|
1
|
Karapetis CS, Liu H, Sorich MJ, Pederson LD, Van Cutsem E, Maughan T, Douillard JY, O'Callaghan CJ, Jonker D, Bokemeyer C, Sobrero A, Cremolini C, Chibaudel B, Zalcberg J, Adams R, Buyse M, Peeters M, Yoshino T, de Gramont A, Shi Q. Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database. Br J Cancer 2024; 130:1269-1278. [PMID: 38402342 PMCID: PMC11015038 DOI: 10.1038/s41416-024-02604-y] [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: 09/26/2023] [Revised: 01/22/2024] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.
Collapse
Affiliation(s)
- C S Karapetis
- Flinders Medical Centre, Adelaide, SA, Australia.
- Flinders University, Adelaide, SA, Australia.
| | - H Liu
- Mayo Clinic, Rochester, NY, USA
| | - M J Sorich
- Flinders University, Adelaide, SA, Australia
| | | | - E Van Cutsem
- University Hospitals Gasthuisberg Leuven and University of Leuven, Leuven, Belgium
| | - T Maughan
- University of Liverpool, Liverpool, UK
| | - J Y Douillard
- University of Nantes and Integrated Centers of Oncology ICO Rene Gauducheau Cancer Nantes, Nantes, France
| | | | - D Jonker
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - C Bokemeyer
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - B Chibaudel
- Franco-British Institute Levallois-Perre, Levallois-Perre, France
| | - J Zalcberg
- Dept of Medical Oncology, Alfred Health and School of Public Health, Monash University, Melbourne, VIC, Australia
| | - R Adams
- Velindre Cancer Centre Cardiff University, Cardiff, UK
| | - M Buyse
- International Drug Development Institute, Louvain-la-Neuve, Belgium
| | - M Peeters
- Antwerp University and Antwerp University Hospital, Antwerp, Belgium
| | - T Yoshino
- National Cancer Centre Hospital East, Kashiwa, Japan
| | - A de Gramont
- Franco-British Institute Levallois-Perre, Levallois-Perre, France
| | - Q Shi
- Mayo Clinic, Rochester, NY, USA
| |
Collapse
|
|
2
|
Leowattana W, Leowattana P, Leowattana T. Systemic treatment for metastatic colorectal cancer. World J Gastroenterol 2023; 29:1569-1588. [PMID: 36970592 PMCID: PMC10037252 DOI: 10.3748/wjg.v29.i10.1569] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/14/2023] Open
Abstract
Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and whole-exome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment, has resulted in tremendous breakthroughs in DNA sequencing technology in recent years. The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage, presence of high-risk pathologic characteristics, microsatellite instability status, patient age, and performance status. Chemotherapy, targeted therapy, and immunotherapy are the main systemic treatments for patients with mCRC. Despite the fact that these novel treatment choices have increased overall survival for mCRC, survival remains optimal for individuals with non-metastatic disease. The molecular technologies currently being used to support our ability to practice personalized medicine; the practical aspects of applying molecular biomarkers to regular clinical practice; and the evolution of chemotherapy, targeted therapy, and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.
Collapse
Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Pathomthep Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| |
Collapse
|
|
3
|
Leowattana W, Leowattana P, Leowattana T. Systemic treatment for metastatic colorectal cancer. World J Gastroenterol 2023; 29:1425-1444. [DOI: 10.3748/wjg.v29.i10.1425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
Abstract
Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and whole-exome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment, has resulted in tremendous breakthroughs in DNA sequencing technology in recent years. The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage, presence of high-risk pathologic characteristics, microsatellite instability status, patient age, and performance status. Chemotherapy, targeted therapy, and immunotherapy are the main systemic treatments for patients with mCRC. Despite the fact that these novel treatment choices have increased overall survival for mCRC, survival remains optimal for individuals with non-metastatic disease. The molecular technologies currently being used to support our ability to practice personalized medicine; the practical aspects of applying molecular biomarkers to regular clinical practice; and the evolution of chemotherapy, targeted therapy, and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.
Collapse
Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Pathomthep Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| |
Collapse
|
|
4
|
Ten Hoorn S, Mol L, Sommeijer DW, Nijman L, van den Bosch T, de Back TR, Ylstra B, van Dijk E, van Noesel CJM, Reinten RJ, Nagtegaal ID, Koopman M, Punt CJA, Vermeulen L. Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer. Clin Colorectal Cancer 2023; 22:67-75. [PMID: 36564280 DOI: 10.1016/j.clcc.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 11/16/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Here we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC). MATERIALS AND METHODS Retrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC. RESULTS Updated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months). CONCLUSION Adding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.
Collapse
Affiliation(s)
- Sanne Ten Hoorn
- Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands
| | - Linda Mol
- Clinical Research Department, Netherlands Comprehensive Cancer Center (IKNL), Nijmegen, The Netherlands
| | - Dirkje W Sommeijer
- Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, The Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Amsterdam, The Netherlands; Flevohospital, Department of Internal Medicine, Almere, The Netherlands
| | - Lisanne Nijman
- Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands
| | - Tom van den Bosch
- Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands; Amsterdam UMC location University of Amsterdam, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands
| | - Tim R de Back
- Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands
| | - Bauke Ylstra
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Erik van Dijk
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Carel J M van Noesel
- Amsterdam UMC location University of Amsterdam, Department of Pathology, Amsterdam, The Netherlands
| | - Roy J Reinten
- Amsterdam UMC location University of Amsterdam, Department of Pathology, Amsterdam, The Netherlands
| | - Iris D Nagtegaal
- Radboud Institute for Molecular Life Sciences, Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Cornelis J A Punt
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, Utrecht, The Netherlands
| | - Louis Vermeulen
- Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
| |
Collapse
|
|
5
|
Ognerubov NA, Ezhova EN. Somatic mutations in colorectal cancer: regional experience. CONSILIUM MEDICUM 2022. [DOI: 10.26442/20751753.2022.5.201796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Introduction. Colorectal cancer is one of the most common malignant neoplasms in economically developed countries, ranking 3rd and 2nd in the structure of morbidity and mortality, respectively. Current knowledge about the molecular features of colorectal cancer is necessary to implement the principle of personalized therapy.
Aim. To study regional features of tumor genomic landscape in colorectal cancer.
Materials and methods. The retrospective study from 2019 to 2022 included 153 patients with stage IIV colorectal cancer aged 32 to 80 years, with a median of 63.8 years. DNA samples extracted from paraffin blocks of tumor tissue were analyzed using a real-time polymerase chain reaction. The study patients included 43.8% of males and 56.2% of females.
Results. Somatic mutations were detected in 48.4% of patients. The maximum number of mutations was detected in the KRAS gene 60 (81%). The mutation rate was significantly higher in females versus males. KRAS mutations predominate in the colon compared to the rectum, accounting for 66.7 and 33.3%, respectively. In tumors of the right colon, these mutations were detected in 18.3% of cases, and in the left colon, 48.4%. NRAS mutations were found in 9.5% of cases, mainly in tumors of the left colon. BRAF mutations were diagnosed in 6 patients, 5 of them were women, and the tumors were localized in the right colon. The highest rate of KRAS mutations was observed in codons 12 and 13, accounting for 86.7% of cases. The G12V mutation occurred in the majority of patients (25%), followed by G12D (20%) and G12A (16.6%).
Conclusion. Somatic mutations in RAS and BRAF genes in colorectal cancer were detected in 48.4% of patients in the Tambov region. Among them, there is a predominance of KRAS mutations 81% in females. KRAS oncogenic mutations are predictors of treatment response and prognosis.
Collapse
|
|
6
|
Janani B, Vijayakumar M, Priya K, Kim JH, Prabakaran DS, Shahid M, Al-Ghamdi S, Alsaidan M, Othman Bahakim N, Hassan Abdelzaher M, Ramesh T. EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges. Vaccines (Basel) 2022; 10:vaccines10040499. [PMID: 35455247 PMCID: PMC9030067 DOI: 10.3390/vaccines10040499] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/05/2023] Open
Abstract
Colorectal carcinoma (CRC) is the most lethal and common form of cancer in the world. It was responsible for almost 881,000 cancer deaths in 2018. Approximately 25% of cases are diagnosed at advanced stages with metastasis—this poses challenges for effective surgical control and future tumor-related mortality. There are numerous diagnostic methods that can be used to reduce the risk of colorectal carcinoma. Among these, targeted nanotherapy aims to eliminate the tumor and any metastasis. Active targeting can increase the effectiveness and quantity of drugs delivered to the target site. Antibodies that target overexpressed receptors on cell surfaces and indicators are coupled with drug-loaded carriers. The major target receptors of chemotherapeutic drugs delivery include VEGFR, EGFR, FGFR, HER2, and TGF. On account of its major and diverse roles in cancer, it is important to target EGFR in particular for better tumor selection, as EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases. The EGFR monoclonal immunoglobulins cetuximab/panitumumab can thus be used to treat colorectal cancer. This review examines carriers that contain cetuximab-conjugated therapeutic drugs as well as their efficacy in anticancer activities.
Collapse
Affiliation(s)
- Balakarthikeyan Janani
- Department of Biochemistry, PSG College of Arts and Science (Autonomous), Bharathiar University, Coimbatore 641014, Tamil Nadu, India;
| | - Mayakrishnan Vijayakumar
- Department of Integrative Bioscience and Biotechnology, College of Life Sciences, Sejong University, 209 Neugdong-ro, Gwangjin-gu, Seoul 05006, Korea; (M.V.); (J.H.K.)
| | - Kannappan Priya
- Department of Biochemistry, PSG College of Arts and Science (Autonomous), Bharathiar University, Coimbatore 641014, Tamil Nadu, India;
- Correspondence: (K.P.); (T.R.)
| | - Jin Hee Kim
- Department of Integrative Bioscience and Biotechnology, College of Life Sciences, Sejong University, 209 Neugdong-ro, Gwangjin-gu, Seoul 05006, Korea; (M.V.); (J.H.K.)
| | - D. S. Prabakaran
- Department of Radiation Oncology, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-gu, Cheongju 28644, Korea;
- Department of Biotechnology, Ayya Nadar Janaki Ammal College (Autonomous), Srivilliputhur Main Road, Sivakasi 626124, Tamil Nadu, India
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
| | - Sameer Al-Ghamdi
- Family and Community Medicine Department, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Mohammed Alsaidan
- Internal Medicine Department, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Nasraddin Othman Bahakim
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
| | - Mohammad Hassan Abdelzaher
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
- Department of Medical Biochemistry, Faculty of Medicine, Al-Azhar University (Assiut Branch), Assiut 71515, Egypt
| | - Thiyagarajan Ramesh
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
- Correspondence: (K.P.); (T.R.)
| |
Collapse
|
|
7
|
Punekar SR, Griffin MM, Masri L, Roman SD, Makarov DV, Sherman SE, Becker DJ. Socioeconomic Determinants of the Use of Molecular Testing in Stage IV Colorectal Cancer. Am J Clin Oncol 2021; 44:597-602. [PMID: 34753883 DOI: 10.1097/coc.0000000000000875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Treatment with epidermal growth factor receptor monoclonal antibodies extends life for patients with advanced colorectal cancers (CRCs) whose tumors exhibit wild-type KRAS, but KRAS testing may be underused. We studied the role of socioeconomic factors in the application of KRAS testing. MATERIALS AND METHODS We identified subjects with stage IV colorectal adenocarcinoma diagnosed 2010-2015 in the Surveillance, Epidemiology, and End Results (SEER) database. We used multivariable logistic regression models to evaluate associations between clinical/demographic factors and the rate of KRAS testing. We used multivariable-adjusted Cox proportional hazards models to assess survival. RESULTS We identified 37,676 patients with stage IV CRC, 31.1% of whom were tested for KRAS mutations, of those who had documented KRAS testing, 44% were KRAS mutant. Patients were more likely to be tested if they were younger (odds ratio [OR]=5.10 for age 20 to 29 vs. 80+, 95% confidence interval [CI]: 3.99-6.54, P<0.01), diagnosed more recently (OR=1.92 for 2015 vs. 2010, 95% CI: 1.77-2.08, P<0.01), or lived in an area of high median household income (OR=1.24 for median household income of >$69,311 vs. <$49,265, 95% CI: 1.14-1.35, P<0.01). Patients were less likely to be tested if they had Medicaid (OR=0.83, 95% CI: 0.77-0.88, P<0.01) or were unmarried (OR=0.78, 95% CI: 0.75-0.82, P<0.0001). The risk of death was decreased in patients who received KRAS testing (hazard ratio=0.77, 95% CI: 0.75-0.80, P<0.01). CONCLUSIONS We found a low rate of KRAS testing in CRC patients with those living in low-income areas less likely to be tested, even after controlling for Medicaid insurance. Our study suggests that socioeconomic disparities persist despite Medicaid insurance.
Collapse
Affiliation(s)
- Salman R Punekar
- Department of Medical Oncology, NYU Langone Laura and Isaac Perlmutter Cancer Center
| | - Megan M Griffin
- Department of Medical Oncology, NYU Langone Laura and Isaac Perlmutter Cancer Center
| | | | | | - Danil V Makarov
- Urology, VA-NYHHS
- Departments of Urology
- Population Health, NYU Grossman School of Medicine, New York, NY
| | - Scott E Sherman
- Department of Medical Oncology, NYU Langone Laura and Isaac Perlmutter Cancer Center
| | - Daniel J Becker
- Department of Medical Oncology, NYU Langone Laura and Isaac Perlmutter Cancer Center
- Departments of Hematology and Oncology
| |
Collapse
|
|
8
|
Cheng WL, Feng PH, Lee KY, Chen KY, Sun WL, Van Hiep N, Luo CS, Wu SM. The Role of EREG/EGFR Pathway in Tumor Progression. Int J Mol Sci 2021; 22:ijms222312828. [PMID: 34884633 PMCID: PMC8657471 DOI: 10.3390/ijms222312828] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.
Collapse
Affiliation(s)
- Wan-Li Cheng
- Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan;
- Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Po-Hao Feng
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Kang-Yun Lee
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Kuan-Yuan Chen
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Lun Sun
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Nguyen Van Hiep
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ching-Shan Luo
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
| | - Sheng-Ming Wu
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence:
| |
Collapse
|
|
9
|
van 't Erve I, Wesdorp NJ, Medina JE, Ferreira L, Leal A, Huiskens J, Bolhuis K, van Waesberghe JHTM, Swijnenburg RJ, van den Broek D, Velculescu VE, Kazemier G, Punt CJA, Meijer GA, Fijneman RJA. KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases. JCO Precis Oncol 2021; 5:PO.21.00223. [PMID: 34820593 PMCID: PMC8608264 DOI: 10.1200/po.21.00223] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/23/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in KRAS G12, G13, Q61, K117, or A146. Patients with mCRC and a KRAS A146 mutation are characterized by high tumor burden and poor prognosis![]()
Collapse
Affiliation(s)
- Iris van 't Erve
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Nina J Wesdorp
- Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Jamie E Medina
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Leonardo Ferreira
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alessandro Leal
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.,Center for Personalized Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | - Karen Bolhuis
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Jan-Hein T M van Waesberghe
- Deparment of Radiology and Molecular Imaging, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Rutger-Jan Swijnenburg
- Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Daan van den Broek
- Department for Laboratory Medicine, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Victor E Velculescu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Geert Kazemier
- Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.,Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Gerrit A Meijer
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Remond J A Fijneman
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| |
Collapse
|
|
10
|
Ten Hoorn S, Sommeijer DW, Elliott F, Fisher D, de Back TR, Trinh A, Koens L, Maughan T, Seligmann J, Seymour MT, Quirke P, Adams R, Richman SD, Punt CJA, Vermeulen L. Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone. Br J Cancer 2021; 125:1080-1088. [PMID: 34253874 PMCID: PMC8505637 DOI: 10.1038/s41416-021-01477-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/08/2021] [Accepted: 06/30/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. METHODS Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. RESULTS When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26-0.75, P = 0.003 and HR 0.12, 95% CI 0.04-0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04-0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36-0.96, P = 0.034). CONCLUSIONS The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.
Collapse
Affiliation(s)
- Sanne Ten Hoorn
- Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Dirkje W Sommeijer
- Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Flevohospital, Department of Internal Medicine, Almere, The Netherlands
| | - Faye Elliott
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - David Fisher
- MRC Clinical Trials Unit, University College London, London, UK
| | - Tim R de Back
- Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Anne Trinh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Lianne Koens
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Tim Maughan
- Department of Oncology, University of Oxford, Oxford, UK
| | - Jenny Seligmann
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - Matthew T Seymour
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - Phil Quirke
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - Richard Adams
- Centre for Trials Research Cardiff University and Velindre Hospital, Cardiff, Wales, UK
| | - Susan D Richman
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - Cornelis J A Punt
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, Utrecht, The Netherlands
| | - Louis Vermeulen
- Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands.
- Oncode Institute, Amsterdam UMC, Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
| |
Collapse
|
|
11
|
Armstrong GR, Khot MI, Tiernan JP, West NP, Perry SL, Maisey TI, Hughes TA, Jayne DG. The utility of c-Met as a diagnostic tissue biomarker in primary colorectal cancer. Int J Exp Pathol 2021; 102:172-178. [PMID: 33951261 PMCID: PMC8139376 DOI: 10.1111/iep.12395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 02/10/2021] [Accepted: 02/16/2021] [Indexed: 12/19/2022] Open
Abstract
The transmembrane protein, cMet, is thought to be overexpressed and activated in colorectal cancer (CRC). This study explored its potential as a diagnostic tissue biomarker for CRC in a large human CRC tissue collection obtained from a randomized clinical trial. Tissue microarrays of matched normal colorectal epithelium and primary cancer were prepared from specimens obtained from 280 patients recruited to the MRC CLASICC trial (ISRCTN 74883561) and interrogated using immunohistochemistry for cMet expression. The distribution and intensity of immunopositivity was graded using a validated, semiquantifiable score, and differences in median scores analysed using the Wilcoxon signedrank test. A receiver operating characteristic (ROC) curve was plotted to measure the diagnostic accuracy of cMet as a biomarker in CRC. Epithelial cell membrane expression of cMet differed significantly between CRC and normal colorectal tissue: median 12.00 (Interquartile range (IQR) 615) versus median 6.00 (IQR 2.7012.00) respectively (P=<.0001). ROCAUC analysis of cMet expression yielded a CRC diagnostic probability of 0.66 (95% CI: 0.61 to 0.70; P<.0001). A score of 14.50 showed high specificity at 85.32% (95% CI 80.33%89.45%) but sensitivity of only 30.92% (CI 25.37%36.90%). Thus cMet is consistently overexpressed in human CRC as compared to normal colorectal epithelium tissue. cMet expression may have a role in diagnosis and prognostication if combined with other biomarkers.
Collapse
Affiliation(s)
- Gemma R Armstrong
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK.,Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Mohammed Ibrahim Khot
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK
| | | | - Nick P West
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK.,Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Sarah L Perry
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK
| | - Tom I Maisey
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK
| | - Thomas A Hughes
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK
| | - David G Jayne
- Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, UK.,Leeds Teaching Hospitals NHS Trust, Leeds, UK
| |
Collapse
|
|
12
|
Williams CJM, Seligmann JF, Elliott F, Shires M, Richman SD, Brown S, Zhang L, Singh S, Pugh J, Xu XM, Muranyi A, Guetter C, Lorsakul A, Kurkure U, Zhao Z, Martin J, Wang X, Nguyen K, Liu WW, Yan D, West NP, Barrett JH, Barnes M, Bai I, Seymour MT, Quirke P, Shanmugam K. Artificial Intelligence-Assisted Amphiregulin and Epiregulin IHC Predicts Panitumumab Benefit in RAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer Res 2021; 27:3422-3431. [PMID: 33888518 DOI: 10.1158/1078-0432.ccr-21-0120] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/22/2021] [Accepted: 03/29/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE High tumor mRNA levels of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with anti-EGFR agent response in metastatic colorectal cancer (mCRC). However, ligand RNA assays have not been adopted into routine practice due to issues with analytic precision and practicality. We investigated whether AREG/EREG IHC could predict benefit from the anti-EGFR agent panitumumab. EXPERIMENTAL DESIGN Artificial intelligence algorithms were developed to assess AREG/EREG IHC in 274 patients from the PICCOLO trial of irinotecan with or without panitumumab (Ir vs. IrPan) in RAS wild-type mCRC. The primary endpoint was progression-free survival (PFS). Secondary endpoints were RECIST response rate (RR) and overall survival (OS). Models were repeated adjusting separately for BRAF mutation status and primary tumor location (PTL). RESULTS High ligand expression was associated with significant PFS benefit from IrPan compared with Ir [8.0 vs. 3.2 months; HR, 0.54; 95% confidence interval (CI), 0.37-0.79; P = 0.001]; whereas low ligand expression was not (3.4 vs. 4.4 months; HR, 1.05; 95% CI, 0.74-1.49; P = 0.78). The ligand-treatment interaction was significant (P interaction = 0.02) and remained significant after adjustment for BRAF-mutation status and PTL. Likewise, RECIST RR was significantly improved in patients with high ligand expression (IrPan vs. Ir: 48% vs. 6%; P < 0.0001) but not those with low ligand expression (25% vs. 14%; P = 0.10; P interaction = 0.01). The effect on OS was similar but not statistically significant. CONCLUSIONS AREG/EREG IHC identified patients who benefitted from the addition of panitumumab to irinotecan chemotherapy. IHC is a practicable assay that may be of use in routine practice.
Collapse
Affiliation(s)
- Christopher J M Williams
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom.,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Jenny F Seligmann
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Faye Elliott
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Michael Shires
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom
| | - Susan D Richman
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom
| | - Sarah Brown
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom
| | - Liping Zhang
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Shalini Singh
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Judith Pugh
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Xiao-Meng Xu
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Andrea Muranyi
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Christoph Guetter
- Roche Tissue Diagnostics, Imaging and Algorithms, Digital Pathology, Santa Clara, California
| | - Auranuch Lorsakul
- Roche Tissue Diagnostics, Imaging and Algorithms, Digital Pathology, Santa Clara, California
| | - Uday Kurkure
- Roche Tissue Diagnostics, Imaging and Algorithms, Digital Pathology, Santa Clara, California
| | - Zuo Zhao
- Roche Tissue Diagnostics, Imaging and Algorithms, Digital Pathology, Santa Clara, California
| | - Jim Martin
- Roche Tissue Diagnostics, Imaging and Algorithms, Digital Pathology, Santa Clara, California
| | - Xingwei Wang
- Roche Tissue Diagnostics, Imaging and Algorithms, Digital Pathology, Santa Clara, California
| | | | - Wen-Wei Liu
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Dongyao Yan
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Nicholas P West
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom
| | - Jennifer H Barrett
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | | | - Isaac Bai
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona
| | - Matthew T Seymour
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Philip Quirke
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom
| | - Kandavel Shanmugam
- Roche Tissue Diagnostics, Medical and Scientific Affairs, Tucson, Arizona.
| |
Collapse
|
|
13
|
Breugom A, Bastiaannet E, Guren M, Kørner H, Boelens P, Dekker F, Kapiteijn E, Gelderblom H, Larsen I, Liefers G, van de Velde C. Treatment strategies and overall survival for incurable metastatic colorectal cancer – A EURECCA international comparison including 21,196 patients from the Netherlands and Norway. Eur J Surg Oncol 2020; 46:1167-1173. [DOI: 10.1016/j.ejso.2020.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/15/2020] [Accepted: 02/10/2020] [Indexed: 12/26/2022] Open
|
|
14
|
Lam KO, Fu MC, Lau KS, Lam KM, Choi CW, Chiu WH, Yuen CM, Kwok LH, Tam FK, Chan WL, Chan SY, Ho PY, Leung TW, Lee HF. Revisiting oral fluoropyrimidine with cetuximab in metastatic colorectal cancer: Real-world data in Chinese population. World J Gastrointest Oncol 2019; 11:1031-1042. [PMID: 31798783 PMCID: PMC6883182 DOI: 10.4251/wjgo.v11.i11.1031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/07/2019] [Accepted: 09/13/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cetuximab in combination with oral fluoropyrimidine (FP) remains controversial in metastatic colorectal cancer (mCRC). In view of the regional variation in the tolerability of FP, we conducted a retrospective analysis to compare oral FP with infusional FP in combination with cetuximab in Chinese population.
AIM To compare the efficacy and safety profile of cetuximab in combination with oral FP and infusional FP in Chinese population in the real-world setting.
METHODS A retrospective cohort study was done to analyse consecutive patients with Kras wild-type mCRC who received first-line treatment with cetuximab and FP-based chemotherapy in our unit from January 2010 to December 2015. Ninety-five eligible patients were included. The median follow-up of our cohort was 65.0 mo.
RESULTS The median progression-free survival (mPFS) and median overall survival (mOS) of the entire cohort were 9.66 mo (95%CI: 7.72–12.5) and 25.8 mo (95%CI: 18.7–35.6), respectively. Between oral FP and infusional FP, there was no statistical significant difference in the mPFS [9.79 mo (95%CI: 7.49–12.7) vs 9.63 mo (95%CI: 6.34–13.4); P = 0.72] and mOS [25.8 mo (95%CI: 15.2–35.6) vs 26.3 mo (95%CI: 18.7–41.2); P = 0.63]. Grade 3 or above adverse events were reported in 28.4% of patients, being similar with oral and infusional FP, and included 10.5% of neutropenia and 2.1% of diarrhoea events.
CONCLUSION The current analysis demonstrates comparable efficacy and safety profiles of cetuximab in combination with oral and infusional FP in Chinese population. The results expand treatment options for Chinese patients and invite revision of existing treatment guidelines to incorporate oral FP-based chemotherapy plus cetuximab.
Collapse
Affiliation(s)
- Ka-On Lam
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
- Clinical Oncology Centre, The University of Hong Kong- Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - Man-Chi Fu
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kin-Sang Lau
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
| | - Kam-Mo Lam
- Department of Pharmacy, Queen Mary Hospital, Hong Kong, China
| | - Cheuk-Wai Choi
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wan-Hang Chiu
- Department of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Cheng-Man Yuen
- Department of Pharmacy, Queen Mary Hospital, Hong Kong, China
| | - Lai-Han Kwok
- Department of Pharmacy, Queen Mary Hospital, Hong Kong, China
| | - Fong-Kit Tam
- Department of Pharmacy, Queen Mary Hospital, Hong Kong, China
| | - Wing-Lok Chan
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
| | - Sum-Yin Chan
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
| | - Pui-Ying Ho
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
| | - To-Wai Leung
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
| | - Ho-Fun Lee
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, China
- Clinical Oncology Centre, The University of Hong Kong- Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| |
Collapse
|
|
15
|
Goel G. Molecular characterization and biomarker identification in colorectal cancer: Toward realization of the precision medicine dream. Cancer Manag Res 2018; 10:5895-5908. [PMID: 30510457 PMCID: PMC6250110 DOI: 10.2147/cmar.s162967] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is a major public health problem, both in the USA and globally. Over the past 20 years, significant advances have been made in the treatment of patients with metastatic CRC (mCRC). Recent efforts in the field of biomarkers have focused on the development of molecular diagnostics to define the subset of patients with mCRC that is likely to derive most benefit from anti-EGFR therapy. Herein, we review the recent advancements in molecular stratification of CRC and the role of current as well as emerging biomarkers in this disease. It is now clear that the presence of activating mutations in the KRAS and NRAS genes serves as reliable predictive markers for resistance to anti-EGFR therapy in mCRC. It is also clear that further improvements in the survival of mCRC patients will probably be made possible only with identification of new predictive molecular biomarkers and their evaluation using rational and innovative clinical trials. The recent advances in DNA sequencing technology and "omics"-based approaches have provided promising new strategies for the development of novel molecular biomarkers in this disease.
Collapse
Affiliation(s)
- Gaurav Goel
- Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,
| |
Collapse
|
|
16
|
Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial. J Clin Oncol 2018; 36:3031-3039. [PMID: 30199311 PMCID: PMC6324088 DOI: 10.1200/jco.2018.78.3183] [Citation(s) in RCA: 169] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone. PATIENTS AND METHODS TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt (KRAS/NRAS, exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability. RESULTS In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings. CONCLUSION The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.
Collapse
Affiliation(s)
- Shukui Qin
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Jin Li
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Liwei Wang
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Jianming Xu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Ying Cheng
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Yuxian Bai
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Wei Li
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Nong Xu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Li-zhu Lin
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Qiong Wu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Yunfeng Li
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Jianwei Yang
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Hongming Pan
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Xuenong Ouyang
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Wensheng Qiu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Kaichun Wu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Jianping Xiong
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Guanghai Dai
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Houjie Liang
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Chunhong Hu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Jun Zhang
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Min Tao
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Qiang Yao
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Junyuan Wang
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Jiongjie Chen
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - S. Peter Eggleton
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| | - Tianshu Liu
- Shukui Qin, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing; Jin Li, Fudan University Cancer Hospital and Tongji University East Hospital; Liwei Wang, Shanghai First People’s Hospital; Jun Zhang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Tianshu Liu, Affiliated Zhongshan Hospital of Fudan University, Shanghai; Jianming Xu, 307 Hospital of the Chinese People’s Liberation Army; Guanghai Dai, Chinese People’s Liberation Army General Hospital; Junyuan Wang and Jiongjie Chen, Merck Serono, Beijing; Ying Cheng, Jilin Cancer Hospital; Wei Li, First Affiliated Hospital of Jilin University, Jilin; Yuxian Bai, Affiliated Hospital of Harbin Medical University, Harbin; Nong Xu, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou; Li-zhu Lin, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou; Qiong Wu, First Affiliated Hospital of Bengbu Medical College, Bengbu; Yunfeng Li, Yunnan Province Cancer Hospital, Kunming; Jianwei Yang, Fujian Province Cancer Hospital; Xuenong Ouyang, Fuzhou General Hospital, Fuzhou; Hongming Pan, Sir Run Run Shaw Hospital Affiliated With School of Medicine, Zhejiang University, Zhejiang; Wensheng Qiu, Affiliated Hospital of Qingdao University, Qingdao; Kaichun Wu, Xijing Hospital, Fourth Military Medical University, Shaanxi; Jianping Xiong, First Affiliated Hospital of Nanchang University, Nanchang; Houjie Liang, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing; Chunhong Hu, Second Xiangya Hospital of Central South University, Changsha; Min Tao, First Affiliated Hospital of Suzhou University, Suzhou; Qiang Yao, Tianjin People’s Hospital, Tianjin, People’s Republic of China; and S. Peter Eggleton, Merck KGaA, Darmstadt, Germany
| |
Collapse
|
|
17
|
Chen D, Li L, Zhang X, Gao G, Shen L, Hu J, Yang M, Liu B, Qian X. FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer: A meta-analysis. Medicine (Baltimore) 2018; 97:e0097. [PMID: 29517682 PMCID: PMC5882422 DOI: 10.1097/md.0000000000010097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis. METHODS RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3. RESULTS The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients. CONCLUSION So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.
Collapse
Affiliation(s)
- Datian Chen
- Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University
- Department of Oncology, Haimen People's Hospital, Haimen
| | - Li Li
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Xiang Zhang
- Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University
| | - Guangyi Gao
- The Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lili Shen
- Department of Oncology, Haimen People's Hospital, Haimen
| | - Jing Hu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Mi Yang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Xiaoping Qian
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| |
Collapse
|
|
18
|
Wang JX, Wu HL, Zhu M, Zhou R. Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer: an Update Meta-Analysis of Randomized Clinical Trials. Pathol Oncol Res 2018; 26:159-166. [PMID: 29383654 DOI: 10.1007/s12253-017-0365-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 11/29/2017] [Indexed: 12/22/2022]
Abstract
Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have showed clinical benefit in combination with chemotherapeutic cytotoxic drugs in the first-line therapy of metastatic colorectal cancer (mCRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unknown. This study aimed to evaluate the impact of the combination of anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy on mCRC patient outcomes by combining the data from randomized clinical trials. Three trials meeting the eligibility criteria, and four randomized studies were included in the meta-analysis. For MCRC patients with KRAS wild type (KRAS-WT), the ORR was superior in patients treated with anti-EGFR compared with those who treated with anti-VEGF therapy. This effect was even better for all RAS-WT patients. Progression-free survival (PFS) rates were not significantly different for KRAS-WT mCRC and all RAS-WT mCRC between the two groups. The overall survival (OS) was higher for RAS wild-type (RAS-WT) mCRC patients who received anti-EGFR, but the KRAS-WT patients compared to the anti-VEGF therapy. The results of our research indicate that superior ORR and OS between the addition of anti-EGFR therapy VS anti-VEGF therapy in all RAS-WT patients with MCRC. There was no significant difference in OS and PFS between the two groups for KRAS-WT mCRC. These results suggest that anti- EGFR monoclonal antibodies can achieve an equivalent efficacy when compared with anti-VEGF therapy of all RAS-WT mCRC patients.
Collapse
Affiliation(s)
- Jian-Xiang Wang
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China
| | - Hai-Long Wu
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China
| | - Meng Zhu
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China
| | - Rui Zhou
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China.
| |
Collapse
|
|
19
|
Nordgård O, Tjensvoll K, Gilje B, Søreide K. Circulating tumour cells and DNA as liquid biopsies in gastrointestinal cancer. Br J Surg 2018; 105:e110-e120. [DOI: 10.1002/bjs.10782] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/02/2017] [Accepted: 11/09/2017] [Indexed: 12/15/2022]
Abstract
Abstract
Background
Blood is the most extensively studied body fluid and, because it contains circulating tumour cells (CTCs) and circulating tumour-derived cell-free DNA (ctDNA), it may represent a liquid biopsy for cancer. Methods for enrichment and detection of CTCs and ctDNA, their clinical applications and future opportunities in gastrointestinal cancers were the focus of this review.
Methods
The PubMed database was searched for literature up to 24 June 2017, with a focus on the past 10 years. Identified articles were further scrutinized for relevant references. Articles were those in English relating to colorectal, gastric and pancreatic cancer.
Results
Both CTCs and ctDNA are in low abundance compared with other cellular components of blood, but effective enrichment and highly sensitive techniques are available for their detection. Potential clinical applications of these liquid biopsies include screening, prognostic stratification, therapy administration, monitoring of treatment effect or resistance, and surveillance. Liquid biopsies provide opportunities to reduce the need for invasive tissue sampling, especially in the context of intratumoral heterogeneity and the need for tumour genotyping.
Conclusion
Liquid biopsies have applications in gastrointestinal cancers to improve clinical decision-making.
Collapse
Affiliation(s)
- O Nordgård
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
- Department of Mathematics and Natural Science, University of Stavanger, Stavanger, Norway
| | - K Tjensvoll
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - B Gilje
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - K Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Clinical Surgery, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
20
|
Abstract
Concurrent with an expansion in the number of agents available for the treatment of advanced CRC, there has been an increase in our understanding of selection biomarkers to optimize the management of patients with this disease. For CRC patients being considered for anti-EGFR therapy, expanded RAS testing is the standard of care to determine the subset of patients who can benefit from cetuximab or panitumumab in conjunction with chemotherapy. A small fraction of patients have HER2 amplification where emerging data suggest treatment with drugs targeting this alteration. Although advanced CRC patients who harbor the BRAF V600E mutation have a poorer prognosis, they are eligible for combinatorial therapy targeting EGFR/BRAF or BRAF/MEK within the MAP kinase signaling pathway. Once primarily thought to be a negative prognostic marker, BRAF V600E mutation is now considered as a positive predictive factor with an opportunity for clinical intervention. A growing body of evidence also supports MSI testing as clinical benefits with immune checkpoint blockade by cancer immunotherapy have been demonstrated in MSI-high patients whose tumors exhibit high mutational burden. It has been established that UGT1A1*28 polymorphism is associated with irinotecan toxicity, but this test is rarely performed as the management strategy has not been identified. No established predictive biomarker for anti-VEGF therapy has yet to be discovered.It is becoming increasingly apparent that our growing understanding of biomarkers is revolutionizing and improving our strategies in the treatment of advanced CRC. Traditional nonselective cytotoxic chemotherapy is gradually being augmented and even in some cases supplanted by selective targeted agents based on our increasing understanding of tumor signaling and mechanism at the molecular level. The prospect of personalized medicine in directing treatment approaches that are optimally beneficial for patients brings tremendous excitement to the growing field of cancer therapeutics. As discussed in this chapter, the concurrent development of molecular biomarkers with new treatment strategies holds great promise of precision medicine in improving outcomes for patients with advanced CRC.
Collapse
Affiliation(s)
- Patrick S Lin
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Thomas J Semrad
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
- Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA, USA.
| |
Collapse
|
|
21
|
Charlton ME, Kahl AR, Greenbaum AA, Karlitz JJ, Lin C, Lynch CF, Chen VW. KRAS Testing, Tumor Location, and Survival in Patients With Stage IV Colorectal Cancer: SEER 2010-2013. J Natl Compr Canc Netw 2017; 15:1484-1493. [PMID: 29223986 PMCID: PMC7458121 DOI: 10.6004/jnccn.2017.7011] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 07/12/2017] [Indexed: 01/05/2023]
Abstract
Purpose:KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression. Cox proportional hazards models assessed relationships between KRAS mutations, tumor location, and risk of all-cause death. Results: Of 22,542 patients, 30% received KRAS testing, and 44% of these had mutations. Those tested tended to be younger, married, and metropolitan area residents, and have private insurance or Medicare. Rates of KRAS testing also varied by registry (range, 20%-46%). Patients with right-sided colon cancer (vs left-sided) tended to be older, female, and black; have mucinous, KRAS-mutant tumors; and have a greater risk of death (hazard ratio [HR], 1.27; 95% CI, 1.22-1.32). KRAS mutations were not associated with greater risk of death in the overall population; however, they were associated with greater risk of death among patients with left-sided colon cancer (HR, 1.19; 95% CI, 1.05-1.33). Conclusions: This large population-based study showed that among patients initially diagnosed with stage IV CRC, right-sided colon cancer was associated with greater risk of death compared with left-sided cancer, and KRAS mutations were only associated with risk of death in left-sided colon cancer. An unexpected finding was that among patients with stage IV disease, right-sided cancer was more commonly seen in black patients versus whites. Future studies should further explore these associations and determine the role of biology versus treatment differences. In addition, use of KRAS testing is increasing, but there is wide geographic variation wherein disparities related to insurance coverage and rurality may warrant further study.
Collapse
Affiliation(s)
- Mary E. Charlton
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Amanda R. Kahl
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Alissa A. Greenbaum
- Department of Surgery, School of Medicine, University of New Mexico, Albuquerque, New Mexico
| | - Jordan J. Karlitz
- Division of Gastroenterology, School of Medicine, Tulane University, New Orleans, Louisiana
| | - Chi Lin
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE
| | - Charles F. Lynch
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Vivien W. Chen
- Louisiana Tumor Registry and Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| |
Collapse
|
|
22
|
Loupakis F, Stein A, Ychou M, Hermann F, Salud A, Österlund P. A Review of Clinical Studies and Practical Guide for the Administration of Triplet Chemotherapy Regimens with Bevacizumab in First-line Metastatic Colorectal Cancer. Target Oncol 2017; 11:293-308. [PMID: 26687849 PMCID: PMC4901088 DOI: 10.1007/s11523-015-0400-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics. A recent advance in therapy is a treatment regimen composed of three chemotherapeutic agents (i.e., triplet chemotherapy: 5-fluorouracil [5-FU]/leucovorin [LV], oxaliplatin, and irinotecan; FOLFOXIRI) in combination with the vascular endothelial growth factor inhibitor bevacizumab. This regimen has been shown to elicit significantly improved objective response rates and median progression-free survival compared with 5-FU/LV and irinotecan in combination with bevacizumab. However, triplet chemotherapy has been associated with increased rates of chemotherapy-related adverse events, and treatment-emergent adverse events should be properly managed to minimize treatment interruption or discontinuation. We present herein a review of clinical studies evaluating the safety and efficacy of FOLFOXIRI with bevacizumab in metastatic colorectal cancer, and propose a practical guide for the management of adverse events associated with the regimen. ![]()
Collapse
Affiliation(s)
- Fotios Loupakis
- Istituto Toscano Tumori, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Via Roma, 67, 56126, Pisa, Italy.
| | - Alexander Stein
- University Cancer Center Hamburg, University of Hamburg, Hamburg, Germany
| | - Marc Ychou
- ICM Val d'Aurelle, 34000, Montpellier, France
| | | | - Antonieta Salud
- Department of Medical Oncology, Arnau de Vilanova University Hospital, Lleida, Spain
| | - Pia Österlund
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
| |
Collapse
|
|
23
|
Charlton ME, Karlitz JJ, Schlichting JA, Chen VW, Lynch CF. Factors Associated With Guideline-recommended KRAS Testing in Colorectal Cancer Patients: A Population-based Study. Am J Clin Oncol 2017; 40:498-506. [PMID: 25844824 PMCID: PMC4591083 DOI: 10.1097/coc.0000000000000191] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer (CRC) patients with KRAS mutations; thus KRAS testing is recommended before treatment. KRAS testing was collected by Surveillance, Epidemiology, and End Results (SEER) registries for 2010 CRC cases, and our goal was to provide the first population-based estimates of testing in the United States. METHODS SEER CRC cases diagnosed in 2010 were evaluated (n=30,351). χ tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing, stratified by stages I-III versus stage IV. Log-rank tests were used to examine survival by testing status. RESULTS KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana. In the model, younger age, being married, living in a metropolitan area, and having primary site surgery were associated with greater odds of receiving KRAS testing. Those who received testing had significantly better survival than those who did not (P<0.0001). Among those who received testing, there was no significant difference in survival by mutated versus wild-type KRAS. Five percent of stage I-III cases received testing. CONCLUSIONS Wide variation in documented KRAS testing for stage IV CRC patients exists among SEER registries. Age remained highly significant in multivariate models, suggesting that it plays an independent role in the patient and/or provider decision to be tested. Further research is needed to determine drivers of variation in testing, as well as reasons for testing in stage I-III cases where it is not recommended.
Collapse
Affiliation(s)
- Mary E. Charlton
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Jordan J. Karlitz
- Division of Gastroenterology, School of Medicine, Tulane University, New Orleans, Louisiana
| | | | - Vivien W. Chen
- Louisiana Tumor Registry and Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Charles F. Lynch
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| |
Collapse
|
|
24
|
Pietrantonio F, Di Bartolomeo M, Cotsoglou C, Mennitto A, Berenato R, Morano F, Coppa J, Perrone F, Iacovelli R, Milione M, Alessi A, Vaiani M, Bossi I, Ricchini F, Scotti M, Caporale M, Bajetta E, de Braud F, Mazzaferro V. Perioperative Triplet Chemotherapy and Cetuximab in Patients With RAS Wild Type High Recurrence Risk or Borderline Resectable Colorectal Cancer Liver Metastases. Clin Colorectal Cancer 2017; 16:e191-e198. [DOI: 10.1016/j.clcc.2016.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/09/2016] [Accepted: 09/22/2016] [Indexed: 12/19/2022]
|
|
25
|
Li L, Ni BB, Zhong QH, Liu YH, Zhang MH, Zhang KP, Chen DC, Wang L. Investigation of correlation between mutational status in key EGFR signaling genes and prognosis of stage II colorectal cancer. Future Oncol 2017; 13:1473-1492. [PMID: 28685592 DOI: 10.2217/fon-2017-0040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aim: To investigate the relationship between mutations of key genes in the EGFR signaling pathway and the prognosis of stage II colorectal cancer patients without chemotherapy. Materials & methods: The incidence of KRAS, NRAS, BRAF, PIK3CA mutations and deficient DNA mismatch repair were assessed in 160 stage II colorectal cancer patients who had been treated by radical operation without adjuvant chemotherapy. Results: Mutations in KRAS, BRAF or PIK3CA were associated with poor prognosis, while the deficient DNA mismatch repair status was not associated with the prognosis. Combining these three markers, the sensitivity of the predicted value for poor progression-free survival and overall survival reached 0.645 (p = 0.002) and 0.709 (p = 0.001), respectively. Conclusion: Knowing the mutation status of KRAS, BRAF or PIK3CA in stage II colorectal cancer can significantly improve the accuracy of prognoses.
Collapse
Affiliation(s)
- Li Li
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal & Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Bei-Bei Ni
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal & Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Qing-Hua Zhong
- Guangdong Provincial Key Laboratory of Colorectal & Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Yan-Hui Liu
- Department of Pathology & Laboratory Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Ming-Hui Zhang
- Department of Pathology & Laboratory Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Ke-Ping Zhang
- Department of Pathology & Laboratory Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Dai-Ci Chen
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal & Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Lei Wang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal & Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| |
Collapse
|
|
26
|
van Brummelen EMJ, de Boer A, Beijnen JH, Schellens JHM. BRAF Mutations as Predictive Biomarker for Response to Anti-EGFR Monoclonal Antibodies. Oncologist 2017; 22:864-872. [PMID: 28576857 PMCID: PMC5507642 DOI: 10.1634/theoncologist.2017-0031] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 02/22/2017] [Indexed: 12/14/2022] Open
Abstract
Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment.In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient.This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti-EGFR mAbs. Based on a review of literature, eight meta-analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti-EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response. IMPLICATIONS FOR PRACTICE In metastatic colorectal cancer (mCRC), therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab is indicated in absence of RAS mutations. Cumulative evidence shows that patients with BRAF mutations, who comprise 10% of the mCRC population, do not benefit from anti-EGFR-antibody treatment. Although guidelines state that evidence for BRAF as a predictive marker is insufficient, we highlight that the quality and quantity of evidence is higher than suggested. We therefore encourage the use of BRAF as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected.
Collapse
Affiliation(s)
- Emilie M J van Brummelen
- Department of Clinical Pharmacology, Amsterdam, The Netherlands
- Department of Molecular Pathology, Amsterdam, The Netherlands
| | - Anthonius de Boer
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jos H Beijnen
- Pharmacy The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jan H M Schellens
- Department of Clinical Pharmacology, Amsterdam, The Netherlands
- Department of Molecular Pathology, Amsterdam, The Netherlands
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| |
Collapse
|
|
27
|
Chan DLH, Segelov E, Wong RS, Smith A, Herbertson RA, Li BT, Tebbutt N, Price T, Pavlakis N. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2017. [PMID: 28654140 DOI: 10.1002/14651858.cd007047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity. OBJECTIVES To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed. SELECTION CRITERIA We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone. DATA COLLECTION AND ANALYSIS We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type). MAIN RESULTS We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression-free survival: I2 = 76%; overall survival: I2 = 40%; and response rate: I2 = 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I2 = 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate-quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I2 = 51%), likely due to the pooling of first-line and second-line studies.The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.Scant information on quality of life was reported in the identified studies. AUTHORS' CONCLUSIONS The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.
Collapse
Affiliation(s)
- David Lok Hang Chan
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia, 2065
| | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Chan DLH, Segelov E, Wong RSH, Smith A, Herbertson RA, Li BT, Tebbutt N, Price T, Pavlakis N, Cochrane Colorectal Cancer Group. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev 2017; 6:CD007047. [PMID: 28654140 PMCID: PMC6481896 DOI: 10.1002/14651858.cd007047.pub2] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity. OBJECTIVES To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed. SELECTION CRITERIA We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone. DATA COLLECTION AND ANALYSIS We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type). MAIN RESULTS We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression-free survival: I2 = 76%; overall survival: I2 = 40%; and response rate: I2 = 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I2 = 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate-quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I2 = 51%), likely due to the pooling of first-line and second-line studies.The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.Scant information on quality of life was reported in the identified studies. AUTHORS' CONCLUSIONS The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.
Collapse
Affiliation(s)
- David Lok Hang Chan
- Royal North Shore HospitalDepartment of Medical OncologySt LeonardsNew South WalesAustralia2065
| | - Eva Segelov
- Monash University and Monash HealthDepartment of OncologyLvl 7, MHTP building, Monash Health 240 Clayton RdClaytonVictoriaAustralia3168
| | - Rachel SH Wong
- University of SydneyDepartment of MedicineSydneyNSWAustralia2006
| | - Annabel Smith
- University of New South WalesDepartment of MedicineSydneyNSWAustralia2052
| | - Rebecca A Herbertson
- Ludwig Institute for Cancer ResearchMelbourne Centre for Clinical SciencesAustin Hospital HSB1145‐163 Studley RoadHeidelbergVictoriaAustralia3084
| | - Bob T. Li
- Memorial Sloan Kettering Cancer CenterThoracic Oncology and Early Drug Development Service1275 York AvenueNew YorkNYUSA10065
| | - Niall Tebbutt
- Olivia Newton‐John Cancer Wellness and Research Centre, Austin HospitalOlivia Newton‐John Cancer Research Institute145‐163 Studley RdHeidelbergVictoriaAustralia3084
| | - Timothy Price
- Olivia Newton‐John Cancer Wellness & Research Centre, Austin HospitalOlivia Newton‐John Cancer Research Institute, Level 5145‐163 Studley RdHeidelbergVictoriaAustralia3084
| | - Nick Pavlakis
- Royal North Shore HospitalDepartment of Medical OncologySt LeonardsNew South WalesAustralia2065
| | | |
Collapse
|
|
29
|
Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Bryan Rumble R, Temple-Smolkin R, B Ventura C, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2017; 141:625-657. [PMID: 28165284 DOI: 10.5858/arpa.2016-0554-cp] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES - To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. METHODS - The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. RESULTS - Twenty-one guideline statements were established. CONCLUSIONS - Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.
Collapse
Affiliation(s)
- Antonia R Sepulveda
- From the 1 Department of Pathology and Cell Biology, Columbia University, New York, NY
| | | | - Carmen J Allegra
- 5 Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
| | - Wayne Grody
- 6 Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA Medical Center, Los Angeles, CA
| | | | - William K Funkhouser
- 8 Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
| | | | - Christopher Lieu
- 9 Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
| | | | - Bruce D Minsky
- 4 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | | | - Daniel J Sargent
- 12 Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Joseph Willis
- 14 Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Jennifer Clark
- 15 ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
| | - Carol Colasacco
- 16 Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - R Bryan Rumble
- 17 American Society of Clinical Oncology, Alexandria, VA
| | | | - Christina B Ventura
- 16 Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - Jan A Nowak
- From the 1 Department of Pathology and Cell Biology, Columbia University, New York, NY
- 2 Department of Pathology
- 3 Department of Gastrointestinal (GI) Medical Oncology
- 4 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
- 5 Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
- 6 Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA Medical Center, Los Angeles, CA
- 7 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
- 8 Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
- 9 Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
- 10 Department of Medical Genetics, Mayo Clinic, Scottsdale, AZ
- 11 Castle Biosciences, Friendswood, TX
- 12 Department of Health Sciences Research, Mayo Clinic, Rochester, MN
- 13 Biocept, San Diego, CA
- 14 Department of Pathology, Case Western Reserve University, Cleveland, OH
- 15 ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
- 16 Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
- 17 American Society of Clinical Oncology, Alexandria, VA
- 18 Association for Molecular Pathology, Bethesda, MD
- 19 Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
| |
Collapse
|
|
30
|
Plano D, Alcolea V, Sanmartín C, Sharma AK. Methods of selecting combination therapy for colorectal cancer patients: a patent evaluation of US20160025730A1. Expert Opin Ther Pat 2017; 27:527-538. [PMID: 28366103 DOI: 10.1080/13543776.2017.1315103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network. Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors. The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation. Expert opinion: To assess the clinical applicability of this invention, further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line (Lim1215). Furthermore, other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed.
Collapse
Affiliation(s)
- Daniel Plano
- a University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry , Campus Universitario , Pamplona , Spain.,b IdiSNA, Instituto de Investigación Sanitaria de Navarra , Pamplona , Spain
| | - Verónica Alcolea
- a University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry , Campus Universitario , Pamplona , Spain.,b IdiSNA, Instituto de Investigación Sanitaria de Navarra , Pamplona , Spain
| | - Carmen Sanmartín
- a University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry , Campus Universitario , Pamplona , Spain.,b IdiSNA, Instituto de Investigación Sanitaria de Navarra , Pamplona , Spain
| | - Arun K Sharma
- c Department of Pharmacology , Penn State Cancer Institute , Hershey , PA , USA
| |
Collapse
|
|
31
|
Fisher DJ, Carpenter JR, Morris TP, Freeman SC, Tierney JF. Meta-analytical methods to identify who benefits most from treatments: daft, deluded, or deft approach? BMJ 2017; 356:j573. [PMID: 28258124 PMCID: PMC5421441 DOI: 10.1136/bmj.j573] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/20/2017] [Indexed: 11/04/2022]
Affiliation(s)
- David J Fisher
- London Hub for Trials Methodology Research, MRC Clinical Trials Unit, University College London, London, UK
| | - James R Carpenter
- London Hub for Trials Methodology Research, MRC Clinical Trials Unit, University College London, London, UK
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - Tim P Morris
- London Hub for Trials Methodology Research, MRC Clinical Trials Unit, University College London, London, UK
| | - Suzanne C Freeman
- London Hub for Trials Methodology Research, MRC Clinical Trials Unit, University College London, London, UK
| | - Jayne F Tierney
- London Hub for Trials Methodology Research, MRC Clinical Trials Unit, University College London, London, UK
| |
Collapse
|
|
32
|
Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble RB, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer. Am J Clin Pathol 2017; 147:221-260. [PMID: 28165529 PMCID: PMC7263311 DOI: 10.1093/ajcp/aqw209] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results: Twenty-one guideline statements were established. Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.
Collapse
Affiliation(s)
- Antonia R. Sepulveda
- From theDepartment of Pathology and Cell Biology, Columbia University, New York, NY; Departments of
| | | | - Carmen J. Allegra
- Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
| | - Wayne Grody
- Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics UCLA Medical Center, Los Angeles, CA
| | | | - William K. Funkhouser
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
| | | | - Christopher Lieu
- Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
| | | | - Bruce D. Minsky
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | | | | | | | - Joseph Willis
- Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Jennifer Clark
- ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
| | - Carol Colasacco
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | | | | | - Christina B. Ventura
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - Jan A. Nowak
- Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
| |
Collapse
|
|
33
|
Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble RB, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn 2017; 19:187-225. [PMID: 28185757 PMCID: PMC5971222 DOI: 10.1016/j.jmoldx.2016.11.001] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 11/07/2016] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. METHODS The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. RESULTS Twenty-one guideline statements were established. CONCLUSIONS Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented. Key Words: Molecular diagnostics; Gastrointestinal; Histology; Genetics; Oncology.
Collapse
Affiliation(s)
- Antonia R Sepulveda
- Department of Pathology and Cell Biology, Columbia University, New York, NY.
| | - Stanley R Hamilton
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Carmen J Allegra
- Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
| | - Wayne Grody
- Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA Medical Center, Los Angeles, CA
| | | | - William K Funkhouser
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
| | - Scott E Kopetz
- Department of Gastrointestinal (GI) Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
| | - Christopher Lieu
- Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
| | | | - Bruce D Minsky
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | | | - Daniel J Sargent
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Joseph Willis
- Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Jennifer Clark
- ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
| | - Carol Colasacco
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | | | | | - Christina B Ventura
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - Jan A Nowak
- Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
| |
Collapse
|
|
34
|
Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble RB, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:1453-1486. [PMID: 28165299 DOI: 10.1200/jco.2016.71.9807] [Citation(s) in RCA: 238] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Purpose Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) -targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature. Methods The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC. A comprehensive literature search that included over 4,000 articles was conducted to gather data to inform this guideline. Results Twenty-one guideline statements (eight recommendations, 10 expert consensus opinions and three no recommendations) were established. Recommendations Evidence supports mutational testing for genes in the EGFR signaling pathway, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize molecular testing for predictive and prognostic molecular biomarkers involve selection of assays, type of specimens to be tested, timing of ordering of tests and turnaround time for testing results. Additional information is available at: www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki.
Collapse
Affiliation(s)
- Antonia R Sepulveda
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Stanley R Hamilton
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Carmen J Allegra
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Wayne Grody
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Allison M Cushman-Vokoun
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - William K Funkhouser
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Scott E Kopetz
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Christopher Lieu
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Noralane M Lindor
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Bruce D Minsky
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Federico A Monzon
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Daniel J Sargent
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Veena M Singh
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Joseph Willis
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Jennifer Clark
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Carol Colasacco
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - R Bryan Rumble
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Robyn Temple-Smolkin
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Christina B Ventura
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Jan A Nowak
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| |
Collapse
|
|
35
|
Abstract
In the last 20 years, improvements in metastatic colorectal cancer treatment lead to a radical raise of outcomes with median survival reaching now more than 30 months. Despite that, the identification of predictive and/or prognostic biomarker still represents a challenging issue, and until today, although clinician and researchers might face with a deeper knowledge of biological mechanisms related to colorectal cancer, many pieces of evidence underline the heterogeneity and the dynamism of such disease. In the present review, we describe the road leading to the discovery of RAS mutations, BRAF V600E mutation, and microsatellite instability role in colorectal cancer; second, we discuss some of the possible major pitfalls of biomarker research, and lastly, we give new suggestions for future research in this field.
Collapse
|
|
36
|
Moth EB, Vardy J, Blinman P. Decision-making in geriatric oncology: systemic treatment considerations for older adults with colon cancer. Expert Rev Gastroenterol Hepatol 2016; 10:1321-1340. [PMID: 27718755 DOI: 10.1080/17474124.2016.1244003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colon cancer is common and can be considered a disease of older adults with more than half of cases diagnosed in patients aged over 70 years. Decision-making about treatment with chemotherapy for older adults may be complicated by age-related physiological changes, impaired functional status, limited social supports, concerns regarding the occurrence of and ability to tolerate treatment toxicity, and the presence of comorbidities. This is compounded by a lack of high quality evidence guiding cancer treatment decisions for older adults. Areas covered: This narrative review evaluates the evidence for adjuvant and palliative systemic therapy in older adults with colon cancer. The value of an adequate assessment prior to making a treatment decision is addressed, with emphasis on the geriatric assessment. Guidance in making a treatment decision is provided. Expert commentary: Treatment decisions should consider goals of care, a patient's treatment preferences, and weigh up relative benefits and harms.
Collapse
Affiliation(s)
- Erin B Moth
- a Concord Cancer Centre , Concord Repatriation General Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
| | - Janette Vardy
- a Concord Cancer Centre , Concord Repatriation General Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
| | - Prunella Blinman
- a Concord Cancer Centre , Concord Repatriation General Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
| |
Collapse
|
|
37
|
Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer. Sci Rep 2016; 6:34523. [PMID: 27739445 PMCID: PMC5064353 DOI: 10.1038/srep34523] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 09/15/2016] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvβ3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.
Collapse
|
|
38
|
Richman SD, Fairley J, Butler R, Deans ZC. How close are we to standardised extended RAS gene mutation testing? The UK NEQAS evaluation. J Clin Pathol 2016; 70:58-62. [PMID: 27681846 PMCID: PMC5256378 DOI: 10.1136/jclinpath-2016-203822] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/19/2016] [Accepted: 05/20/2016] [Indexed: 12/15/2022]
Abstract
AIMS Since 2008, KRAS mutation status in exon 2 has been used to predict response to anti-EGFR therapies. Recent evidence has demonstrated that NRAS status is also predictive of response. Several retrospective 'extended RAS' analyses have been performed on clinical trial material. Despite this, are we really moving towards such extended screening practice in reality? METHODS Data were analysed from four consecutive UK National External Quality Assessment Service for Molecular Genetics Colorectal cancer External Quality Assessment schemes (during the period 2014-2016), with up to 110 laboratories (worldwide) participating in each scheme. Testing of four or five tumour samples is required per scheme. Laboratories provided information on which codons were routinely screened, and provided genotyping and interpretation results for each sample. RESULTS At least 85% of laboratories routinely tested KRAS codons 12, 13 and 61. Over the four schemes, an increasing number of laboratories routinely tested KRAS codons 59, 117 and 146. Furthermore, more laboratories were introducing next generation sequencing technologies. The pattern of 'extended testing' was reassuringly similar for NRAS, although fewer laboratories currently test for mutations in this gene. Alarmingly, still only 36.1% and 24.1% of participating laboratories met the ACP Molecular Pathology and Diagnostics Group and American Society of Clinical Oncology guidelines, respectively, for extended RAS testing in the latest assessment. CONCLUSIONS Despite recommendations in the UK and USA on extended RAS testing, there has clearly been, based on these results, a delay in implementation. Inadequate testing results in patients being subjected to harmful treatment regimens, which would not be the case, were routine practice altered, in line with evidence-based guidelines.
Collapse
Affiliation(s)
- Susan D Richman
- Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James University Hospital, Leeds, UK
| | - Jennifer Fairley
- UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK
| | - Rachel Butler
- Cardiff and Vale UHB-Medical Genetics University Hospital of Wales, Cardiff, Wales, UK
| | - Zandra C Deans
- UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK
| |
Collapse
|
|
39
|
Menke-van der Houven van Oordt CW, Gootjes EC, Huisman MC, Vugts DJ, Roth C, Luik AM, Mulder ER, Schuit RC, Boellaard R, Hoekstra OS, van Dongen GA, Verheul HMW. 89Zr-cetuximab PET imaging in patients with advanced colorectal cancer. Oncotarget 2016; 6:30384-93. [PMID: 26309164 PMCID: PMC4745807 DOI: 10.18632/oncotarget.4672] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 07/10/2015] [Indexed: 12/12/2022] Open
Abstract
Monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) are used in the treatment of advanced colorectal cancer (mCRC). Approximately 50% of patients benefit despite patient selection for RAS wild type (wt) tumors. Based on the hypothesis that tumor targeting is required for clinical benefit of anti-EGFR treatment, biodistribution and tumor uptake of (89)Zr-cetuximab by Positron Emission Tomography (PET), combining the sensitivity of PET with the specificity of cetuximab for EGFR was evaluated. Ten patients with wt K-RAS mCRC received 37 ± 1 MBq (89)Zr-cetuximab directly (<2 h) after the first therapeutic dose of cetuximab. PET-scans were performed from 1 hour to 10 days post injection (p.i.). Biodistribution was determined for blood and organs. Uptake in tumor lesions was quantified by Standardized Uptake Value (SUV) and related to response. In 6 of 10 patients (89)Zr-cetuximab uptake in tumor lesions was detected. Four of 6 patients with (89)Zr-cetuximab uptake had clinical benefit, while progressive disease was observed in 3 of 4 patients without (89)Zr-cetuximab uptake. Taken together, tumor uptake of 89Zr-cetuximab can be visualized by PET imaging. The strong relation between uptake and response warrants further clinical validation as an innovative selection method for cetuximab treatment in patients with wt RAS mCRC.
Collapse
Affiliation(s)
| | - Elske C Gootjes
- Dept of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Marc C Huisman
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Danielle J Vugts
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Chantal Roth
- Dept of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Anne Marije Luik
- Dept of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Emma R Mulder
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Robert C Schuit
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Ronald Boellaard
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Otto S Hoekstra
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Guus Ams van Dongen
- Dept of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Henk M W Verheul
- Dept of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
|
40
|
Zhou J, Zhao R, Wen F, Zhang P, Tang R, Chen H, Zhang J, Li Q. Economic evaluation study (CHEER-compliant): Cost-effectiveness analysis of RAS screening for treatment of metastatic colorectal cancer based on the CALGB 80405 trial. Medicine (Baltimore) 2016; 95:e3762. [PMID: 27399059 PMCID: PMC5058788 DOI: 10.1097/md.0000000000003762] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cetuximab (Cetux)/Bevacizumab (Bev) treatments have shown considerably survival benefits for patients with metastatic colorectal cancer (mCRC) in the last decade. But they are costly. Currently, no data is available on the health economic implications of testing for extended RAS wild-type (wt) prior to Cetux/Bev treatments of patients with mCRC. This paper aimed to evaluate the cost-effectiveness of predictive testing for extended RAS-wt status in mCRC in the context of targeting the use of Cetux/Bev.Markov model 1 was conducted to provide evidence evaluating the cost-effectiveness of predictive testing for KRAS-wt or extended RAS-wt status based on treatments of chemotherapy plus Cetux/Bev. Markov model 2 assessed the cost-effectiveness of FOLFOX plus Cetux/Bev or FOLFIRI plus Cetux/Bev in extended RAS-wt population. Primary base case data were identified from the CALGB 80405 trial and the literatures. Costs were estimated from West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated.In analysis 1, the cost per QALY was $88,394.09 for KRAS-Cetux, $80,797.82 for KRAS-Bev, $82,590.72 for RAS-Cetux, and $75,358.42 for RAS-Bev. The ICER for RAS-Cetux versus RAS-Bev was $420,700.50 per QALY gained. In analysis 2, the cost per QALY was $81,572.61, $80,856.50, $80,592.22, and $66,794.96 for FOLFOX-Cetux, FOLFOX-Bev, FOLFIRI-Cetux, and FOLFIRI-Bev, respectively. The analyses showed that the extended RAS-wt testing was less costly and more effective versus KRAS-wt testing before chemotherapy plus Cetux/Bev. Furthermore, FOLFIRI plus Bev was the most cost-effective strategy compared with others in extended RAS-wt population.It was economically favorable to identify patients with extended RAS-wt status. Furthermore, FOLFIRI plus Bev was the preferred strategy in extended RAS-wt patients.
Collapse
Affiliation(s)
- Jing Zhou
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
| | - Rongce Zhao
- Division of Liver Transplantation, Department of Liver Surgery, West China Hospital, Sichuan University, China
| | - Feng Wen
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
| | - Pengfei Zhang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
| | - Ruilei Tang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
| | - Hongdou Chen
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
| | - Jian Zhang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy
- Correspondence: Qiu Li, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, China (e-mail: , )
| |
Collapse
|
|
41
|
Moriarity A, O'Sullivan J, Kennedy J, Mehigan B, McCormick P. Current targeted therapies in the treatment of advanced colorectal cancer: a review. Ther Adv Med Oncol 2016; 8:276-93. [PMID: 27482287 DOI: 10.1177/1758834016646734] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Treatment strategies for metastatic colorectal cancer (mCRC) patients have undergone dramatic changes in the past decade and despite improved patient outcomes, there still exist areas for continued development. The introduction of targeted agents has provided clinicians with additional treatment options in mCRC, however, results have been mixed at best. These novel therapies were designed to interfere with specific molecules involved in the cellular carcinogenesis pathway and ultimately deliver a more focused treatment. Currently, their use in mCRC has been limited primarily as an adjunct to conventional chemotherapy regimens. This review explores the relevant cell-signaling networks in colorectal cancer, provides focus on the current targeted agent armamentarium approved for use in mCRC and explores the usefulness of predictive mCRC biomarkers.
Collapse
Affiliation(s)
- Andrew Moriarity
- St James's Hospital, Surgical Oncology, St James's St, Dublin 8, Ireland
| | | | | | | | | |
Collapse
|
|
42
|
Molecular markers of prognosis and therapeutic targets in metastatic colorectal cancer. Surg Oncol 2016; 25:190-9. [PMID: 27566022 DOI: 10.1016/j.suronc.2016.05.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/19/2016] [Indexed: 12/18/2022]
Abstract
Metastatic disease ultimately occurs in approximately 50-70% of patients presenting with colorectal cancer. In patients with advanced disease, there is significant variability in individual patient outcomes. To improve understanding of tumor behavior, markers such as KRAS and BRAF mutation status are increasingly utilized. Additionally, newer surrogates of tumor biology, such as telomerase activity and the prevalence of circulating tumor cells and circulating tumor DNA, have generated increasing interest due to clinical potential. While the extent to which these newer markers can predict outcome and guide therapy is yet to be determined, KRAS mutation status is currently used to guide systemic therapy in selected patients. Furthermore, advances in our understanding of various tumorigenic pathways (such as the mitogen activated protein kinase pathway) have enabled newer targeted agents, including BRAF inhibitors. Interestingly, although inhibition of BRAF in patients has not translated into improved outcomes, characterization of BRAF mutations led to an association with microsatellite instability. A unique histologic characteristic of certain tumors in patients with microsatellite instability is the infiltration by lymphocytes at the tumor-stromal interface. This feature highlights the biology of the tumor in its microenvironment and underlies the efficacy of the programmed-death inhibitor, pembrolizumab, in patients with microsatellite unstable metastatic colorectal cancer. With an increasing number of prognostic markers and therapeutic options in metastatic colorectal cancer, the multidisciplinary approach becomes critical for appropriate treatment decisions.
Collapse
|
|
43
|
Barth RF, Wu G, Meisen WH, Nakkula RJ, Yang W, Huo T, Kellough DA, Kaumaya P, Turro C, Agius LM, Kaur B. Design, synthesis, and evaluation of cisplatin-containing EGFR targeting bioconjugates as potential therapeutic agents for brain tumors. Onco Targets Ther 2016; 9:2769-81. [PMID: 27274273 PMCID: PMC4869632 DOI: 10.2147/ott.s99242] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The aim of this study was to evaluate four different platinated bioconjugates containing a cisplatin (cis-diamminedichloroplatinum [cis-DDP]) fragment and epidermal growth factor receptor (EGFR)-targeting moieties as potential therapeutic agents for the treatment of brain tumors using a human EGFR-expressing transfectant of the F98 rat glioma (F98EGFR) to assess their efficacy. The first two bioconjugates employed the monoclonal antibody cetuximab (C225 or Erbitux®) as the targeting moiety, and the second two used genetically engineered EGF peptides. C225-G5-Pt was produced by reacting cis-DDP with a fifth-generation polyamidoamine dendrimer (G5) and then linking it to C225 by means of two heterobifunctional reagents. The second bioconjugate (C225-PG-Pt) employed the same methodology except that polyglutamic acid was used as the carrier. The third and fourth bioconjugates used two different EGF peptides, PEP382 and PEP455, with direct coordination to the Pt center of the cis-DDP fragment. In vivo studies with C225-G5-Pt failed to demonstrate therapeutic activity following intracerebral (ic) convection-enhanced delivery (CED) to F98EGFR glioma-bearing rats. The second bioconjugate, C225-PG-Pt, failed to show in vitro cytotoxicity. Furthermore, because of its high molecular weight, we decided that lower molecular weight peptides might provide better targeting and microdistribution within the tumor. Both PEP382-Pt and PEP455-Pt bioconjugates were cytotoxic in vitro and, based on this, a pilot study was initiated using PEP455-Pt. The end point for this study was tumor size at 6 weeks following tumor cell implantation and 4 weeks following ic CED of PEP455-Pt to F98 glioma-bearing rats. Neuropathologic examination revealed that five of seven rats were either tumor-free or only had microscopic tumors at 42 days following tumor implantation compared to a mean survival time of 20.5 and 26.3 days for untreated controls. In conclusion, we have succeeded in reformatting the toxicity profile of cis-DDP and demonstrated the therapeutic efficacy of the PEP455-Pt bioconjugate in F98 glioma-bearing rats.
Collapse
Affiliation(s)
- Rolf F Barth
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Gong Wu
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - W Hans Meisen
- Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA
| | - Robin J Nakkula
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Weilian Yang
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Tianyao Huo
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - David A Kellough
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Pravin Kaumaya
- Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH, USA; Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA
| | - Claudia Turro
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
| | - Lawrence M Agius
- Department of Pathology, Mater Dei Hospital, University of Malta Medical School, Msida, Malta
| | - Balveen Kaur
- Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA
| |
Collapse
|
|
44
|
Kocoglu H, Velibeyoglu FM, Karaca M, Tural D. Clinical efficacy and drug resistance of anti-epidermal growth factor receptor therapy in colorectal cancer. World J Gastrointest Oncol 2016; 8:1-7. [PMID: 26798432 PMCID: PMC4714138 DOI: 10.4251/wjgo.v8.i1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 10/06/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC (mCRC), such as monoclonal antibodies against epidermal growth factor receptor (anti-EGFR), which provided additional clinical benefits in mCRC. However, anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment. Thus, KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because; approximately fifty percent (40%-60%) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment. This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet. Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms.
Collapse
|
|
45
|
Miroddi M, Sterrantino C, Simonelli I, Ciminata G, Phillips RS, Calapai G. Risk of grade 3-4 diarrhea and mucositis in colorectal cancer patients receiving anti-EGFR monoclonal antibodies regimens: A meta-analysis of 18 randomized controlled clinical trials. Crit Rev Oncol Hematol 2015; 96:355-71. [PMID: 26160607 DOI: 10.1016/j.critrevonc.2015.06.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Revised: 05/07/2015] [Accepted: 06/10/2015] [Indexed: 12/22/2022] Open
|
|
46
|
Kapogiannatos G, Margaritis D, Alevizou R, Gogoulou I, Nomicos A, Digalakis M. Immunohistochemical expression of EGFR in colorectal adenocarcinoma and its correlation with the presence of lymph node metastases. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s13126-015-0242-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
47
|
Allegra CJ, Rumble RB, Hamilton SR, Mangu PB, Roach N, Hantel A, Schilsky RL. Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol 2015; 34:179-85. [PMID: 26438111 DOI: 10.1200/jco.2015.63.9674] [Citation(s) in RCA: 200] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE An American Society of Clinical Oncology Provisional Clinical Opinion (PCO) offers timely clinical direction after publication or presentation of potentially practice-changing data from major studies. This PCO update addresses the utility of extended RAS gene mutation testing in patients with metastatic colorectal cancer (mCRC) to detect resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy. CLINICAL CONTEXT Recent results from phase II and III clinical trials in mCRC demonstrate that patients whose tumors harbor RAS mutations in exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146) are unlikely to benefit from therapy with MoAbs directed against EGFR, when used as monotherapy or combined with chemotherapy. RECENT DATA In addition to the evidence reviewed in the original PCO, 11 systematic reviews with meta-analyses, two retrospective analyses, and two health technology assessments based on a systematic review were obtained. These evaluated the outcomes for patients with mCRC with no mutation detected or presence of mutation in additional exons in KRAS and NRAS. PCO: All patients with mCRC who are candidates for anti-EGFR antibody therapy should have their tumor tested in a Clinical Laboratory Improvement Amendments-certified laboratory for mutations in both KRAS and NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146). The weight of current evidence indicates that anti-EGFR MoAb therapy should only be considered for treatment of patients whose tumor is determined to not have mutations detected after such extended RAS testing.
Collapse
Affiliation(s)
- Carmen J Allegra
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| | - R Bryan Rumble
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| | - Stanley R Hamilton
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| | - Pamela B Mangu
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| | - Nancy Roach
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| | - Alexander Hantel
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| | - Richard L Schilsky
- Carmen J. Allegra, University of Florida, Gainesville, FL; R. Bryan Rumble, Pamela B. Mangu, and Richard L. Schilsky, American Society of Clinical Oncology; Nancy Roach, Fight Colorectal Cancer, Alexandria, VA; Stanley R. Hamilton, University of Texas MD Anderson Cancer Center, Houston, TX; and Alexander Hantel, Edward Cancer Center, Naperville, IL
| |
Collapse
|
|
48
|
Chan DL, Pavlakis N, Shapiro J, Price TJ, Karapetis CS, Tebbutt NC, Segelov E. Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature. PLoS One 2015; 10:e0135599. [PMID: 26275292 PMCID: PMC4537274 DOI: 10.1371/journal.pone.0135599] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 07/23/2015] [Indexed: 12/22/2022] Open
Abstract
IMPORTANCE The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. OBJECTIVE To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. DATA SOURCES MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts. STUDY SELECTION Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations. DATA EXTRACTION AND SYNTHESIS Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity. RESULTS EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81-1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69-0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87-1.09) and PFS HR 0.92 (95% CI 0.83-1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72-0.94) compared to capecitabine (HR 1.09; 95% CI 0.91-1.30) and bolus 5FU (HR 1.07; 95% CI 0.79-1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002). CONCLUSION AND RELEVANCE The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.
Collapse
Affiliation(s)
- David L. Chan
- Royal North Shore Hospital, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia
- * E-mail:
| | - Nick Pavlakis
- Royal North Shore Hospital, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia
| | - Jeremy Shapiro
- Department of Medical Oncology, Monash University, Victoria, Australia
| | - Timothy J. Price
- The Queen Elizabeth Hospital and University of Adelaide, South Australia, Australia
| | - Christos S. Karapetis
- Flinders University and Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Bedford Park, South Australia, Australia
| | | | - Eva Segelov
- St Vincent’s Clinical School, University of New South Wales, NSW, Australia
| |
Collapse
|
|
49
|
Lianos GD, Glantzounis GK, Mangano A, Rausei S, Roukos DH. Colorectal liver metastases guidelines, tumor heterogeneity and clonal evolution: can this be translated to patient benefit? Future Oncol 2015; 10:1723-6. [PMID: 25303052 DOI: 10.2217/fon.14.91] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Georgios D Lianos
- Centre for Biosystems & Genomic Network Medicine, CBS.GenNetMed, University of Ioannina, Ioannina, GR 451 10, Greece
| | | | | | | | | |
Collapse
|
|
50
|
Hutchinson RA, Adams RA, McArt DG, Salto-Tellez M, Jasani B, Hamilton PW. Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer. J Transl Med 2015; 13:217. [PMID: 26149458 PMCID: PMC4492076 DOI: 10.1186/s12967-015-0531-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 05/12/2015] [Indexed: 02/06/2023] Open
Abstract
The treatment of cancer is becoming more precise, targeting specific oncogenic drivers with targeted molecular therapies. The epidermal growth factor receptor has been found to be over-expressed in a multitude of solid tumours. Immunohistochemistry is widely used in the fields of diagnostic and personalised medicine to localise and visualise disease specific proteins. To date the clinical utility of epidermal growth factor receptor immunohistochemistry in determining monoclonal antibody efficacy has remained somewhat inconclusive. The lack of an agreed reproducible scoring criteria for epidermal growth factor receptor immunohistochemistry has, in various clinical trials yielded conflicting results as to the use of epidermal growth factor receptor immunohistochemistry assay as a companion diagnostic. This has resulted in this test being removed from the licence for the drug panitumumab and not performed in clinical practice for cetuximab. In this review we explore the reasons behind this with a particular emphasis on colorectal cancer, and to suggest a way of resolving the situation through improving the precision of epidermal growth factor receptor immunohistochemistry with quantitative image analysis of digitised images complemented with companion molecular morphological techniques such as in situ hybridisation and section based gene mutation analysis.
Collapse
Affiliation(s)
- Ryan A Hutchinson
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK.
- Waring Laboratory, Department of Pathology, Centre for Translational Pathology, University of Melbourne, Parkville, 3010, VIC, Australia.
| | - Richard A Adams
- Institute of Cancer and Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK.
| | - Darragh G McArt
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK.
| | - Manuel Salto-Tellez
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK.
| | - Bharat Jasani
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 010000, Kazakhstan.
| | - Peter W Hamilton
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK.
| |
Collapse
|