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Platt JR, Pennycook S, Muthoo CE, Westwood AC, Frood R, Beggs AD, Scarsbrook A, Seligmann JF, Tolan DJM. Colon cancer biology and treatment in the era of precision oncology: A primer for Radiologists. Eur J Radiol 2025; 185:112000. [PMID: 39978239 DOI: 10.1016/j.ejrad.2025.112000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/07/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
In the era of precision oncology, systemic therapies for colon cancer are becoming increasingly biomarker-led, with implications for patients in the neoadjuvant, adjuvant and metastatic settings. As the landscape for colon cancer treatment evolves and becomes more complex, it is important that all members of the multidisciplinary team keep abreast of developments to ensure the most effective care is delivered to patients. As core members of the colorectal multidisciplinary team, Radiologists play a central role throughout the patient journey. This review serves as an educational summary of current and emerging treatment pathways in colon cancer, standards for biomarker testing, mechanisms of action for key drugs, important treatment-related complications, relevant tumour biology that underpins patterns of disease and treatment response, and the specific implications systemic therapies have for cancer imaging and Radiologists. We also highlight the increasing role for radiology in patient stratification and the importance of imaging biomarkers. It is crucial that Radiologists understand the current landscape of colon cancer treatment and emerging strategies on the horizon in clinical trials. Only through engagement across the wider multidisciplinary team will we deliver true personalised medicine for patients with colon cancer.
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Affiliation(s)
- James R Platt
- Division of Oncology, Leeds Institute of Medical Research at St James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Stephanie Pennycook
- Department of Medical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
| | - Chand E Muthoo
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
| | - Alice C Westwood
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Russell Frood
- Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK.
| | - Andrew D Beggs
- Department of Cancer and Genomics, University of Birmingham, Birmingham, UK.
| | - Andrew Scarsbrook
- Leeds Institute of Medical Research at St James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Jenny F Seligmann
- Division of Oncology, Leeds Institute of Medical Research at St James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Damian J M Tolan
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
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Napolitano S, Ciardiello D, Cioli E, Martinelli E, Troiani T, Giulia Zampino M, Fazio N, De Vita F, Ciardiello F, Martini G. BRAFV600E mutant metastatic colorectal cancer: Current advances in personalized treatment and future perspectives. Cancer Treat Rev 2025; 134:102905. [PMID: 40009904 DOI: 10.1016/j.ctrv.2025.102905] [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: 01/25/2025] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 02/28/2025]
Abstract
Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), identifying a subgroup of patients who derive modest benefit from standard treatments and have extremely poor prognosis. The evolution of molecular profiling and the implementation of next generation sequencing in the evaluation of a patient with BRAF-mutated mCRC has currently led to the discovery of actionable alterations. Targeting multiple pathways of resistance in BRAF-mutated mCRC may be the most efficacious route. Then, over a short period of time, the treatment landscape BRAF-mutated mCRC patients has shifted dramatically. Finally, novel treatment strategies are available. This review will discuss on currently approved treatments for BRAF V600E mutated mCRC and will try and portray the changing landscape in this setting in the era of targeted molecular therapy.
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Affiliation(s)
- Stefania Napolitano
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy.
| | - Davide Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Eleonora Cioli
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erika Martinelli
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Teresa Troiani
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Maria Giulia Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Ferdinando De Vita
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giulia Martini
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, 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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4
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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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Salva de Torres C, Baraibar I, Saoudi González N, Ros J, Salva F, Rodríguez-Castells M, Alcaraz A, García A, Tabernero J, Élez E. Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer. Int J Mol Sci 2024; 25:6967. [PMID: 39000083 PMCID: PMC11241496 DOI: 10.3390/ijms25136967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.
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Affiliation(s)
| | - Iosune Baraibar
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Nadia Saoudi González
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Javier Ros
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Francesc Salva
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Marta Rodríguez-Castells
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Adriana Alcaraz
- Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (A.A.); (A.G.)
| | - Ariadna García
- Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (A.A.); (A.G.)
| | - Josep Tabernero
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Elena Élez
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
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Jalali A, Smith S, Kim G, Wong H, Lee M, Yeung J, Loft M, Wong R, Shapiro JD, Kosmider S, Tie J, Ananda S, Ma B, Burge M, Jennens R, Lee B, Johns J, Lim L, Dean A, Nott L, Gibbs P. Early onset metastatic colorectal cancer in Australia. Cancer Treat Res Commun 2024; 40:100827. [PMID: 38885543 DOI: 10.1016/j.ctarc.2024.100827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/29/2024] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.
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Affiliation(s)
- A Jalali
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Western Health, VIC, Australia; Department of Medical Oncology, Northern Health, VIC, Australia; Department of Medical Oncology, Latrobe Regional Hospital, VIC, Australia.
| | - S Smith
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, St Vincent's Hospital Melbourne, VIC, Australia
| | - G Kim
- Department of Medical Oncology, Western Health, VIC, Australia
| | - H Wong
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, VIC, Australia
| | - M Lee
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Western Health, VIC, Australia; Department of Medical Oncology, Eastern Health, VIC, Australia; Eastern Health Clinical School, Monash University, VIC, Australia
| | - J Yeung
- Department of Colorectal Surgery, Western Health, University of Melbourne, VIC, Australia; Department of Surgery, Western Precinct, University of Melbourne, VIC, Australia
| | - M Loft
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia
| | - R Wong
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Eastern Health Clinical School, Monash University, VIC, Australia; Department of Surgery, Western Precinct, University of Melbourne, VIC, Australia
| | - J D Shapiro
- Department of Medical Oncology, Cabrini Hospital, VIC, Australia
| | - S Kosmider
- Department of Medical Oncology, Western Health, VIC, Australia
| | - J Tie
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, VIC, Australia
| | - S Ananda
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Western Health, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, VIC, Australia
| | - B Ma
- The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong
| | - M Burge
- Department of Medical Oncology, Royal Brisbane Hospital, QLD, Australia
| | - R Jennens
- Department of Medical Oncology, Epworth Health, VIC, Australia
| | - B Lee
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Northern Health, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, VIC, Australia
| | - J Johns
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia
| | - L Lim
- Department of Medical Oncology, Eastern Health, VIC, Australia
| | - A Dean
- Department of Medical Oncology, St John of God Hospital, WA, Australia
| | - L Nott
- Department of Medical Oncology, Royal Hobart Hospital, TAS, Australia
| | - P Gibbs
- Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia; Department of Medical Oncology, Western Health, VIC, Australia
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Kotani D, Takashima A, Kato T, Satoh T, Masuishi T, Komatsu Y, Shiozawa M, Esaki T, Izawa N, Takeuchi S, Bando H, Iwasa S, Hasegawa H, Yamaguchi T, Taniguchi H, Ushida Y, Oizaki T, Inoue C, Yoshino T. Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAF V600E-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program. Clin Colorectal Cancer 2024; 23:174-182.e6. [PMID: 38553360 DOI: 10.1016/j.clcc.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS The EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. RESULTS Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. CONCLUSION The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.
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Affiliation(s)
| | | | | | | | | | | | | | - Taito Esaki
- National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Naoki Izawa
- St. Marianna University School of Medicine Hospital, Kanagawa, Japan
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Kureyama Y, Hanaoka Y, Tomita D, Matoba S, Kuroyanagi H. Pancreatitis After Treatment With Encorafenib, Binimetinib, and Cetuximab for BRAF V600E Mutation-Positive Colorectal Cancer. Cureus 2024; 16:e60188. [PMID: 38741697 PMCID: PMC11089837 DOI: 10.7759/cureus.60188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2024] [Indexed: 05/16/2024] Open
Abstract
BRAF V600E mutation-positive advanced recurrent colorectal cancer has a poor prognosis. Encorafenib, binimetinib, and cetuximab were approved for use to treat this cancer in 2020 in Japan. Here, we present the case of a patient with BRAF V600E mutation-positive colorectal cancer, who was treated with encorafenib, binimetinib, and cetuximab, and developed grade 3 pancreatitis at our hospital. After pancreatitis treatment, the drug doses were reduced from 300 mg to 225 mg of encorafenib and from 90 mg to 60 mg of binimetinib, and the treatment was resumed. Since then, no grade 3 or higher adverse events were observed. Although pancreatitis has been reported to occur after the use of encorafenib and binimetinib, it is rare. With appropriate dose reduction and attention to side effects, this regimen is considered feasible for the long-term treatment of BRAF V600E mutation-positive advanced recurrent colorectal cancer in patients aged >70 years.
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Affiliation(s)
- Yuika Kureyama
- Department of Colorectal Surgery, Toranomon Hospital, Tokyo, JPN
| | - Yutaka Hanaoka
- Department of Colorectal Surgery, Toranomon Hospital, Tokyo, JPN
| | - Daisuke Tomita
- Department of Colorectal Surgery, Toranomon Hospital, Tokyo, JPN
| | - Shuichiro Matoba
- Department of Colorectal Surgery, Toranomon Hospital, Tokyo, JPN
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9
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Osterlund E, Ristimäki A, Mäkinen MJ, Kytölä S, Kononen J, Pfeiffer P, Soveri LM, Keinänen M, Sorbye H, Nunes L, Salminen T, Nieminen L, Uutela A, Halonen P, Ålgars A, Sundström J, Kallio R, Ristamäki R, Lamminmäki A, Stedt H, Heervä E, Kuopio T, Sjöblom T, Isoniemi H, Glimelius B, Osterlund P. Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts. Int J Cancer 2024; 154:488-503. [PMID: 37724848 DOI: 10.1002/ijc.34733] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 09/21/2023]
Abstract
BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.
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Affiliation(s)
- Emerik Osterlund
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Department of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
| | - Ari Ristimäki
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
- Faculty of Medicine, Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Markus J Mäkinen
- Department of Pathology, Oulu University Hospital, Oulu, Finland
- Translational Medicine Research Unit, Department of Pathology, University of Oulu, Oulu, Finland
- Medical Research Center Oulu, Oulu, Finland
| | - Soili Kytölä
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
- Department of Genetics, University of Helsinki, Helsinki, Finland
| | - Juha Kononen
- Departemnt of Oncology, Central hospital of Central Finland, Jyväskylä, Finland
- Docrates hospital, Helsinki, Finland
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Leena-Maija Soveri
- Home Care, Geriatric Clinic and Palliative Care, Joint Municipal Authority for Health Care and Social Services in Keski-Uusimaa, Hyvinkää, Finland
- Department of Oncology, Helsinki University Hospital, Helsinki, Finland
| | - Mauri Keinänen
- Department of Genetics, Fimlab Laboratories, Tampere, Finland
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Luís Nunes
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Tapio Salminen
- Department of Oncology, Tampere University Hospital, Tampere, Finland
- Department of Oncology, University of Tampere, Tampere, Finland
| | - Lasse Nieminen
- Department of Pathology, Tampere University Hospital, Tampere, Finland
- Department of Pathology, University of Tampere, Tampere, Finland
| | - Aki Uutela
- Department of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
- Department of Surgery, University of Helsinki, Helsinki, Finland
- Department of Transplant and HPB Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Päivi Halonen
- Department of Oncology, Helsinki University Hospital, Helsinki, Finland
- Department of Oncology, University of Helsinki, Helsinki, Finland
| | - Annika Ålgars
- Department of Oncology, Turku University Hospital, Turku, Finland
- Department of Oncology, University of Turku, Turku, Finland
| | - Jari Sundström
- Department of Pathology, Turku University Hospital, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Raija Kallio
- Department of Oncology, Oulu University Hospital, Oulu, Finland
- Department of Oncology, University of Oulu, Oulu, Finland
| | - Raija Ristamäki
- Department of Oncology, Turku University Hospital, Turku, Finland
- Department of Oncology, University of Turku, Turku, Finland
| | - Annamarja Lamminmäki
- Department of Oncology, Kuopio University Hospital, Kuopio, Finland
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Hanna Stedt
- Department of Oncology, Kuopio University Hospital, Kuopio, Finland
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Eetu Heervä
- Department of Oncology, Turku University Hospital, Turku, Finland
- Department of Oncology, University of Turku, Turku, Finland
| | - Teijo Kuopio
- Department of Pathology, Central Finland Hospital Nova, Jyväskylä, Finland
- Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | - Tobias Sjöblom
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Helena Isoniemi
- Department of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
- Department of Surgery, University of Helsinki, Helsinki, Finland
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Pia Osterlund
- Department of Oncology, Tampere University Hospital, Tampere, Finland
- Department of Oncology, University of Tampere, Tampere, Finland
- Department of Surgery, University of Helsinki, Helsinki, Finland
- Department of Transplant and HPB Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK
- Department of Gastrointestinal Oncology, Karolinska Universitetssjukhuset, Stockholm, Sweden
- Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden
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10
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Cherri S, Oneda E, Zanotti L, Zaniboni A. Optimizing the first-line treatment for metastatic colorectal cancer. Front Oncol 2023; 13:1246716. [PMID: 37909027 PMCID: PMC10614157 DOI: 10.3389/fonc.2023.1246716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023] Open
Abstract
Colorectal cancer represents an important oncological challenge both for its incidence, which makes it an important health problem, and for its biological complexity, which has made clinical results very difficult in terms of outcome for this category of patients. To date these diseases should not be treated as a single entity but it is necessary to distinguish colorectal cancers based on characteristics that nowadays are essential to have greater therapeutic benefits. These include the sideness of the disease, the state of microsatellites, the presence of prognostic and predictive mutations of response to treatments currently available in clinical practice, which are associated with new therapeutic targets. The greatest challenge in the future will be to circumvent the resistance mechanisms that make this disease very difficult to treat with good long-term results by studying effective combination treatments with a good toxicity profile. Once such combinations or targeted treatments are consolidated, it will be desirable to shift the best therapies to the first line treatment to make them immediately accessible to the patient. It will also be essential to refine the selection of patients who can benefit from these treatments.
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Affiliation(s)
- Sara Cherri
- Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy
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11
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Loft M, Shapiro J, Lee M, Wong R, Tie J, Kosmider S, Wong V, Jalali A, Lee B, Ananda SS, Gibbs P. Compliance with Therapeutic Goods Association prescribing information: weekly or second weekly cetuximab for the treatment of metastatic colorectal cancer. Intern Med J 2023; 53:1610-1617. [PMID: 35668542 DOI: 10.1111/imj.15835] [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: 04/04/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications. AIM To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes. METHODS We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. RESULTS Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in >70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P < 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P < 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis. CONCLUSION This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.
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Affiliation(s)
- Matthew Loft
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
| | - Jeremy Shapiro
- Department of Medical Oncology, Cabrini Hospital, Melbourne, Victoria, Australia
| | - Margaret Lee
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
- Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia
| | - Rachel Wong
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Jeanne Tie
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
- Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Suzanne Kosmider
- Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
| | - Vanessa Wong
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | - Azim Jalali
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
| | - Belinda Lee
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Sumitra S Ananda
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
- Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
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12
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Tian B, Chen G, Shi X, Jiang L, Jiang T, Li Q, Yuan L, Qin J. Preliminary exploration of the effects of environmental factors on the microsatellite status of BRAF-mutated colorectal cancer. World J Surg Oncol 2023; 21:264. [PMID: 37620872 PMCID: PMC10463889 DOI: 10.1186/s12957-023-03106-6] [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: 04/23/2023] [Accepted: 07/12/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND To investigate the expression of EBV products and frequency of gallstone disease (GD) among different microsatellite status in colorectal cancer (CRC) with BRAFV600E mutation. METHODS We collected 30 CRC patients with BRAFV600E mutation and 10 BRAF ( -) CRC patients as well as 54 healthy subjects. Tumor tissue samples were collected to detect the mutation of BRAF, KRAS, and TP53. Microsatellite status was determined by immunohistochemistry and PCR. EBER in situ hybridization was performed to detect EBV. In addition, we also collected clinical information about the patients. RESULTS We found that although EBV products were detected in CRC, there were no significant differences in the EBV distribution between the different BRAF groups. Our study demonstrated that BRAFV600E mutation and BRAFV600E with MSI were significantly more frequent in the right CRC. Furthermore, the KRAS mutation rate in the BRAF-wild-type group was proved to be significantly higher than that in the BRAF mutation group. In addition, we revealed that BRAF mutation and MSI were independent risk factors of TNM stage. The frequency of GD was higher in CRC patients than in general population, and although there was no significant difference between CRC with or without BRAFV600E mutation, the highest frequency of GD was found in MSS CRC with BRAFV600E mutation. CONCLUSIONS EBV plays a role in CRC, but is not a determinant of different microsatellite status in CRC with BRAFV600E mutation. The frequency of GD in MSS CRC with BRAFV600E mutation is significantly higher than that in the general population.
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Affiliation(s)
- Binle Tian
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Guiming Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Xiaoqin Shi
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Liren Jiang
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Tao Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Lin Yuan
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China.
| | - Jian Qin
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China.
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13
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Ji J, Sandhu J, Wang C, Fakih M. Metastatic pattern is a prognostic factor in BRAF V600E mutant colorectal cancer. Cancer Treat Res Commun 2023; 35:100714. [PMID: 37126990 DOI: 10.1016/j.ctarc.2023.100714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/23/2023] [Accepted: 04/25/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND Despite recent advancements in the treatment of metastatic BRAFV600E colorectal cancer (CRC), prognosis remains poor. However, a some patients with BRAFV600E disease have superior outcomes compared to the overall cohort and the prognostic factors associated with this improved survival are not well understood. METHODS We conducted a single center retrospective review of patients with metastatic CRC and available next generation sequencing data. Patients with confirmed BRAFV600E disease were selected for the final analysis. We collected baseline demographic characteristics, concurrent mutations, and metastatic pattern. The primary endpoint was overall survival (OS). Univariate and multivariable logistic regression was used to examine the association between baseline concurrent somatic mutations and sites of metastatic disease with survival. RESULTS Of 466 patients with metastatic CRC, 50 harbored BRAFV600E disease and 42 were included in the final analysis. The median OS in this cohort was 18.7 months (95% CI: 5.55-31.8). There was no association between baseline concurrent somatic mutations and OS. On univariate analysis, patients with lymph node only disease at the time of metastatic disease were more likely to have longer OS (hazard ratio [HR] = 0.30, 95% CI: 0.09-0.98, p = 0.047) and patients with peritoneal disease were more likely to have shorter OS (HR = 2.78, 95% CI: 1.12-6.88, p = 0.03). However, these associations did not retain statistical significance on multivariable analysis. CONCLUSIONS The pattern of metastatic disease in BRAFV600E CRC may be a prognostic factor and future studies are needed to better understand the underlying mechanisms and potentially change clinical practice for a select patient population. MICROABSTRACT Select patients with metastatic BRAFV600E colorectal cancer may have better than expected survival but are not well characterized. We conducted a retrospective review of 42 patients with metastatic BRAFV600E colorectal cancer and showed that lymph node only disease at the time of metastatic disease was associated with superior survival.
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Affiliation(s)
- Jingran Ji
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | - Jaideep Sandhu
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | - Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
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14
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Udagawa S, Ooki A, Shinozaki E, Fukuda K, Yamaguchi K, Osumi H. Circulating Tumor DNA: The Dawn of a New Era in the Optimization of Chemotherapeutic Strategies for Metastatic Colo-Rectal Cancer Focusing on RAS Mutation. Cancers (Basel) 2023; 15:1473. [PMID: 36900264 PMCID: PMC10001242 DOI: 10.3390/cancers15051473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/10/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Genotyping of tumor tissues to assess RAS and BRAF V600E mutations enables us to select optimal molecularly targeted therapies when considering treatment strategies for patients with metastatic colorectal cancer. Tissue-based genetic testing is limited by the difficulty of performing repeated tests, due to the invasive nature of tissue biopsy, and by tumor heterogeneity, which can limit the usefulness of the information it yields. Liquid biopsy, represented by circulating tumor DNA (ctDNA), has attracted attention as a novel method for detecting genetic alterations. Liquid biopsies are more convenient and much less invasive than tissue biopsies and are useful for obtaining comprehensive genomic information on primary and metastatic tumors. Assessing ctDNA can help track genomic evolution and the status of alterations in genes such as RAS, which are sometimes altered following chemotherapy. In this review, we discuss the potential clinical applications of ctDNA, summarize clinical trials focusing on RAS, and present the future prospects of ctDNA analysis that could change daily clinical practice.
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Affiliation(s)
| | | | | | | | | | - Hiroki Osumi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
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15
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Tang YL, Li DD, Duan JY, Sheng LM, Wang X. Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments. World J Gastroenterol 2023; 29:926-948. [PMID: 36844139 PMCID: PMC9950860 DOI: 10.3748/wjg.v29.i6.926] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/24/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.
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Affiliation(s)
- Yuan-Ling Tang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dan-Dan Li
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Duan
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei-Ming Sheng
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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16
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Sakata H, Murase M, Kato T, Yamaguchi K, Sugihara K, Suzuki S, Yoshino T. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. Int J Clin Oncol 2023; 28:139-144. [PMID: 36355316 PMCID: PMC9823055 DOI: 10.1007/s10147-022-02264-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 10/30/2022] [Indexed: 11/12/2022]
Abstract
BACKGROUND Triplet and doublet regimens of encorafenib plus cetuximab with and without binimetinib, respectively, were approved in Japan for unresectable, metastatic, BRAF V600E-mutated colorectal cancer (mCRC) that had progressed after 1-2 prior chemotherapies. This early post-marketing phase vigilance (EPPV) study collected adverse drug reactions (ADRs) from Japanese patients to ensure safety measures as appropriate. METHODS Patients with BRAF V600E mCRC who received the triplet or doublet regimens in Japan were selected for this study. ADRs were collected as spontaneous reports between November 27, 2020 and May 26, 2021. Serious ADRs were evaluated according to guidelines of the International Council for Harmonisation and the EudraVigilance list of Important Medical Event Terms. RESULTS An estimated 550 Japanese patients with mCRC received the triplet or doublet regimens during the 6-month EPPV period. Overall, 101 and 42 patients reported ADRs and serious ADRs, respectively. No ADRs leading to death were reported. The most frequently reported ADRs were nausea (17 patients), serous retinal detachment (16), decreased appetite (12), diarrhea (11), and vomiting (11). Among the important identified/potential risks that are defined in the risk management plans for encorafenib and binimetinib, eye disorder-related ADRs were observed in 32 patients, rhabdomyolysis-related ADRs in 12, hemorrhage-related ADRs in 7, and hepatic dysfunction-related ADRs in 7. Of 22 patients with serious eye disorders, 20 recovered or were recovering during the EPPV period. CONCLUSION The safety profile in this EPPV study was similar to that from the phase III BEACON CRC study and no new safety concerns were identified.
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Affiliation(s)
- Hidenori Sakata
- Department of Pharmacovigilance, Ono Pharmaceutical, Co., Ltd., 1-5, Dosho-Machi 2-Chome, Chuo-Ku, Osaka, 541-8526 Japan
| | - Maki Murase
- Department of Oncology Medical Affairs, Ono Pharmaceutical, Co., Ltd., 3-8-20, Marunouchi, Naka-Ku, Nagoya, Aichi, 460-0002 Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-Ku, Osaka, 540-0006 Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-Ku, Tokyo, 135-8550 Japan
| | - Kenichi Sugihara
- Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-Ku, Tokyo, 113-8510 Japan
| | - Shigenobu Suzuki
- Department of Ophthalmic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan
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17
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Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer. J Clin Med 2022; 11:jcm11247523. [PMID: 36556139 PMCID: PMC9783354 DOI: 10.3390/jcm11247523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.
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18
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O'Riordan E, Bennett MW, Daly L, Power DG. The implication of BRAF mutation in advanced colorectal cancer. Ir J Med Sci 2022; 191:2467-2474. [PMID: 34877621 PMCID: PMC9672001 DOI: 10.1007/s11845-021-02689-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/09/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND Advanced colorectal cancer (CRC) is frequently a lethal disease. Mutations in the BRAF gene is a key driver in CRC pathogenesis and confers a poor prognosis. To date, Irish data on this molecular subtype of CRC is lacking. AIMS Our aim was to compare the natural history of Irish patients with BRAF (BRAFMUT) metastatic CRC with a control group of metastatic CRC patients without BRAF mutation (BRAFWT wild- type). METHOD A retrospective observational analysis of advanced CRC patients with known BRAFMUT was conducted by chart review. BRAFMUT patients were identified from the Cork University Hospital (CUH) histopathology database. Controls with known BRAFWT were randomly selected from the database. Demographic characteristics and clinicopathological data were recorded. Survival was assessed with Kaplan-Meier curve/Cox proportional hazard models. RESULTS Twenty patients with BRAFMUT and 36 with BRAFWT were studied. BRAFMUT were more likely female (75% vs 33%, p = 0.007) and right-sided (65% vs 31.4%, p = 0.033). Median overall survival was lower in BRAFMUT group (17.3 months (95% CI 0-40.8)) compared to patients with BRAFWT (median survival not reached, log rank p = 0.001). On multivariate analysis, BRAFMUT was independently associated with an increased risk of mortality (HR 12.76 (95% CI 3.15-51.7), p < 0.001). CONCLUSION BRAFMUT advanced colorectal cancer was associated with significantly reduced overall survival in this Irish CRC population. Knowledge of mutation status should now be considered standard of care and should dictate management. Surgeons should be aware of this genetic signature as the natural history of the disease may mitigate against an aggressive surgical strategy. A prospective study should be conducted to further corroborate these findings.
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Affiliation(s)
- Emma O'Riordan
- School of Medicine, University College Cork, Cork, Republic of Ireland.
| | | | - Louise Daly
- School of Food & Nutritional Sciences, University College Cork, Cork, Republic of Ireland
| | - Derek G Power
- Department of Medical Oncology, Mercy & Cork University Hospitals, Cork, Republic of Ireland
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19
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Lee B, Gately L, Lok SW, Tran B, Lee M, Wong R, Markman B, Dunn K, Wong V, Loft M, Jalili A, Anton A, To R, Andrews M, Gibbs P. Leveraging Comprehensive Cancer Registry Data to Enable a Broad Range of Research, Audit and Patient Support Activities. Cancers (Basel) 2022; 14:cancers14174131. [PMID: 36077668 PMCID: PMC9454529 DOI: 10.3390/cancers14174131] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/21/2022] [Accepted: 08/24/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Registry data has the potential to support a broad range of research, audit and education initiatives. Here, we describe the experience and learnings of a series of large multi-institutional cancer registries that leverage real-world clinical data for a range of purposes, that informs the conduct and output of each registry in a virtuous cycle. Lessons learnt include the need for careful and continuous curation of information being collected, regular database updates, and the need for a continued focus on data quality. As a standalone resource, each registry has supported numerous projects, but linkage with external datasets with patients in common has enhanced the research potential. Multiple projects have linked registry data with matched tissue specimens to support the discovery and valiation of prognostic and predictive markers in the tumour and blood specimens. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly studies exploring the best use of drug options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data. Abstract Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.
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Affiliation(s)
- Belinda Lee
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Northern Health, Epping, VIC 3076, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- School of Medicine and Dentistry, University of Melbourne, Parkville, VIC 3010, Australia
- Correspondence:
| | - Lucy Gately
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Cabrini Haematology and Oncology Centre, Malvern, VIC 3144, Australia
| | - Sheau Wen Lok
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
| | - Ben Tran
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
| | - Margaret Lee
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Eastern Health, Melbourne, VIC 3151, Australia
- Department of Medical Oncology, Western Hospital, Melbourne, VIC 3021, Australia
| | - Rachel Wong
- Department of Medical Oncology, Eastern Health, Melbourne, VIC 3151, Australia
- Eastern Health Clinical School, Monash University, Clayton, VIC 3800, Australia
| | - Ben Markman
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Alfred Health, Melbourne, VIC 3004, Australia
| | - Kate Dunn
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
| | - Vanessa Wong
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Ballarat Health Service, Ballarat Central, VIC 3350, Australia
| | - Matthew Loft
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Azim Jalili
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Northern Health, Epping, VIC 3076, Australia
- Department of Medical Oncology, Western Hospital, Melbourne, VIC 3021, Australia
| | - Angelyn Anton
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Eastern Health, Melbourne, VIC 3151, Australia
| | - Richard To
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- School of Medicine and Dentistry, University of Melbourne, Parkville, VIC 3010, Australia
| | - Miles Andrews
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Oncology, Alfred Health, Melbourne, VIC 3004, Australia
| | - Peter Gibbs
- Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- School of Medicine and Dentistry, University of Melbourne, Parkville, VIC 3010, Australia
- Department of Medical Oncology, Western Hospital, Melbourne, VIC 3021, Australia
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Alfaro Alfaro ÁE, Murillo Castillo B, Cordero García E, Tascón J, Morales AI. Colon Cancer Pharmacogenetics: A Narrative Review. PHARMACY 2022; 10:95. [PMID: 36005935 PMCID: PMC9413567 DOI: 10.3390/pharmacy10040095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 12/16/2022] Open
Abstract
Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.
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Affiliation(s)
| | | | | | - Javier Tascón
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana I. Morales
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
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Mosca M, Filippini DM, Tober N, Rojas FL, Rihawi K, Di Fabio F. Unexpected response to fourth-line paclitaxel in a patient with metastatic oropharyngeal squamous cell carcinoma, immunotherapy-refractory: a case report. Anticancer Drugs 2022; 33:691-695. [PMID: 35324531 DOI: 10.1097/cad.0000000000001302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
In recent years, immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab have revolutionized the treatment landscape in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, many patients do not respond to ICIs for reasons that remain largely unknown. For patients who progress on ICIs, chemotherapy and/or biologic therapies are the most widely used treatments based on the clinician's choice, with no defined sequence strategy. We report the experience of a patient with metastatic oropharyngeal squamous cell cancer p16 and human papillomavirus-DNA positive who received chemotherapy with weekly paclitaxel after progressing on nivolumab. Our patient presented a partial response to fourth line paclitaxel, which lasted more than 2 years, with an improvement of his quality of life too. These results support the hypothesis of synergism between immunotherapy and conventional chemotherapies. Even in the setting of immune-refractory disease, immunotherapy may affect tumor immune microenvironment thus leading to a synergistic effect with conventional chemotherapy and achieving unexpected results.
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Affiliation(s)
- Mirta Mosca
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
| | - Daria Maria Filippini
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nastassja Tober
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
| | - Fabiola Lorena Rojas
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Karim Rihawi
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Di Fabio
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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22
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Bell PD, Pai RK. Immune Response in Colorectal Carcinoma: A Review of Its Significance as a Predictive and Prognostic Biomarker. Histopathology 2022; 81:696-714. [PMID: 35758208 DOI: 10.1111/his.14713] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 11/30/2022]
Abstract
Colorectal carcinoma is a leading cause of cancer-related death worldwide. There is significant prognostic heterogeneity in stage II and III tumours, necessitating the development of new biomarkers to better identify patients at risk of disease progression. Recently, the tumour immune environment, particularly the type and quantity of T lymphocytes, has been shown to be a useful biomarker in predicting prognosis for patients with colorectal carcinoma. In this review, the significance of the immune response in colorectal carcinoma, including its influence on prognosis and response to therapy, will be detailed.
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Affiliation(s)
- Phoenix D Bell
- Department of Pathology, University of Pittsburgh Medical Centre, Pittsburgh, PA, 15213, USA
| | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Centre, Pittsburgh, PA, 15213, USA
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23
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Crockett SD, Barry EL, Mott LA, Snover DC, Wallace K, Baron JA. Predictors of Incident Serrated Polyps: Results from a Large Multicenter Clinical Trial. Cancer Epidemiol Biomarkers Prev 2022; 31:1058-1067. [PMID: 35506244 DOI: 10.1158/1055-9965.epi-21-1226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/07/2022] [Accepted: 02/16/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Serrated polyps (SP) are important colorectal cancer precursors, yet their epidemiology is incompletely understood. We measured risk factors for incident sessile-serrated lesions (SSL) and microvesicular (MVHP) and goblet-cell rich (GCHP) hyperplastic polyp subtypes. METHODS We conducted a cohort study of patients undergoing colonoscopic surveillance nested within a chemoprevention trial. Outcomes of interest were ≥1 SPs, including SSLs, MVHPs, and GCHPs specifically. Multivariable generalized estimating equation models were used to estimate adjusted risk ratios (RR) and 95% confidence intervals (CI) for different polyp types. RESULTS Among 2,102 participants, a total of 1,615 SPs (including 212 SSLs) were found among 758 participants during follow-up. Prior history of SPs was strongly associated with subsequent occurrence of SPs. There was no apparent association between age, sex, or education and risk of SPs. Black participants were at lower risk of SSLs and MVHPs, but higher risk of GCHPs compared with white participants [RR, 0.40; 95% CI, 0.16-0.99); RR, 0.63 (95% CI, 0.42-0.96); and RR, 1.83 (95% CI, 1.23-2.72) respectively]. Alcohol and smoking exposure were also associated with SPs, including hyperplastic polyp subtypes in particular. CONCLUSIONS In this prospective study, the risk of SP subtypes differed by race, alcohol, and smoking status, and prior history of SPs. Risk factor associations for SPs differ from risk factors for conventional adenomas, supporting the concept of etiologic heterogeneity of colorectal cancer. IMPACT These findings allow for better risk stratification of patients undergoing colorectal cancer screening and could inform screening test selection.
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Affiliation(s)
- Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Elizabeth L Barry
- Department of Epidemiology, Geisel Dartmouth School of Medicine, Lebanon, New Hampshire
| | - Leila A Mott
- Department of Epidemiology, Geisel Dartmouth School of Medicine, Lebanon, New Hampshire
| | - Dale C Snover
- University of Minnesota (Retired), Minneapolis, Minnesota
| | - Kristin Wallace
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - John A Baron
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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24
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Yekedüz E, Akbulut H, Utkan G, Ürün Y. Genomic Landscape of Actionable Mutations in Primary and Metastatic Tissues of Colon Adenocarcinoma. Cureus 2022; 14:e24175. [PMID: 35592200 PMCID: PMC9110093 DOI: 10.7759/cureus.24175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2022] [Indexed: 11/05/2022] Open
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25
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Ros J, Saoudi N, Salvà F, Baraibar I, Alonso G, Tabernero J, Elez E. Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies. Expert Opin Investig Drugs 2022; 31:235-247. [PMID: 35133234 DOI: 10.1080/13543784.2022.2040016] [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] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status and over the last few years several promising new biomarkers have also been identified. Circulating tumor DNA has reshaped the prognosis of localized CRC. These genomic findings can guide treatment management to improve clinical outcomes. AREAS COVERED Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, al clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented. EXPERT OPINION The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide the treatment of patients with CRC has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low, however the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Department of Precision Medicine, Medical Oncology, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Campania, Italy
| | - Nadia Saoudi
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Francesc Salvà
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Iosune Baraibar
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Guzman Alonso
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Gaggianesi M, Mangiapane LR, Modica C, Pantina VD, Porcelli G, Di Franco S, Lo Iacono M, D’Accardo C, Verona F, Pillitteri I, Turdo A, Veschi V, Brancato OR, Muratore G, Pistone G, Bongiorno MR, Todaro M, De Maria R, Stassi G. Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells. Cancers (Basel) 2022; 14:cancers14030673. [PMID: 35158939 PMCID: PMC8833549 DOI: 10.3390/cancers14030673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/16/2021] [Accepted: 01/25/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Compelling evidence has shown that cancer stem cells (CSCs) are responsible for high resistance to conventional anti-cancer therapies. Here, we demonstrate that the tumor microenvironment protects CR-CSCs from EGFR/HER2, BRAF and PI3K targeting, promoting CD44v6 and Myc expression. Alternatively, as a substitution for HER2 and BRAF, the Myc transcription inhibitor can overcome the protective effects of microenvironmental cytokines, impairing the survival of CR-CSCs. These data highlight the targeting of Myc and PI3K activity as a novel therapeutic strategy against advanced colorectal cancer. Abstract Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression.
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Affiliation(s)
- Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Laura Rosa Mangiapane
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Chiara Modica
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Vincenzo Davide Pantina
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Gaetana Porcelli
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Melania Lo Iacono
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Caterina D’Accardo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Francesco Verona
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Irene Pillitteri
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Alice Turdo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Ornella Roberta Brancato
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Giampaolo Muratore
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Giuseppe Pistone
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Maria Rita Bongiorno
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Fondazione Policlinico A Gemelli IRCCS, 00168 Roma, Italy
- Correspondence: (R.D.M.); (G.S.); Tel.: +39-06-3015-4914 (R.D.M.); +39-091-2389-0813 (G.S.)
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
- Correspondence: (R.D.M.); (G.S.); Tel.: +39-06-3015-4914 (R.D.M.); +39-091-2389-0813 (G.S.)
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Multi-Omic Approaches in Colorectal Cancer beyond Genomic Data. J Pers Med 2022; 12:jpm12020128. [PMID: 35207616 PMCID: PMC8880341 DOI: 10.3390/jpm12020128] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent tumours and one of the major causes of morbidity and mortality globally. Its incidence has increased in recent years and could be linked to unhealthy dietary habits combined with environmental and hereditary factors, which can lead to genetic and epigenetic changes and induce tumour development. The model of CRC progression has always been based on a genomic, parametric, static and complex approach involving oncogenes and tumour suppressor genes. Recent advances in omics sciences have sought a paradigm shift to a multiparametric, immunological-stromal, and dynamic approach for a better understanding of carcinogenesis and tumour heterogeneity. In the present paper, we review the most important preclinical and clinical data and present recent discoveries in the field of transcriptomics, proteomics, metagenomics and radiomics in CRC disease.
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Akhoundova D, Pietge H, Hussung S, Kiessling M, Britschgi C, Zoche M, Rechsteiner M, Weber A, Fritsch RM. Targeting Secondary and Tertiary Resistance to BRAF Inhibition in BRAF V600E-Mutated Metastatic Colorectal Cancer. JCO Precis Oncol 2022; 5:1082-1087. [PMID: 34994629 DOI: 10.1200/po.21.00107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Dilara Akhoundova
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland
| | - Heike Pietge
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland
| | - Saskia Hussung
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland
| | - Michael Kiessling
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland
| | - Christian Britschgi
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland
| | - Martin Zoche
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Markus Rechsteiner
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Ralph M Fritsch
- Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland
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Ji J, Wang C, Fakih M. Rechallenge With BRAF and anti-EGFR Inhibitors in Patients With Metastatic Colorectal Cancer Harboring BRAF Mutation Who Progressed on Cetuximab and Encorafenib With or Without Binimetinib: A Case Series. Clin Colorectal Cancer 2021; 21:267-271. [DOI: 10.1016/j.clcc.2021.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/07/2021] [Accepted: 12/11/2021] [Indexed: 11/27/2022]
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Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data. Cancers (Basel) 2021; 13:cancers13236018. [PMID: 34885128 PMCID: PMC8656546 DOI: 10.3390/cancers13236018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary This experimental preclinical study developed a strategy to identify signatures for the personalized treatment of colon cancer focusing on target-specific drug combinations. Tumor growth inhibition was analyzed in a preclinical phase II study using 25 patient-derived xenograft models (PDX) treated with drug combinations blocking alternatively activated oncogenic pathways. Results reveal an improved response by combinatorial treatment in some defined molecular subgroups and potential alternative treatment options in KRAS- and BRAF-mutated colon cancer. Abstract The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs.
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Cherri S, Libertini M, Zaniboni A. New drugs for the treatment of metastatic colorectal cancer. World J Gastrointest Oncol 2021; 13:1551-1560. [PMID: 34853636 PMCID: PMC8603451 DOI: 10.4251/wjgo.v13.i11.1551] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/01/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) represents one of the most frequent malignancies in terms of incidence and mortality, thus representing the third leading cause of cancer death worldwide. In the last decade, few drugs have enriched the treatment landscape of metastatic CRC and have significantly affected prognosis. Unlike other neoplasms, metastatic CRC patients who have exhausted treatment options often still maintain a good performance status. There are many challenges to increasing potential treatment options, notably a better understanding of disease biology and the mechanisms of resistance underlying cancer treatment failure. The development of new drugs for metastatic CRC certainly represents one of the most important challenges in medical oncology. This article discusses the main limitations in the development of new drugs and potential future scenarios. In particular, we addressed three questions: (1) The main limitations of targeted therapy in the treatment of metastatic CRC (mCRC); (2) New target armamentarium that could escape primary and secondary resistance and lead to more personalized mCRC therapy; and (3) Future directions.
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Affiliation(s)
- Sara Cherri
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
| | - Michela Libertini
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
| | - Alberto Zaniboni
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
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Pashirzad M, Khorasanian R, Fard MM, Arjmand MH, Langari H, Khazaei M, Soleimanpour S, Rezayi M, Ferns GA, Hassanian SM, Avan A. The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer. Curr Cancer Drug Targets 2021; 21:932-943. [PMID: 34732116 DOI: 10.2174/1568009621666211103113339] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/16/2021] [Accepted: 08/24/2021] [Indexed: 11/22/2022]
Abstract
The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.
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Affiliation(s)
- Mehran Pashirzad
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Reihaneh Khorasanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Maryam Mahmoudi Fard
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Mohammad-Hassan Arjmand
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Hadis Langari
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Saman Soleimanpour
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Majid Rezayi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Gordon A Ferns
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO. United States
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
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Personeni N, Smiroldo V, Giunta EF, Prete MG, Rimassa L, Bregni G, Sclafani F. Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives. Cancers (Basel) 2021; 13:4506. [PMID: 34572729 PMCID: PMC8472765 DOI: 10.3390/cancers13184506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/01/2021] [Accepted: 09/01/2021] [Indexed: 01/09/2023] Open
Abstract
Substantial improvements have characterized the systemic treatment of metastatic colorectal cancer (mCRC) over the past 20 years. Besides strong evidence that supports the use of RAS and BRAF status as prognostic and predictive indicators of disease and response, novel technologies have made possible the incorporation of emerging biomarkers for the management of mCRC. On one hand, the discovery of point mutations, amplifications, fusions, and gene expression profiles highlights the genomic and dynamic complexity of CRC. On the other, such discoveries are leading to newer biomarker-driven strategies that add to existing anti-epidermal growth factor receptor (EGFR) and anti-angiogenic approaches. In addition, the availability of a wide molecular profiling has relevant implications for patient prognosis and treatment benefits. Here, we will review the molecular underpinnings and clinical data supporting novel targeted treatments under development for refractory mCRC harboring BRAF mutations, KRAS G12C mutations, HER2 amplification, and less common molecular alterations, such as the re-arrangements of NTRK, ALK, and ROS1. Additionally, we will discuss novel strategies driving the rechallenge of EGFR antibodies and the incorporation of newer anti-angiogenic agents in the therapeutic armamentarium.
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Affiliation(s)
- Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy; (N.P.); (M.G.P.)
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy;
| | - Valeria Smiroldo
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy;
| | - Emilio Francesco Giunta
- Medical Oncology Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Pansini 5, 80131 Naples, Italy;
| | - Maria Giuseppina Prete
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy; (N.P.); (M.G.P.)
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy;
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy; (N.P.); (M.G.P.)
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy;
| | - Giacomo Bregni
- Department of Medical Oncology, Institut Jules Bordet–Université Libre de Bruxelles (ULB), Boulevard de Waterloo 121, 1000 Bruxelles, Belgium; (G.B.); (F.S.)
| | - Francesco Sclafani
- Department of Medical Oncology, Institut Jules Bordet–Université Libre de Bruxelles (ULB), Boulevard de Waterloo 121, 1000 Bruxelles, Belgium; (G.B.); (F.S.)
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The Prognostic Value of Locoregional Interventions for BRAF V600E Metastatic Colorectal Cancer: A Retrospective Cohort Analysis. Biomolecules 2021; 11:biom11091268. [PMID: 34572480 PMCID: PMC8468777 DOI: 10.3390/biom11091268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 01/01/2023] Open
Abstract
The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22–0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01–1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04–0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21–1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.
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Precision oncology in metastatic colorectal cancer - from biology to medicine. Nat Rev Clin Oncol 2021; 18:506-525. [PMID: 33864051 DOI: 10.1038/s41571-021-00495-z] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
Abstract
Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.
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Park R, Lopes L, Lee S, Riano I, Saeed A. The prognostic and predictive impact of BRAF mutations in deficient mismatch repair/microsatellite instability-high colorectal cancer: systematic review/meta-analysis. Future Oncol 2021; 17:4221-4231. [PMID: 34323124 DOI: 10.2217/fon-2021-0552] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I-IV patients (hazard ratio: 1.57; 95% CI: 1.23-1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48-2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.
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Affiliation(s)
- Robin Park
- MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA
| | - Laercio Lopes
- MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA
| | - Sunggon Lee
- Department of Medicine, Korea University, Seoul 02841, Korea
| | - Ivy Riano
- MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66205, USA
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Saravani K, Salarzaei M, Parooie F. Effect of KRAS and BRAF mutations in metastatic colorectal cancer patients: A systematic review and meta-analysis based on tumor sidedness and KRAS subtypes. Hum Antibodies 2021; 29:275-284. [PMID: 34334388 DOI: 10.3233/hab-210451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Metastatic or recurrent colorectal cancer (MRCRC) has a poor prognosis. The aim of the present meta-analysis was to assess the prevalence of different subtypes of KRAS mutation and BRAF mutation in metastatic CRC patients, and evaluate the relationship between the tumor sidedness and prevalence of KRAS and BRAF mutation. METHODS We searched MEDLINE/PubMed, the Cochrane Library, and ClinicalTrials.gov from January 2010 to July 2020. The data were extracted independently according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The statistical analysis was done using STATA and Meta-Disk 1.4 applications. RESULTS Overall, 6699 colorectal cancer patients were included. KRAS and BRAF mutation was reported in 28% and 6% of patients, respectively. The overall prevalence of right primary and left primary metastatic CRC patients with mutated KRAS was 40% and 60%. However, the prevalence BRAF mutated right primary and left primary metastatic CRC patients was 37% and 63%. The overall HR was 2.38 for patients with metastatic CRC who had a mutated type of KRAS. Our study showed a mean overall survival of 35.4 month for KRAS mutant and a 10.12 month survival for BRAF mutant patients with metastatic colorectal cancer patients. CONCLUSION The prevalence of KRAS and BRAF mutations varied significantly according to the location of the tumor. BRAF mutations are more commonly found in metastatic colorectal cancers on the right side. Liver was the most common site of metastases in patients with mutant KRAS and the mortality of patients with mutant KRAS was 2.3 times higher than the patients with wild types. These results help to better describe the population of mCRC patients and can have implications for improving and organizing anti-EGFR therapies. Further research is needed to assess differences in survival through mutation status and primary tumor location.
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Oncological evaluation in the perioperative period using cfDNA with BRAF V600E mutation in patients with colorectal cancer. Sci Rep 2021; 11:13263. [PMID: 34168268 PMCID: PMC8225636 DOI: 10.1038/s41598-021-92795-8] [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: 03/06/2021] [Accepted: 06/16/2021] [Indexed: 11/16/2022] Open
Abstract
The detection of circulating cell-free DNA (cfDNA) by liquid biopsy is reported to provide prognostic information in colorectal cancer (CRC). Although the frequency of BRAF V600E mutation in CRC is less than 10%, it is associated with poor responses to conventional chemotherapy. We conducted a prospective study to investigate the relationship between the perioperative mutant allele frequency (MAF) of BRAF V600E and tumor recurrence, and to evaluate the possibility of early detection of recurrence. Among 362 patients who underwent radical resection, cfDNA was extracted from the perioperative blood of 11 CRC patients with BRAF V600E mutation and analyzed using the digital polymerase chain reaction (dPCR) system. The median follow-up time was 22 months, and there were four cases of recurrence. Although there was no correlation between recurrence and the perioperative MAF of BRAF V600E, tumor diameter was correlated with the MAF (p = 0.024), and the MAF increased with time in two patients from whom additional samples were obtained prior to recurrence. In this study, we identified a correlation between the pathological tumor diameter and the MAF, but it was difficult to predict recurrence by measuring cfDNA with BRAF V600E mutation in the perioperative period of radical resection of CRC.
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Guarini C, Grassi T, Pezzicoli G, Porta C. Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer. Int J Mol Sci 2021; 22:6813. [PMID: 34202896 PMCID: PMC8268006 DOI: 10.3390/ijms22136813] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2's role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.
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Affiliation(s)
- Chiara Guarini
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Teresa Grassi
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Gaetano Pezzicoli
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Camillo Porta
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
- Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, 70124 Bari, Italy
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Impact of BRAF mutations on clinical outcomes following liver surgery for colorectal liver metastases: An updated meta-analysis. Eur J Surg Oncol 2021; 47:2722-2733. [PMID: 34099355 DOI: 10.1016/j.ejso.2021.05.039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 05/25/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Data regarding clinical outcomes of patients undergoing hepatic resection for BRAF-mutated colorectal liver metastases (CRLM) are scarce. Most of the studies report an impaired median overall survival (OS) in BRAF-mutated patients, but controversial Results regarding both recurrence-free survival (RFS) and recurrence patterns. The purpose of this updated meta-analysis was to better precise the impact of BRAF mutations on clinical outcomes following liver surgery for CRLM study, especially on recurrence. METHODS A systematic literature review was performed to identify articles reporting clinical outcomes including both OS and RFS, recurrence patterns, and clinicopathological details of patients who underwent complete liver resection for CRLM, stratified according to BRAF mutational status. RESULTS Thirteen retrospective studies, including 5192 patients, met the inclusion criteria. The analysis revealed that both OS (OR = 1.981; 95% CI = [1.613-2.432]) and RFS (OR = 1.49; 95% CI [1.01-2.21]) were impaired following liver surgery for CRLM in BRAF-mutated patients. Risks of both hepatic (OR = 0.42; 95% CI [0.18-0.98]) and extrahepatic recurrences (OR = 0.53; 95% CI [0.33-0.83] were significantly higher in BRAF-mutated patients. These patients tended to have higher rates of right-sided colon primary tumors, primary positive lymph nodes, and multiple CRLM. CONCLUSIONS This meta-analysis confirms that BRAF mutations impair both OS and RFS following liver surgery. Therefore, BRAF mutational status should probably be included in further prognostic scores for the assessment of the expected clinical outcomes following surgery for CRLM.
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Cerrito MG, Grassilli E. Identifying Novel Actionable Targets in Colon Cancer. Biomedicines 2021; 9:biomedicines9050579. [PMID: 34065438 PMCID: PMC8160963 DOI: 10.3390/biomedicines9050579] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/10/2021] [Accepted: 05/14/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high-throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations.
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Vemala RNG, Katti SV, Sirohi B, Manikandan D, Nandakumar G. Molecular Oncology in Management of Colorectal Cancer. Indian J Surg Oncol 2021; 12:169-180. [PMID: 33994743 PMCID: PMC8119525 DOI: 10.1007/s13193-021-01289-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 02/10/2021] [Indexed: 11/28/2022] Open
Abstract
Colorectal cancers are the third most common cancers in the world. Management of both primary and metastatic colorectal cancers has evolved over the last couple of decades. Extensive research in molecular oncology has helped us understand and identify these complex intricacies in colorectal cancer biology and disease progression. These advances coupled with improved knowledge on various mutations have helped develop targeted chemotherapeutics and has allowed planning an effective treatment regimen in this era of immunotherapy with precision. The diverse chemotherapeutic and biological agents at our disposal can make decision making a very complex process. Molecular profile, including CIN, RAS, BRAF mutations, microsatellite instability, ctDNA, and consensus molecular subtypes, are some of the important factors which are to be considered while planning an individualized treatment regimen. This article summarizes the current status of molecular oncology in the management of colorectal cancer and should serve as a practical guide for the clinical team.
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Affiliation(s)
| | | | | | | | - Govind Nandakumar
- Columbia Asia Hospitals, Bengaluru, India
- Weill Cornell Medical College, New York, USA
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Foroughi S, Wong HL, Tie J, Wong R, Lee M, Lee B, Jones I, Skinner I, Burgess AW, Gibbs P. Characteristics and outcomes of participants in colorectal cancer biomarker trials versus a real-world cohort. Acta Oncol 2021; 60:482-490. [PMID: 33377792 DOI: 10.1080/0284186x.2020.1862907] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The restrictive eligibility criteria of therapy-focused cancer clinical trials can limit the external validity of the results. The characteristics and survival outcomes of patients enrolled in stand-alone biomarker studies have yet to be explored. We examined the characteristics of patients enrolled in a series of biomarker studies in stage II and III colorectal cancer (CRC) and of the broader patient population from which the study cohorts were recruited. MATERIAL AND METHODS We examined three distinct trial scenarios: a retrospective cohort study (RCS) where archival tissue samples were analyzed, a prospective observational study (POS) where blood samples were collected but patients received standard treatment and a randomized clinical trial (RCT) where biomarker analysis could inform clinical care. Clinical data for each study time period were extracted from a prospective registry. RESULTS For all CRC patients (n = 4033) in this study, the median age was 70 years and 54% were ECOG 0. For patients in the RCS (n = 450), POS (n = 284) and RCT (n = 230), the median age was 72, 65 and 64 years, with 45%, 74% and 79% being ECOG 0. For the POS and RCT, 33% and 36% of all patients with the relevant disease stage were enrolled over the study recruitment period. Survival outcomes were similar for patients in the RCS and POS. RCT outcome data are not available. CONCLUSION As for therapy-based trials, enrollment in prospective biomarker studies may be selective, despite relatively broad eligibility criteria. Characteristics and recruitment were similar for POS and RCT patients, indicating study complexity may not necessarily limit patient recruitment. For the prospective biomarker study cohorts examined, the selective recruitment did not significantly impact survival outcomes, suggesting potential for high external validity.
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Affiliation(s)
- Siavash Foroughi
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
| | - Hui-li Wong
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Jeanne Tie
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
| | - Rachel Wong
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Eastern Health, Box Hill, Australia
- Eastern Health Clinical School, Monash University, Box Hill, Australia
| | - Margaret Lee
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
- Department of Medical Oncology, Eastern Health, Box Hill, Australia
- Eastern Health Clinical School, Monash University, Box Hill, Australia
| | - Belinda Lee
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Medical Oncology, The Northern Hospital, Epping, Australia
| | - Ian Jones
- Department of Surgery, Royal Melbourne Hospital, Parkville, Australia
| | - Iain Skinner
- Department of Surgery, Western Health, St Albans, Australia
- Department of Surgery, Werribee Mercy Hospital, Werribee, Australia
| | - Antony W. Burgess
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Surgery, Royal Melbourne Hospital, Parkville, Australia
| | - Peter Gibbs
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
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UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI. JOURNAL OF ONCOLOGY 2021; 2021:6686517. [PMID: 33777142 PMCID: PMC7972843 DOI: 10.1155/2021/6686517] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/12/2021] [Accepted: 02/25/2021] [Indexed: 12/22/2022]
Abstract
Background Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.
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Li S, Hu H, Ding D, Zhu Y, Huang J. Cost-Effectiveness Analysis of Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Metastatic Colorectal Cancer in the USA. Adv Ther 2021; 38:1650-1659. [PMID: 33569738 DOI: 10.1007/s12325-021-01627-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 01/15/2021] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Recently the phase 3 BEACON trial showed that the combination of encorafenib, cetuximab, and binimetinib versus cetuximab and irinotecan/FOLFIRI improved overall survival in pre-treated patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation. However, whether the benefits of these therapies justify their high costs has not been estimated in the USA. The purpose of this study was to evaluate the cost-effectiveness of BEC (binimetinib, encorafenib, and cetuximab), EC (encorafenib and cetuximab), and CI/CF (cetuximab with irinotecan or FOLFIRI) in patients with BRAF V600E-mutated mCRC after first- and second-line therapy. METHODS A Markov model was constructed to determine the costs and effects of BEC, EC, and CI/CF on the basis of BEACON trial outcomes data. Health outcomes were measured in life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses characterized parameters influencing cost-effectiveness. Subgroup analyses were conducted as well. RESULTS The QALYs gained in BEC, EC, and CI/CF were 0.62, 0.54, and 0.40, respectively. BEC resulted in ICERs of $883,895.73/QALY and $1,646,846.14/QALY versus CI/CF and EC, respectively. Compared with CI/CF, the ICER was $435,449.88/QALY in EC. The most sensitive parameters in the comparison among the three arms were the utilities of progressive disease and progression-free survival. Probabilistic sensitivity analyses showed that the probability of BEC and EC being cost-effective was 0%. In subgroup analyses, the ICER remained above the willingness-to-pay threshold of $150,000 per QALY. CONCLUSION BEC and EC were not cost-effective regimens for patients with pre-treated mCRC with BRAF V600E mutation.
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Affiliation(s)
- Shuosha Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Huabin Hu
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, 510655, China
| | - Dong Ding
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Youwen Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Ros J, Baraibar I, Sardo E, Mulet N, Salvà F, Argilés G, Martini G, Ciardiello D, Cuadra JL, Tabernero J, Élez E. BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer. Ther Adv Med Oncol 2021; 13:1758835921992974. [PMID: 33747149 PMCID: PMC7903827 DOI: 10.1177/1758835921992974] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 01/13/2021] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. AREAS COVERED This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. EXPERT OPINION Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.
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Affiliation(s)
- Javier Ros
- Department of Medical Oncology, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, Barcelona, Catalunya 08035, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Iosune Baraibar
- Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Catalunya, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Emilia Sardo
- Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Catalunya, Spain
| | - Nuria Mulet
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Institut Catala d’ Oncologia, Barcelona, Spain
| | - Francesc Salvà
- Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Catalunya, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Guillem Argilés
- Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Catalunya, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Giulia Martini
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Caserta, Campania, Italy
| | - Davide Ciardiello
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Caserta, Campania, Italy
| | | | - Josep Tabernero
- Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, UVic-UCC, Passeig Vall d’Hebron, Barcelona, Spain
| | - Elena Élez
- Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Catalunya, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Wong V, Lee M, Wong R, Tie J, Shapiro J, Desai J, Nott L, Steel S, Burge M, Ma B, Khattak A, Hong W, Gibbs P. BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset? Target Oncol 2021; 16:227-236. [PMID: 33599905 DOI: 10.1007/s11523-021-00793-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary. OBJECTIVES To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS. RESULTS Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively. CONCLUSION LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.
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Affiliation(s)
- Vanessa Wong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
| | - Margaret Lee
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Western Health, St Albans, VIC, Australia.,Eastern Health, Box Hill, VIC, Australia
| | - Rachel Wong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Eastern Health, Box Hill, VIC, Australia.,Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia
| | - Jeanne Tie
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Western Health, St Albans, VIC, Australia.,Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | | | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Louise Nott
- Royal Hobart Hospital, Hobart, TAS, Australia
| | - Simone Steel
- Peninsula Private Hospital, Frankston, VIC, Australia
| | - Matthew Burge
- Royal Brisbane and Women's Hospital, Herston, QLD, Australia
| | - Brigette Ma
- Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | | | - Wei Hong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Peter Gibbs
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Western Health, St Albans, VIC, Australia
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Ishimaru K, Kawai K, Nozawa H, Sasaki K, Murono K, Emoto S, Ishii H, Anzai H, Sonoda H, Yamauchi S, Sugihara K, Ishihara S. Hazard function analysis of metastatic recurrence after colorectal cancer surgery-A nationwide retrospective study. J Surg Oncol 2021; 123:1015-1022. [PMID: 33444465 DOI: 10.1002/jso.26378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND OBJECTIVES An optimal postoperative surveillance protocol for colorectal cancer (CRC) is dependent on understanding the time line of recurrence. By hazard function analysis, this study aimed at evaluating the time of occurrence of metastasis. METHODS A total of 21,671 Stage I-III colon cancer patients were retrospectively included from the Japanese study group for postoperative follow-up of colorectal cancer database. RESULTS The 5-year incidence by metastasized organ was 6.3% for liver (right:left = 5.5%:7.0%, p = .0067), 6.0% for lung (right:left:rectum = 3.7%:4.4%:8.8%, p = 7.05E-45), and 2.0% for peritoneal (right:left:rectum = 3.1%:2.0%:1.2%, p = 1.29E-12). The peak of liver metastasis hazard rate (HR) (0.67 years) was earlier and higher than those of other metastases. The peak HR tended to be delayed in early stage CRCs (0.91, 0.76, and 0.52 years; for Stages I, II, and III, respectively). When analyzed as per the primary tumor location (right-sided, left-sided, and rectum), the peak HR for lung metastasis was twice as high for rectal cancer than for colon cancer, and peritoneal metastasis had a high HR in right-sided colon cancers. CONCLUSION The time course for the risk of recurrence in various metastatic organs based on the primary tumor site was clearly visualized in this study. This will aid in individualizing postoperative surveillance schedules.
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Affiliation(s)
- Kazuhiro Ishimaru
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Ishii
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Anzai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hirofumi Sonoda
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | | | | | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
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Duan J, Yang Y, Yin L, Zhang X, Tang Y, Zhang S, Gong H, Xiao M, Li M, Li Q, Li X, Yang L, Fan Q, Wang Y. Preliminary Study on the Identification of BRAF V600E Mutation in Colorectal Cancer by Near-Infrared Spectroscopy. Onco Targets Ther 2020; 13:13077-13085. [PMID: 33376356 PMCID: PMC7764696 DOI: 10.2147/ott.s287814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction In metastatic colorectal cancer (mCRC), the B-type Raf kinase (BRAF)V600E mutation is a molecular biomarker of poor prognosis and is of great importance to drug target. Currently, the commonly used methods for detecting BRAFV600E mutation include immunohistochemistry (IHC) and gene sequencing, but both present certain limitations. Near-infrared (NIR) spectroscopy is a spectroscopy technology that takes advantage of the electromagnetic wavelength between visible light and mid-infrared light. Methods IHC was used to detect the expression of BRAFV600E protein with the BRAFV600E (VE1) antibody in 42 cases of paraffin-embedded (FFPE) mCRC tissue sections. The NIR-discriminant analysis model (NIRS-DA) was established using 6 cases of wild-type and 6 cases of mutant-type BRAF specimens. Results IHC detection results revealed 13 cases of weakly positive (+), 1 case of moderately positive (++), and 28 cases of negative (-) CRC. Compared with the next-generation sequencing (NGS) results, the positive rate was 66.7%. The classification accuracy of calibration (CAC) was 100% compared with the results of NGS, demonstrating that the BRAFV600E mutant NIRS-DA model, verified by 2 cases of wild-type and 2 cases of mutant-type CRC samples was established. The NIRS-DA model was used to predict gene mutation in the CRC samples, 7 cases were positive (+), and 35 cases were negative (-), and the classification accuracy of prediction (CAP) was 83.3% (35/42). Discussion The NIRS-DA model-predicted results were in high agreement with the detection results of NGS, and the difference in IHC is not statistically significant (P>0.05). However, this study is a preliminary discussion on a methodology due to its small sample size.
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Affiliation(s)
- Jiale Duan
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Yanping Yang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Lei Yin
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Xue Zhang
- School of Pharmacy, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Yi Tang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Shuxian Zhang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Hanjuan Gong
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Ming Xiao
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Ming Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Qingshu Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Xian Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Lian Yang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Qi Fan
- School of Pharmacy, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Yalan Wang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
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Mineur L, François E, Plassot C, Phelip JM, Miglianico L, Dourthe LM, Bonichon N, Moreau L, Guimbaud R, Smith D, Achille E, Hervé R, Bons JM, Remy S, Faroux R, Villing AL, Mahamat A, Rabbia I, Soulié P, Baumgaertner I, Mathé N, Vazquez L, Boustany R. PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer. PLoS One 2020; 15:e0243997. [PMID: 33347495 PMCID: PMC7752147 DOI: 10.1371/journal.pone.0243997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 12/01/2020] [Indexed: 11/18/2022] Open
Abstract
Background Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. Patients and methods PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. Results A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6–12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. Conclusions ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.
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Affiliation(s)
- L. Mineur
- Institut Sainte-Catherine, Avignon, France
| | | | - C. Plassot
- Institut Universitaire de Recherche Clinique, Montpellier, France
| | - J. M. Phelip
- Hopital universitaire CHU Nord Saint Etienne, Saint Etienne, France
| | | | | | | | - L. Moreau
- Clinique les Domes, Clermont-Ferrand, France
| | | | - D. Smith
- Hopital Saint-André, Bordeaux, France
| | - E. Achille
- Clinique de l’Orangerie, Strasbourg, France
| | - R. Hervé
- CH Privé Clairval, Marseille, France
| | - J. M. Bons
- Polyclinique Saint-Francois, Desertine, France
| | - S. Remy
- Centre d’Oncologie de la côte Basque, Bayonne, France
| | | | | | | | - I. Rabbia
- Cabinet médical, Orange, Paris, France
| | | | | | - N. Mathé
- Centre Clinique de Soyaux, Soyaux, France
| | - L. Vazquez
- Institut Sainte-Catherine, Avignon, France
- * E-mail:
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