TP53 mutation and right-sidedness are associated with shorter OS in patients treated with anti-EGFR based therapy but not with anti-VEGF based therapy. The confirmation of the predictive value of TP53 mutation status in a larger cohort is warranted. Electronic supplementary material The online version of this article (10.1186/s12885-017-3955-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Florian Huemer
- IIIrd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020, Salzburg, Austria.,Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020, Salzburg, Austria.,Cancer Cluster Salzburg, 5020, Salzburg, Austria
| | - Josef Thaler
- Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, 4600, Wels, Austria
| | - Gudrun Piringer
- Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, 4600, Wels, Austria
| | - Hubert Hackl
- Division of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Lisa Pleyer
- IIIrd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020, Salzburg, Austria.,Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020, Salzburg, Austria.,Cancer Cluster Salzburg, 5020, Salzburg, Austria
| | - Clemens Hufnagl
- IIIrd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020, Salzburg, Austria.,Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020, Salzburg, Austria.,Cancer Cluster Salzburg, 5020, Salzburg, Austria
| | - Lukas Weiss
- IIIrd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020, Salzburg, Austria.,Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020, Salzburg, Austria.,Cancer Cluster Salzburg, 5020, Salzburg, Austria
| | - Richard Greil
- IIIrd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020, Salzburg, Austria. .,Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020, Salzburg, Austria. .,Cancer Cluster Salzburg, 5020, Salzburg, Austria.
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Strickler JH, Wu C, Bekaii-Saab T. Targeting BRAF in metastatic colorectal cancer: Maximizing molecular approaches. Cancer Treat Rev 2017; 60:109-119. [PMID: 28946014 DOI: 10.1016/j.ctrv.2017.08.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 08/08/2017] [Accepted: 08/11/2017] [Indexed: 02/07/2023]
Abstract
Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7-10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.
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Affiliation(s)
- John H Strickler
- Duke University School of Medicine, 20 Duke Medicine Circle, Durham, NC 27710, USA
| | - Christina Wu
- Emory University, 1365-C Clifton Rd NE, Atlanta, GA 30322, USA
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Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. CRC develops as a consequence of genomic instability, characterized by various genetic and epigenetic alterations. Its molecular heterogeneity explains the large variability in patient prognosis and treatment response, emphasizing the need for development of accurate prognostic and predictive biomarkers. This article delineates the different pathways of colorectal carcinogenesis and its molecular subtype classification. With this review, we aim to provide a comprehensive overview of the current and future biomarkers guiding clinical decision-making and CRC treatment.
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Affiliation(s)
- Pieter-Jan Cuyle
- Department of Gastroenterology/Digestive Oncology, Imelda General Hospital, Bonheiden, Belgium
- Department of Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg Leuven, Leuven, Belgium
| | - Hans Prenen
- Department of Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg Leuven, Leuven, Belgium
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Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS. Invest New Drugs 2017; 35:491-498. [PMID: 28353122 DOI: 10.1007/s10637-017-0458-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/16/2017] [Indexed: 12/22/2022]
Abstract
Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon's optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.
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Garde Noguera J, Jantus-Lewintre E, Gil-Raga M, Evgenyeva E, Maciá Escalante S, Llombart-Cussac A, Camps Herrero C. Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis. Mol Clin Oncol 2017; 6:403-408. [PMID: 28451421 DOI: 10.3892/mco.2017.1149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 12/02/2016] [Indexed: 01/28/2023] Open
Abstract
The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild-type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7-15.2 vs. RAS wild-type: 12 months, 95% CI: 9.67-14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3-25.6 vs. RAS wild-type: 24 months, 95% CI: 18.7-29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild-type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5-19.4 vs. 10 months, 95% CI: 4.2-15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5-35.4 vs. 15 months, 95% CI: 12.4-17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine-oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.
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Affiliation(s)
- Javier Garde Noguera
- Medical Oncology Department, Hospital Arnau de Vilanova of Valencia, 46015 Valencia, Spain
| | - Eloisa Jantus-Lewintre
- Molecular Oncology Laboratory, University General Hospital of Valencia, Research Foundation, 46014 Valencia, Spain
| | - Mireia Gil-Raga
- Medical Oncology Department, Hospital de Sagunto, 46520 Valencia, Spain
| | - Elena Evgenyeva
- Pathology Department, Hospital Marina-Salud de Denia, 03700 Dénia, Spain
| | | | | | - Carlos Camps Herrero
- Medical Oncology and Molecular Laboratory Department, University General Hospital of Valencia, University of Valencia, 46014 Valencia, Spain
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Riechelmann R, Grothey A. Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies. Ther Adv Med Oncol 2017; 9:106-126. [PMID: 28203302 PMCID: PMC5298403 DOI: 10.1177/1758834016676703] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Even though significant improvements in the treatment of colorectal cancer (CRC) have been made in recent years, survival rates for metastatic colorectal cancer (mCRC) are poor. Effective treatment options for metastatic colorectal cancer remain limited, and new therapeutic strategies are desperately needed. Several tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) that target angiogenesis, a critical process for facilitating tumor cell growth, invasion, and metastasis, are either approved or in clinical development for the treatment of mCRC. Many of these agents have shown efficacy in mCRC, both as single agents and in combination with standard chemotherapy regimens. However, there is a need for predictive markers of response to identify those patients most likely to benefit from antiangiogenic therapy, and, to date, no markers of this type have been validated in patients. Additionally, because antiangiogenic agents typically cause cytostatic as opposed to cytotoxic antitumor effects, it is important to determine the best strategies for evaluating therapeutic response in mCRC to ensure maximum clinical benefit. In this review, we summarize the efficacy and tolerability of approved and investigational antiangiogenic agents for the treatment of mCRC. We also discuss potential markers of response to antiangiogenic agents and how these markers, along with appropriate endpoint selection, can improve clinical trial design.
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Affiliation(s)
- Rachel Riechelmann
- Instituto do Cancer do Estado de São Paulo, Av. Doutor Arnaldo 251, 5° Andar, CEP 01246-000, São Paulo, SP, Brazil
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Xu RH, Li J, Bai Y, Xu J, Liu T, Shen L, Wang L, Pan H, Cao J, Zhang D, Fan S, Hua Y, Su W. Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study. J Hematol Oncol 2017; 10:22. [PMID: 28103904 PMCID: PMC5244709 DOI: 10.1186/s13045-016-0384-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 12/30/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients. METHODS A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS). RESULTS In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86-5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95-1.58); (hazard ratio [HR] 0.30; 95% CI 0.15-0.59; P < 0.001). The median OS was 7.72 versus 5.52 months (HR 0.71; 95% CI 0.38-1.34). The most common grade 3-4 adverse events were hypertension and hand-foot skin reaction. CONCLUSIONS Fruquintinib showed a significant PFS benefit of 3.7 months in patients with treatment-refractory mCRC. The safety profile was consistent with that of VEGFR tyrosine kinase inhibitors. A randomized phase III confirmatory study in mCRC is underway. TRIAL REGISTRATION NCT01975077 and NCT02196688.
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Affiliation(s)
- Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, 200032, China. .,Department of Oncology, Tongji University Shanghai East Hospital, No. 150 Jimo Road, Pudong District, Shanghai, 200120, China.
| | - Yuxian Bai
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jianming Xu
- Department of Medical Oncology, 307th Hospital of PLA, Academy of Military Medical Sciences, Beijing, 100071, China
| | - Tianshu Liu
- Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, 200032, China
| | - Lin Shen
- Department of Medical Oncology, Beijing Cancer Hospital, Beijing, 100142, China
| | - Liwei Wang
- Department of Medical Oncology, Shanghai First People's Hospital, Shanghai, 200090, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Junning Cao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, 200032, China
| | - Dongsheng Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Songhua Fan
- Hutchison MediPharma Ltd, Shanghai, 201203, China
| | - Ye Hua
- Hutchison MediPharma Ltd, Shanghai, 201203, China
| | - Weiguo Su
- Hutchison MediPharma Ltd, Shanghai, 201203, China
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Abstract
Colorectal cancer is commonly diagnosed throughout the world, and treatment options have greatly expanded over the last 2 decades. Targeting angiogenesis has been a major focus of study in a variety of malignancy types. Targeting angiogenesis has been achieved by several mechanisms in colorectal cancer, including use of antiangiogenic small molecule tyrosine kinase inhibitors (TKIs). There have been many attempts and failures to prove efficacy of TKIs in the treatment of colorectal cancer including sorafenib, sunitinib, vatalanib, and tivozanib. Regorafenib was the first TKI to demonstrate efficacy and is an orally active inhibitor of angiogenic (including the vascular endothelial growth factor receptors 1, 2, and 3), stromal, and oncogenic receptor tyrosine kinases. There are ongoing investigations of both regorafenib and ninetanib; however, there remains a critical need to better understand novel combinations with TKIs that could prove more efficacious than available options.
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Nakayama I, Shinozaki E, Matsushima T, Wakatsuki T, Ogura M, Ichimura T, Ozaka M, Takahari D, Suenaga M, Chin K, Mizunuma N, Yamaguchi K. Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients. BMC Cancer 2017; 17:38. [PMID: 28068936 PMCID: PMC5223326 DOI: 10.1186/s12885-016-2994-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 12/13/2016] [Indexed: 12/22/2022] Open
Abstract
Background After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer. Methods Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status. Results The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab. Conclusions Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2994-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Tomohiro Matsushima
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Mariko Ogura
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Takashi Ichimura
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Masato Ozaka
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Mitsukuni Suenaga
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Nobuyuki Mizunuma
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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Bai L, Wang F, Li ZZ, Ren C, Zhang DS, Zhao Q, Lu YX, Wang DS, Ju HQ, Qiu MZ, Wang ZQ, Wang FH, Xu RH. Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first-line treatment for patients with metastatic colorectal cancer: Results of a registry-based cohort analysis. Medicine (Baltimore) 2016; 95:e4531. [PMID: 28002313 PMCID: PMC5181797 DOI: 10.1097/md.0000000000004531] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Clinical data were collected from a single-center registry study where mCRC patients received first-line fluoropyrimidine-based chemotherapy combined with either bevacizumab (188 patients with KRAS wild-type or mutated tumors) or cetuximab (101 patients with KRAS wild-type tumors) between January 2009 and December 2013. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics. No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival (PFS) (10.6 vs 8.7 months, P = 0.317), median overall survival (OS) (27.7 vs 28.3 months, P = 0.525), or overall response rate (43.1% vs 53.5%, P = 0.108). For the subset of patients with peritoneal dissemination, bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS (9.6 vs 6.1 months) and OS (26.3 vs 12.7 months), but not for patients without peritoneal dissemination (PFS, 10.6 vs 9.1 months; OS, 27.9 vs 30.7 months) (all unadjusted and adjusted interaction P < 0.05). Our study suggests that bevacizumab- or cetuximab-based regimens have similar effectiveness as first-line treatment of mCRC in Chinese population. Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment. Future prospective studies are required to further confirm these results.
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Affiliation(s)
- Long Bai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Zhe-zhen Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Dong-sheng Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Qi Zhao
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yun-xin Lu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - De-shen Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Huai-qiang Ju
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Miao-zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Zhi-qiang Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Feng-hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Rui-hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
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