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1
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Pirvu EE, Severin E, Patru RI, Nita I, Toma SA, Croitoru BE, Munoz Groza AE, Marinescu G. Treatment Strategies' Impact on Progression-Free Survival According to RMST Function in Metastatic Colorectal Cancer Patients: A Retrospective Study from Romania. J Clin Med 2024; 13:6174. [PMID: 39458124 PMCID: PMC11508923 DOI: 10.3390/jcm13206174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/13/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Background: This retrospective study investigates the impact of various treatment strategies on progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), a significant global health issue. Methods: We employed the restricted mean survival time (RMST) to evaluate how different treatments affect PFS over a defined period. The study included 225 patients with mCRC who were treated between 2015 and 2023 at the Oncology Department of Colțea Clinical Hospital in Bucharest. To assign KRAS status, mutation data from exons 2, 3, and 4 of the KRAS gene were required. Eligibility criteria included a confirmed histopathological diagnosis of colorectal adenocarcinoma, a valid RAS mutation test from a solid biopsy, radiological confirmation of stage IV disease by computed tomography, and at least one line of systemic treatment in the metastatic setting. Results: Our analysis revealed a small difference in PFS based on KRAS status, but this difference was not statistically significant. Neither sex nor the urban versus rural environment impacted PFS; however, the data indicated that educational level affected survival outcomes. Conclusions: Consistent with existing literature, our findings showed no survival benefit from locoregional treatments such as surgery of the primary tumor or curative radiotherapy at diagnosis. In contrast, resection of hepatic metastases was associated with improved survival outcomes.
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Affiliation(s)
- Edvina Elena Pirvu
- Department of Genetics, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | - Emilia Severin
- Department of Genetics, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Raluca Ileana Patru
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | - Irina Nita
- Department of Medical Oncology, Medicover Hospital, 020331 Bucharest, Romania
| | - Stefania Andreea Toma
- Department of Medical Oncology, Ponderas Academic Hospital, 014142 Bucharest, Romania
| | - Bianca Elena Croitoru
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
| | | | - Gabriela Marinescu
- Department of Medical Oncology, “Coltea” Clinical Hospital, 030167 Bucharest, Romania
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2
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Khan F, Akhtar S, Kamal MA. Nanoinformatics and Personalized Medicine: An Advanced Cumulative Approach for Cancer Management. Curr Med Chem 2023; 30:271-285. [PMID: 35692148 DOI: 10.2174/0929867329666220610090405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/10/2022] [Accepted: 03/15/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Even though the battle against one of the deadliest diseases, cancer, has advanced remarkably in the last few decades and the survival rate has improved significantly; the search for an ultimate cure remains a utopia. Nanoinformatics, which is bioinformatics coupled with nanotechnology, endows many novel research opportunities in the preclinical and clinical development of personalized nanosized drug carriers in cancer therapy. Personalized nanomedicines serve as a promising treatment option for cancer owing to their noninvasiveness and their novel approach. Explicitly, the field of personalized medicine is expected to have an enormous impact soon because of its many advantages, namely its versatility to adapt a drug to a cohort of patients. OBJECTIVE The current review explains the application of this newly emerging field called nanoinformatics to the field of precision medicine. This review also recapitulates how nanoinformatics could hasten the development of personalized nanomedicine for cancer, which is undoubtedly the need of the hour. CONCLUSION This approach has been facilitated by a humongous impending field named Nanoinformatics. These breakthroughs and advances have provided insight into the future of personalized medicine. Imperatively, they have been enabling landmark research to merge all advances, creating nanosized particles that contain drugs targeting cell surface receptors and other potent molecules designed to kill cancerous cells. Nanoparticle- based medicine has been developing and has become a center of attention in recent years, focusing primely on proficient delivery systems for various chemotherapy drugs.
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Affiliation(s)
- Fariya Khan
- Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow - 226026, UP, India
| | - Salman Akhtar
- Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow - 226026, UP, India.,Novel Global Community Educational Foundation, Hebersham, NSW2770, Australia
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontier Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.,King Fahad Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.,Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh.,Enzymoics, 7, Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, Australia
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3
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Fernandes MC, Horvat N. Editorial for "A Deep Learning Model Based on MRI and Clinical Factors Facilitates Noninvasive Prediction of KRAS Mutation in Rectal Cancer". J Magn Reson Imaging 2022; 56:1669-1670. [PMID: 35575434 DOI: 10.1002/jmri.28233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/04/2022] [Indexed: 01/04/2023] Open
Affiliation(s)
- Maria Clara Fernandes
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Natally Horvat
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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4
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Pandey V, Zhang X, Poh HM, Wang B, Dukanya D, Ma L, Yin Z, Bender A, Periyasamy G, Zhu T, Rangappa KS, Basappa B, Lobie PE. Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival. ACS Pharmacol Transl Sci 2022; 5:761-773. [PMID: 36110371 PMCID: PMC9469493 DOI: 10.1021/acsptsci.2c00044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Indexed: 11/28/2022]
Abstract
Trefoil factor 3 (TFF3) is a secreted protein with an established oncogenic function and a highly significant association with clinical progression of various human malignancies. Herein, a novel small molecule that specifically targets TFF3 homodimeric functions was identified. Utilizing the concept of reversible covalent interaction, 2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) was identified as a molecule that interacted with TFF3. AMPC monomerized the cellular and secreted TFF3 homodimer at the cysteine (Cys)57-Cys57 residue with subsequent more rapid degradation of the generated TFF3 monomers. Hence, AMPC treatment also resulted in cellular depletion of TFF3 with consequent decreased cell viability in various human carcinoma-derived TFF3 expressing cell lines, including estrogen receptor positive (ER+) mammary carcinoma (MC). AMPC treatment of TFF3 expressing ER+ MC cells significantly suppressed total cell number in a dose-dependent manner. Consistently, exposure of TFF3 expressing ER+ MC cells to AMPC decreased soft agar colony formation, foci formation, and growth in suspension culture and inhibited growth of preformed colonies in 3D Matrigel. AMPC increased apoptosis in TFF3 expressing ER+ MC cells associated with decreased activity of EGFR, p38, STAT3, AKT, and ERK, decreased protein levels of CCND1, CCNE1, BCL2, and BCL-XL, and increased protein levels of TP53, CDKN1A, CASP7, and CASP9. siRNA-mediated depletion of TFF3 expression in ER+ MC cells efficiently abrogated AMPC-stimulated loss of cell viability and CASPASE 3/7 activities. Furthermore, in mice bearing ER+ MC cell-generated xenografts, AMPC treatment significantly impeded xenograft growth. Hence, AMPC exemplifies a novel mechanism by which small molecule drugs may inhibit a dimeric oncogenic protein and provides a strategy to impede TFF3-dependent cancer progression.
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Affiliation(s)
- Vijay Pandey
- Tsinghua
Berkeley Shenzhen Institute and Institute of Biopharmaceutical and
Health Engineering, Tsinghua Shenzhen International
Graduate School, Shenzhen 518055, PR China
| | - Xi Zhang
- Shenzhen
Bay Laboratory, Shenzhen 518055, PR China
| | - Han-Ming Poh
- Cancer Science
Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599
| | - Baocheng Wang
- Tsinghua
Berkeley Shenzhen Institute and Institute of Biopharmaceutical and
Health Engineering, Tsinghua Shenzhen International
Graduate School, Shenzhen 518055, PR China
| | - Dukanya Dukanya
- Laboratory
of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006 Karnataka, India
| | - Lan Ma
- Tsinghua
Berkeley Shenzhen Institute and Institute of Biopharmaceutical and
Health Engineering, Tsinghua Shenzhen International
Graduate School, Shenzhen 518055, PR China
- Shenzhen
Bay Laboratory, Shenzhen 518055, PR China
| | - Zhinan Yin
- Biomedical
Translational Research Institute, Jinan
University, 601 Huangpu Avenue West, Guangzhou 510632, PR China
- Zhuhai Institute
of Translational Medicine Zhuhai People’s Hospital Affiliated
with Jinan University, Jinan University, Zhuhai, Guangdong 519000, PR China
| | - Andreas Bender
- Centre for
Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom
| | - Ganga Periyasamy
- DOS in Chemistry, Bangalore University, JB Campus, Bangalore 560001, India
| | - Tao Zhu
- Department
of Oncology of the First Affiliated Hospital, Division of Life Sciences
and Medicine, University of Science and
Technology of China, Hefei, Anhui 230027, China
- Hefei National
Laboratory for Physical Sciences, the CAS Key Laboratory of Innate
Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Kanchugarakoppal S. Rangappa
- Laboratory
of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006 Karnataka, India
| | - Basappa Basappa
- Laboratory
of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006 Karnataka, India
| | - Peter E. Lobie
- Tsinghua
Berkeley Shenzhen Institute and Institute of Biopharmaceutical and
Health Engineering, Tsinghua Shenzhen International
Graduate School, Shenzhen 518055, PR China
- Shenzhen
Bay Laboratory, Shenzhen 518055, PR China
- Cancer Science
Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599
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Cleyle J, Hardy MP, Minati R, Courcelles M, Durette C, Lanoix J, Laverdure JP, Vincent K, Perreault C, Thibault P. Immunopeptidomic analyses of colorectal cancers with and without microsatellite instability. Mol Cell Proteomics 2022; 21:100228. [PMID: 35367648 PMCID: PMC9134101 DOI: 10.1016/j.mcpro.2022.100228] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is the second leading cause of cancer death worldwide, and the incidence of this disease is expected to increase as global socioeconomic changes occur. Immune checkpoint inhibition therapy is effective in treating a minority of colorectal cancer tumors; however, microsatellite stable tumors do not respond well to this treatment. Emerging cancer immunotherapeutic strategies aim to activate a cytotoxic T cell response against tumor-specific antigens, presented exclusively at the cell surface of cancer cells. These antigens are rare and are most effectively identified with a mass spectrometry-based approach, which allows the direct sampling and sequencing of these peptides. Although the few tumor-specific antigens identified to date are derived from coding regions of the genome, recent findings indicate that a large proportion of tumor-specific antigens originate from allegedly noncoding regions. Here, we employed a novel proteogenomic approach to identify tumor antigens in a collection of colorectal cancer-derived cell lines and biopsy samples consisting of matched tumor and normal adjacent tissue. The generation of personalized cancer databases paired with mass spectrometry analyses permitted the identification of more than 30,000 unique MHC I-associated peptides. We identified 19 tumor-specific antigens in both microsatellite stable and unstable tumors, over two-thirds of which were derived from noncoding regions. Many of these peptides were derived from source genes known to be involved in colorectal cancer progression, suggesting that antigens from these genes could have therapeutic potential in a wide range of tumors. These findings could benefit the development of T cell-based vaccines, in which T cells are primed against these antigens to target and eradicate tumors. Such a vaccine could be used in tandem with existing immune checkpoint inhibition therapies, to bridge the gap in treatment efficacy across subtypes of colorectal cancer with varying prognoses. Data are available via ProteomeXchange with identifier PXD028309.
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Affiliation(s)
- Jenna Cleyle
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada; Molecular Biology Program, Université de Montréal, Montreal, Quebec, Canada
| | - Marie-Pierre Hardy
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Robin Minati
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada; Molecular Biology Program, Université de Montréal, Montreal, Quebec, Canada
| | - Mathieu Courcelles
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Chantal Durette
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Joel Lanoix
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Jean-Philippe Laverdure
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Krystel Vincent
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Claude Perreault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada; Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.
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McFall T, Stites EC. Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach. Cell Rep 2021; 37:110096. [PMID: 34910921 PMCID: PMC8867612 DOI: 10.1016/j.celrep.2021.110096] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 06/29/2021] [Accepted: 11/15/2021] [Indexed: 01/05/2023] Open
Abstract
Mutations can be important biomarkers that influence the selection of specific cancer treatments. We recently combined mathematical modeling of RAS signaling network biochemistry with experimental cancer cell biology to determine why KRAS G13D is a biomarker for sensitivity to epidermal growth factor receptor (EGFR)-targeted therapies. The critical mechanistic difference between KRAS G13D and the other most common KRAS mutants is impaired binding to tumor suppressor Neurofibromin (NF1). Here, we hypothesize that impaired binding to NF1 is a "biophysical biomarker" that defines other RAS mutations that retain therapeutic sensitivity to EGFR inhibition. Both computational and experimental investigations support our hypothesis. By screening RAS mutations for this biophysical characteristic, we identify 10 additional RAS mutations that appear to be biomarkers for sensitivity to EGFR inhibition. Altogether, this work suggests that personalized medicine may benefit from migrating from gene-based and allele-based biomarker strategies to biomarkers based on biophysically defined subsets of mutations.
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Affiliation(s)
- Thomas McFall
- Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
| | - Edward C Stites
- Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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7
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Molecular Genetics and the Role of Molecularly Targeted Agents in Metastatic Colorectal Carcinoma. J Gastrointest Cancer 2021; 51:387-400. [PMID: 31273629 DOI: 10.1007/s12029-019-00272-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is the third most common malignancy and fourth leading cancer-related deaths worldwide. In the USA, CRC is the third most commonly diagnosed cancer in both men and women. It is caused by genetic components and potential environmental factors such as consumption of processed meat, red meat, animal fats, low fiber intake, and obesity. Despite the utilization of effective screening modalities and guidelines in the USA, a significant number of patients are diagnosed with advanced, metastatic disease at the time of presentation to the physician. Recent advances in the understanding of molecular medicine with subsequent development and incorporation of newer therapeutic agents into current chemotherapeutic regimens have improved outcomes; however, the management of metastatic CRC remains challenging, particularly for the treating oncologists. METHODS We conducted a literature search on CRC mainly related to molecular genetics, targeted biologic agents, and published clinical trials. We also searched and reviewed ongoing clinical trials from Clinicaltrials.gov. RESULTS AND CONCLUSIONS Alterations in several oncogenes are associated with CRC, among those RAS, BRAF, and HER2 are of current clinical importance. Chemotherapy drugs, along with vascular endothelial growth factor or epidermal growth factor receptor monoclonal antibodies, are proven to be efficient with manageable toxicity profiles in metastatic CRC. Additional researches on Her-2-directed therapy, BRAF-targeted agents, immunotherapeutic, and newer molecularly targeted agents are needed for further improvement in outcome.
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8
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Arici S, Hamdard J, Sakin A, Sengiz Erhan S, Atci MM, Cekin R, Saka B, Köse E, Saydam T, Geredeli C, Cihan S, Bilici A. The conversion of RAS status in metastatic colorectal cancer patients after first-line biological agent treatment. Colorectal Dis 2021; 23:206-212. [PMID: 33002301 DOI: 10.1111/codi.15389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/25/2020] [Accepted: 09/22/2020] [Indexed: 02/08/2023]
Abstract
AIM The aim was to investigate the RAS discordance between initial and recurrent metastasectomy specimens in metastatic colorectal cancer (mCRC) patients treated with chemotherapy (CT) plus biological agents in a first-line setting. METHODS Patients who had been treated with CT plus bevacizumab or cetuximab or panitumumab followed by R0 resection for potentially resectable colorectal cancer liver metastases were scanned. Among these, patients who developed resectable new metastases after a disease-free interval longer than 6 months were included in the study. We compared the RAS mutation status between the first biopsy and the second metastasectomy specimen. RESULTS A total of 82 mCRC patients treated with CT plus biological agents in a first-line setting were included in the study. The first biopsy assessment showed wild-type RAS tumours in 39 (47.6%) patients and mutant RAS tumours in 43 (52.4%) patients. The mean time for new operable liver metastasis after R0 resection was 15.5 months. In the second metastasectomy specimens, the numbers of wild-type and mutant RAS tumours were 30 (36.6%) and 52 (63.4%), respectively. The comparison with the first biopsy specimens showed RAS status conversions in 17 (20.7%) patients. Univariate comparison between patients with and without RAS status conversion revealed that grade, pathological T stage, wild-type RAS tumour and longer biological agent use time in the first-line treatment were significant factors for RAS conversion. CONCLUSION Our results suggest that re-biopsy is needed for an optimal second-line treatment decision in mCRC patients regardless of backbone biological agent, especially in patients with wild-type RAS mCRC.
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Affiliation(s)
- Serdar Arici
- Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Jamshid Hamdard
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul, Turkey
| | - Abdullah Sakin
- Department of Medical Oncology, Yuzuncu Yil University Medical School, Van, Turkey
| | - Selma Sengiz Erhan
- Department of Pathology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Muhammed Mustafa Atci
- Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Ruhper Cekin
- Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Burcu Saka
- Department of Pathology, Faculty of Medicine, Medipol University, Istanbul, Turkey
| | - Emin Köse
- Department of Surgery, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Tuba Saydam
- Department of Surgery, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Caglayan Geredeli
- Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Sener Cihan
- Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Ahmet Bilici
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul, Turkey
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9
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Liu M, Shen X, Pan W. Outcome weighted ψ-learning for individualized treatment rules. Stat (Int Stat Inst) 2020; 10:e343. [PMID: 34937955 PMCID: PMC8691757 DOI: 10.1002/sta4.343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/02/2020] [Indexed: 11/12/2022]
Abstract
An individualized treatment rule is often employed to maximize a certain patient-specific clinical outcome based on his/her clinical or genomic characteristics as well as heterogeneous response to treatments. Although developing such a rule is conceptually important to personalized medicine, existing methods such as the partial least squares Qian and Murphy (2011) suffers from the difficulty of indirect maximization of a patient's clinical outcome, while the outcome weighted learning Y. Zhao, Zeng, Rush, and Kosorok (2012) is not robust against any perturbation of the outcome. In this article, we propose a weighted ψ-learning method to optimize an individualized treatment rule, which is robust against any data perturbation near the decision boundary by seeking the maximum separation. To solve nonconvex minimization, we employ a difference convex algorithm to relax the non-convex minimization iteratively based on a decomposition of the cost function into a difference of two convex functions. On this ground, we also introduce a variable selection method for further removing redundant variables for a higher performance. Finally, we illustrate the proposed method by simulations and a lung health study and demonstrate that it yields higher performances in terms of accuracy of prediction of individualized treatment.
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Affiliation(s)
- Mingyang Liu
- School of Statistics, University of Minnesota, MN, Minneapolis
| | - Xiaotong Shen
- School of Statistics, University of Minnesota, MN, Minneapolis
| | - Wei Pan
- Division of Biostatistics, University of Minnesota, MN, Minneapolis
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10
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Metges JP, Douillard JY, Ramée JF, Dupuis O, Senellart H, Porneuf M, Deguiral P, Achour NE, Edeline J, Cumin I, Artignan X, Faroux R, Stampfli C, Cojocarasu O, Gourlaouen A, Bideau K, Meyer VG, Fichet A, Klein V, Touchefeu Y, Besson D, Desclos H, Barraya R, Alavi Z, Campion L, Lagadec DD, Marhuenda F, Grudé F. Efficacy and safety of panitumumab in a cohort of patients with metastatic colorectal cancer in France: PANI OUEST, a post-EMA-approval descriptive study with a geriatric oncology focus. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:695-705. [PMID: 33169707 DOI: 10.5152/tjg.2020.19219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS The Bretagne-Pays de la Loire cancer observatory, an oncology network created by the French Ministry of Health, is specifically dedicated to assess the use of new targeted anticancer therapies in routine practice. In line with the French National Cancer III program, our cancer network set up a real-life cohort, which is independent of the pharmaceutical industry, for patients with colorectal cancer to monitor patient safety and quality of care and promote pharmacovigilance. MATERIALS AND METHODS Panitumumab monotherapy was assessed in 243 patients with wild-type Kirsten rat sarcoma who were treated for metastatic colorectal cancer (mCRC) between July 2008 and December 2010 after prior chemotherapy using oxaliplatine and irinotecan. This was a post-European medicine agency marketing (EMA-M) study Results: This study shed light on the best practices, strategic adaptations, clinical results (treatment objective responses, 13%; progression free survival, 2.99 months [2.73-3.15]; and overall survival, 6.8 months [5.49-8.38]) as well as expected or unexpected (grade 3 or 4: 11.5%) secondary effects in the phase IV panitumumab treatment of mCRC. CONCLUSION Our results are similar to those by Amado whose phase III study led to obtaining EMA-M for panitumumab and tend to confirm the antitumor activity of this antiepidermal growth factor receptor antibody in the treatment of mCRC. In addition, our results opened avenues to further assessment of panitumumab use as monotherapy as well as its benefit-risk ratio while taking into account the patients' general and clinical characteristics. In 2012, the French National Authority for Health appended these data to the panitumumab transparency committee report.
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Affiliation(s)
- Jean-Philippe Metges
- Observatoire dédié au Cancer BPL, siège médical ICO site Paul Papin, France;C.H.R.U., Hôpital Morvan, Institut de cancérologie et d'hématologie, Brest, France
| | - Jean-Yves Douillard
- Observatory of Cancer BPL, Angers, France;West Institut of Cancer (ICO), René Gauducheau, Boulevard Jacques Monod, Saint-Herblain, France
| | | | - Olivier Dupuis
- Private Hospital Jean Bernard/Clinique Victor Hugo Le Mans, Le Mans, France
| | - Helene Senellart
- West Institut of Cancer (ICO), René Gauducheau, Boulevard Jacques Monod, Saint-Herblain, France
| | - Marc Porneuf
- Hospital Center of Yves le Foll, Saint-Brieuc, France;C.H. Lannion Trestel, Venelle de Kergomar, Lannion, France
| | | | - Nach Eddine Achour
- Private Hospital Pasteur-Lanroze, Brest, France;Private Hospital CMC de la Baie de Morlaix, Morlaix, France
| | - Julien Edeline
- C.R.L.C.C. Eugène Marquis, Avenue de la Bataille Flandres-Dunkerque, Rennes, France
| | | | - Xavier Artignan
- C.H.P, 6 Boulevard de la Boutière, Saint-Gregoire, France;Private Hospital Sévigné, Cesson Sevigne, France
| | - Roger Faroux
- Hospital Center of Vendée, La Roche Sur Yon, France
| | | | | | | | | | - Véronique Guérin Meyer
- West Institut of Cancer (ICO), Paul Papin, Angers, France;Hospital Center of Saumur, Saumur, France
| | | | - Vincent Klein
- Hospital Center of Vannes, Vannes, France;Private Hospital Océane, Vannes, France
| | - Yann Touchefeu
- University Hospital of. Nantes Hôtel Dieu, Nantes, France
| | | | | | | | | | - Loic Campion
- West Institut of Cancer (ICO), René Gauducheau, Boulevard Jacques Monod, Saint-Herblain, France
| | | | - Fanny Marhuenda
- Observatory of Cancer BPL, Angers, France;West Institut of Cancer (ICO), Paul Papin, Angers, France
| | - Francoise Grudé
- Observatory of Cancer BPL, Angers, France;West Institut of Cancer (ICO), Paul Papin, Angers, France
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11
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Landscape of transcriptome variations uncovering known and novel driver events in colorectal carcinoma. Sci Rep 2020; 10:432. [PMID: 31949199 PMCID: PMC6965099 DOI: 10.1038/s41598-019-57311-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 12/20/2019] [Indexed: 12/27/2022] Open
Abstract
We focused on an integrated view of genomic changes in Colorectal cancer (CRC) and distant normal colon tissue (NTC) to test the effectiveness of expression profiling on identification of molecular targets. We performed transcriptome on 16 primary coupled CRC and NTC tissues. We identified pathways and networks related to pathophysiology of CRC and selected potential therapeutic targets. CRC cells have multiple ways to reprogram its transcriptome: a functional enrichment analysis in 285 genes, 25% mutated, showed that they control the major cellular processes known to promote tumorigenesis. Among the genes showing alternative splicing, cell cycle related genes were upregulated (CCND1, CDC25B, MCM2, MCM3), while genes involved in fatty acid metabolism (ACAAA2, ACADS, ACAT1, ACOX, CPT1A, HMGCS2) were downregulated. Overall 148 genes showed differential splicing identifying 17 new isoforms. Most of them are involved in the pathogenesis of CRC, although the functions of these variants remain unknown. We identified 2 in-frame fusion events, KRT19-KRT18 and EEF1A1-HSP90AB1, encoding for chemical proteins in two CRC patients. We draw a functional interactome map involving integrated multiple genomic features in CRC. Finally, we underline that two functional cell programs are prevalently deregulated and absolutely crucial to determinate and sustain CRC phenotype.
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Khan K, Valeri N, Dearman C, Rao S, Watkins D, Starling N, Chau I, Cunningham D. Targeting EGFR pathway in metastatic colorectal cancer- tumour heterogeniety and convergent evolution. Crit Rev Oncol Hematol 2019; 143:153-163. [PMID: 31678702 DOI: 10.1016/j.critrevonc.2019.09.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/28/2019] [Accepted: 09/03/2019] [Indexed: 12/30/2022] Open
Abstract
Despite significant progress in management of metastatic colorectal cancer (mCRC) pertaining to better screening procedures and amelioration of the therapeutic armamentarium with targeted therapies, prognosis remains poor. Targeting epidermal growth factor receptor (EGFR) has been of particular interest owing to favourable efficacy benefits demonstrated by monoclonal antibodies (cetuximab and panitumumab) in various clinical settings and development of predictive biomarkers informing treatment decisions respectively. In spite of optimal patient selection based on RAS mutation status, primary and secondary resistance to monoclonal antibodies is higher than desired. Further research into predictive biomarkers is therefore essential, but has, to date, been conducted with considerable limitations. Whilst molecular heterogeneity has been demonstrated by several studies in mCRC, for incomprehensible reasons, multiple resistant genetic alterations that emerge under the selective pressure of EGFR-targeted therapies are somehow able to influence the biological and clinical behaviour of cancer cells, despite being detectable at extremely low frequencies. Intriguingly, these subclonal events largely seem to converge on RAS/RAF/MAPK pathway in patients treated with EGFR-targeted monoclonal antibodies. This review describes the clinical and biological evolution and development of EGFR targeted therapies in mCRC, the challenges in the presence of molecular complexities, the role of cell free (cf)-DNA and future strategies that could lead to further optimal discovery of clinically meaningful biomarkers and application of precision medicine.
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Affiliation(s)
- Khurum Khan
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK; Gastrointestinal Unit, University College London Hospitals, 250 Euston Road London, NW1 2AF, UK
| | - Nicola Valeri
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK
| | - Charles Dearman
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK
| | - Sheela Rao
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK
| | - David Watkins
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK
| | - Naureen Starling
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK
| | - Ian Chau
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK
| | - David Cunningham
- Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK.
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Westin SN, Sill MW, Coleman RL, Waggoner S, Moore KN, Mathews CA, Martin LP, Modesitt SC, Lee S, Ju Z, Mills GB, Schilder RJ, Fracasso PM, Birrer MJ, Aghajanian C. Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study. Gynecol Oncol 2019; 155:420-428. [PMID: 31623857 DOI: 10.1016/j.ygyno.2019.09.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.
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Affiliation(s)
- Shannon N Westin
- Department of Gynecologic Oncology, University of Texas M. D Anderson Cancer Center, USA.
| | - Michael W Sill
- NRG Oncology Statistics and Data Management Center Buffalo Office, Roswell Park Cancer Institute, USA.
| | - Robert L Coleman
- Department of Gynecologic Oncology, University of Texas M. D Anderson Cancer Center, USA.
| | - Steven Waggoner
- Department of Gynecologic Oncology, Case Western Reserve University, USA.
| | - Kathleen N Moore
- Department of Gynecologic Oncology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, USA.
| | - Cara A Mathews
- Department of Gynecologic Oncology, Women & Infants Hospital, USA.
| | - Lainie P Martin
- Department of Hematology/Oncology, Fox Chase Cancer Center, USA.
| | - Susan C Modesitt
- Director of Gynecologic Oncology Division, University of Virginia, USA.
| | - Sanghoon Lee
- Department of Medicine and the UVA Cancer Center, University of Virginia, USA.
| | - Zhenlin Ju
- Department of Bioinformatics and Computational Biology, University of Texas M. D Anderson Cancer Center, USA.
| | - Gordon B Mills
- Department of Medicine and the UVA Cancer Center, University of Virginia, USA.
| | - Russell J Schilder
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, USA.
| | - Paula M Fracasso
- Department of Systems Biology, University of Texas M.D Anderson Cancer Center, USA.
| | | | - Carol Aghajanian
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, USA.
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Chen CL, Chen CK, Ho CL, Chi WM, Yeh CH, Hu SP, Friebe P, Palmer S, Huang CS. Clinical Evaluation of IntelliPlex™ KRAS G12/13 Mutation Kit for Detection of KRAS Mutations in Codon 12 and 13: A Novel Multiplex Approach. Mol Diagn Ther 2019; 23:645-656. [DOI: 10.1007/s40291-019-00418-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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15
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Wan F, Titman AC, Jaki TF. Subgroup analysis of treatment effects for misclassified biomarkers with time‐to‐event data. J R Stat Soc Ser C Appl Stat 2019. [DOI: 10.1111/rssc.12364] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Multipoint Kras oncogene mutations potentially indicate mucinous carcinoma on the entire spectrum of mucinous ovarian neoplasms. Oncotarget 2018; 7:82097-82103. [PMID: 27888800 PMCID: PMC5347677 DOI: 10.18632/oncotarget.13449] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 10/28/2016] [Indexed: 01/22/2023] Open
Abstract
Kras mutation is a common phenomenon in many human neoplasms. We aimed to assess the Kras mutational status along the histological continuum from normal ovaries to the development of benign, borderline and malignant ovarian mucinous neoplasms. We analyzed 41 cases of malignant, 10 cases of borderline, 7 cases of benign mucinous ovarian tumors and 7 cases of normal ovarian tissue. The prevalence of Kras mutations in the normal ovary was 0.00% (n=0/7), while the prevalence in benign, borderline and malignant mucinous neoplasms was 57.14% (n=4/7), 90.00% (n=9/10) and 75.61% (n=31/41), respectively. Multiple Kras mutations were detected in 6 cases of mucinous carcinoma, including 5 double mutations with G13D/V14I (n=1), G12V/G13S (n=1), G12D/G13S (n=3) and one triple mutation with A11V/G13N/V14I (n=1). We identified six cases with 3 novel Kras mutations not previously described in the COSMIC database, which included A11V (n=3) and V14I (n=2) in mucinous carcinomas, and A11T (n=1) in a mucinous borderline tumor. In conclusion, Kras mutation appears to be one of the imperative events in the ovarian mucinous adenoma–borderline tumor–carcinoma sequence, as increased numbers of Kras mutations have been shown to be the strongest predictor of unequivocal malignancy in ovarian mucinous neoplasms.
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Módos O, Reis H, Niedworok C, Rübben H, Szendröi A, Szász MA, Tímár J, Baghy K, Kovalszky I, Golabek T, Chlosta P, Okon K, Peyronnet B, Mathieu R, Shariat SF, Hollósi P, Nyirády P, Szarvas T. Mutations of KRAS, NRAS, BRAF, EGFR, and PIK3CA genes in urachal carcinoma: Occurence and prognostic significance. Oncotarget 2018; 7:39293-39301. [PMID: 27283768 PMCID: PMC5129933 DOI: 10.18632/oncotarget.9828] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 05/29/2016] [Indexed: 01/21/2023] Open
Abstract
Purpose Targeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma (UrC). The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer. Materials and Methods Mutational hot-spots of selected genes were tested in 22 UrC samples by pyrosequencing. Mutational patterns were compared to those published for colorectal and urothelial cancers. Furthermore, we sought correlations between mutations and clinicopathological and follow-up data. Results We found 11 mutations in 10 of 22 (45%) patients. The most frequently mutated gene was KRAS (27%) followed by BRAF (18%) and NRAS (5%), while no mutations were detected in the EGFR and PIK3CA genes. No correlation was found between the mutation status and clinicopathological parameters (Sheldon/Mayo stage, tumor grade, metastases). Furthermore, none of the mutations correlated with progression-free or overall survival. Conclusions The mutation pattern of UrC is more similar to colorectal than to urothelial cancer. However, the mutation characteristics of UrC seems to be unique suggesting that clinical decision-making for UrC cannot be simply adopted from urothelial or colorectal carcinoma. The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC.
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Affiliation(s)
- Orsolya Módos
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Henning Reis
- Institute of Pathology, University of Duisburg-Essen, Essen, Germany
| | | | - Herbert Rübben
- Department of Urology, University of Duisburg-Essen, Essen, Germany
| | - Attila Szendröi
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Marcell A Szász
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - József Tímár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Kornélia Baghy
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Tomasz Golabek
- Department of Urology, Jagiellonian University, Krakow, Poland
| | - Piotr Chlosta
- Department of Urology, Jagiellonian University, Krakow, Poland
| | - Krzysztof Okon
- Department of Pathomorphology, Jagiellonian University, Krakow, Poland
| | - Benoit Peyronnet
- Department of Urology, Rennes University Hospital, Rennes, France
| | - Romain Mathieu
- Department of Urology, Rennes University Hospital, Rennes, France
| | - Shahrokh F Shariat
- Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Péter Hollósi
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.,Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Péter Nyirády
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Tibor Szarvas
- Department of Urology, Semmelweis University, Budapest, Hungary.,Department of Urology, University of Duisburg-Essen, Essen, Germany
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Morgan RG, Mortensson E, Legge DN, Gupta B, Collard TJ, Greenhough A, Williams AC. LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity. Br J Cancer 2017; 118:558-565. [PMID: 29149105 PMCID: PMC5830587 DOI: 10.1038/bjc.2017.412] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/18/2017] [Accepted: 10/19/2017] [Indexed: 12/25/2022] Open
Abstract
Background: LGR5 serves as a co-receptor for Wnt/β-catenin signalling and marks normal intestinal stem cells; however, its role in colorectal cancer (CRC) remains controversial. LGR5+ cells are known to exist outside the stem cell niche during CRC progression, and the requirement for epidermal growth factor (EGF) signalling within early adenomas remains to be fully elucidated. Methods: Epidermal growth factor and gefitinib treatments were performed in EGF-responsive LGR5+ early adenoma RG/C2 cells. 2D growth assays were measured using an IncuCyte. LGR5 or MEK1/2 silencing studies were executed using siRNA and LGR5 expression was assessed by qRT–PCR and immunoblotting. Ki67 level and cell cycle status were analysed by flow cytometry. Results: Epidermal growth factor suppresses expression of LGR5 at both the transcript and protein level in colorectal adenoma and carcinoma cells. Suppression of LGR5 reduces the survival of EGF-treated adenoma cells by increasing detached cell yield but also inducing a proliferative state, as evidenced by elevated Ki67 level and enhanced cell cycle progression. Repression of LGR5 further increases the sensitivity of adenoma cells to EGFR inhibition. Conclusions: LGR5 has an important role in the EGF-mediated survival and proliferation of early adenoma cells and could have clinical utility in predicting response of CRC patients to EGFR therapy.
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Affiliation(s)
- R G Morgan
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - E Mortensson
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - D N Legge
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - B Gupta
- European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - T J Collard
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - A Greenhough
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - A C Williams
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
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Rapid and accurate detection of KRAS mutations in colorectal cancers using the isothermal-based optical sensor for companion diagnostics. Oncotarget 2017; 8:83860-83871. [PMID: 29137388 PMCID: PMC5663560 DOI: 10.18632/oncotarget.20038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 07/25/2017] [Indexed: 01/23/2023] Open
Abstract
Although KRAS mutational status testing is becoming a companion diagnostic tool for managing patients with colorectal cancer (CRC), there are still several difficulties when analyzing KRAS mutations using the existing assays, particularly with regard to low sensitivity, its time-consuming, and the need for large instruments. We developed a rapid, sensitive, and specific mutation detection assay based on the bio-photonic sensor termed ISAD (isothermal solid-phase amplification/detection), and used it to analyze KRAS gene mutations in human clinical samples. To validate the ISAD-KRAS assay for use in clinical diagnostics, we examined for hotspot KRAS mutations (codon 12 and codon 13) in 70 CRC specimens using PCR and direct sequencing methods. In a serial dilution study, ISAD-KRAS could detect mutations in a sample containing only 1% of the mutant allele in a mixture of wild-type DNA, whereas both PCR and direct sequencing methods could detect mutations in a sample containing approximately 30% of mutant cells. The results of the ISAD-KRAS assay from 70 clinical samples matched those from PCR and direct sequencing, except in 5 cases, wherein ISAD-KRAS could detect mutations that were not detected by PCR and direct sequencing. We also found that the sensitivity and specificity of ISAD-KRAS were 100% within 30 min. The ISAD-KRAS assay provides a rapid, highly sensitive, and label-free method for KRAS mutation testing, and can serve as a robust and near patient testing approach for the rapid detection of patients most likely to respond to anti-EGFR drugs.
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20
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Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer. Am J Clin Oncol 2017; 39:236-42. [PMID: 24517959 DOI: 10.1097/coc.0000000000000045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.
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Matsunaga Y, Adachi Y, Sasaki Y, Koide H, Motoya M, Nosho K, Takagi H, Yamamoto H, Sasaki S, Arimura Y, Tokino T, Carbone DP, Imai K, Shinomura Y. The effect of forced expression of mutated K-RAS gene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy. Mol Carcinog 2017; 56:515-526. [PMID: 27312358 DOI: 10.1002/mc.22513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 05/09/2016] [Accepted: 06/14/2016] [Indexed: 08/29/2023]
Abstract
Mutation in K-RAS (K-RAS-MT) plays important roles in both cancer progression and resistance to anti-epidermal growth factor receptor (EGFR) therapy in gastrointestinal tumors. Insulin-like growth factor-1 receptor (IGF-1R) signaling is required for carcinogenicity and progression of many tumors as well. We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K-RAS mutation using an anti-IGF-1R monoclonal antibody. In this study, we sought to evaluate effects of forced K-RAS-MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti-EGFR therapy and IGF-1R-targeted therapy for these transfectants. We made stable transfectants of K-RAS-MT in two gastrointestinal cancer cell lines, colorectal RKO and pancreatic BxPC-3. We assessed the effect of forced expression of K-RAS-MT on proliferation, apoptosis, migration, and invasion in gastrointestinal cancer cells. Then we assessed anti-tumor effects of dominant negative IGF-1R (IGF-1R/dn) and an IGF-1R inhibitor, picropodophyllin, on the K-RAS-MT transfectants. Overexpression of K-RAS-MT in gastrointestinal cancer cell lines led to more aggressive phenotypes, with increased proliferation, decreased apoptosis, and increased motility and invasion. IGF-1R blockade suppressed cell growth, colony formation, migration, and invasion, and up-regulated chemotherapy-induced apoptosis of gastrointestinal cancer cells, even when K-RAS-MT was over-expressed. IGF-1R blockade inhibited the Akt pathway more than the extracellular signal-regulated kinase (ERK) pathway in the K-RAS-MT transfectants. IGF-1R/dn, moreover, inhibited the growth of murine xenografts expressing K-RAS-MT. Thus, K-RAS-MT might be important for progressive phonotype observed in gastrointestinal cancers. IGF-1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K-RAS is mutated. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Yasutaka Matsunaga
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Yasushi Adachi
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
- Sapporo Shirakaba-Dai Hospital, Sapporo, Japan
| | - Yasushi Sasaki
- Medical Genome Sciences, Research Institute of Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Hideyuki Koide
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Masayo Motoya
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Katsuhiko Nosho
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Hideyasu Takagi
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Hiroyuki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Shigeru Sasaki
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Yoshiaki Arimura
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
| | - Takashi Tokino
- Medical Genome Sciences, Research Institute of Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - David P Carbone
- James Cancer Center, The Ohio State University Medical Center, Columbus, Ohio
| | - Kohzoh Imai
- The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan
| | - Yasuhisa Shinomura
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan
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Loree JM, Kopetz S, Raghav KPS. Current companion diagnostics in advanced colorectal cancer; getting a bigger and better piece of the pie. J Gastrointest Oncol 2017; 8:199-212. [PMID: 28280626 PMCID: PMC5334060 DOI: 10.21037/jgo.2017.01.01] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 11/18/2016] [Indexed: 12/19/2022] Open
Abstract
While the treatment of colorectal cancer continues to rely heavily on conventional cytotoxic therapy, an increasing number of targeted agents are under development. Many of these treatments require companion diagnostic tests in order to define an appropriate population that will derive benefit. In addition, a growing number of biomarkers provide prognostic information about a patient's malignancy. As we learn more about these biomarkers and their assays, selecting the appropriate companion diagnostic becomes increasingly important. In the case of many biomarkers, there are numerous assays which could provide the same information to a treating physician, however each assay has strengths and weaknesses. Institutions must balance cost, assay sensitivity, turn-around time, and labor resources when selecting which assay to offer. In this review we will discuss the current state of companion diagnostics available in metastatic colorectal cancer and explore emerging biomarkers and their assays. We will focus on KRAS, BRAF, HER2, and PIK3CA testing, as well as microsatellite stability assessment and multigene panels.
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Affiliation(s)
- Jonathan M Loree
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kanwal P S Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Davidson M, Cunningham D. Molecular Stratification of Colorectal Cancer: Moving from the Laboratory to Clinical Practice. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0347-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Lohinai Z, Klikovits T, Moldvay J, Ostoros G, Raso E, Timar J, Fabian K, Kovalszky I, Kenessey I, Aigner C, Renyi-Vamos F, Klepetko W, Dome B, Hegedus B. KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep 2017; 7:39721. [PMID: 28051122 PMCID: PMC5209707 DOI: 10.1038/srep39721] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023] Open
Abstract
Current guidelines lack comprehensive information on the metastatic site-specific role of KRAS mutation in lung adenocarcinoma (LADC). We investigated the effect of KRAS mutation on overall survival (OS) in this setting. In our retrospective study, 500 consecutive Caucasian metastatic LADC patients with known KRAS mutational status were analyzed after excluding 32 patients with EGFR mutations. KRAS mutation incidence was 28.6%. The most frequent metastatic sites were lung (45.6%), bone (26.2%), adrenal gland (17.4%), brain (16.8%), pleura (15.6%) and liver (11%). Patients with intrapulmonary metastasis had significantly increased KRAS mutation frequency compared to those with extrapulmonary metastases (35% vs 26.5%, p = 0.0125). In contrast, pleural dissemination and liver involvement were associated with significantly decreased KRAS mutation incidence (vs all other metastatic sites; 17% (p < 0.001) and 16% (p = 0.02) vs 33%, respectively). Strikingly, we found a significant prognostic effect of KRAS status only in the bone metastatic subcohort (KRAS-wild-type vs KRAS-mutant; median OS 9.7 v 3.7 months; HR, 0.49; 95% CI, 0.31 to 0.79; p = 0.003). Our study suggests that KRAS mutation frequency in LADC patients shows a metastatic site dependent variation and, moreover, that the presence of KRAS mutation is associated with significantly worse outcome in bone metastatic cases.
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Affiliation(s)
- Zoltan Lohinai
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
| | - Thomas Klikovits
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
| | - Judit Moldvay
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Gyula Ostoros
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Erzsebet Raso
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Jozsef Timar
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
- Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary
| | - Katalin Fabian
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - István Kenessey
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Clemens Aigner
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
- Department of Thoracic Surgery, Ruhrlandklinik Essen, University Hospital of University Duisburg-Essen, Essen, Germany
| | - Ferenc Renyi-Vamos
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
| | - Walter Klepetko
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
| | - Balazs Dome
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Balazs Hegedus
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
- Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary
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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.
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Affiliation(s)
- Andrew Moriarity
- St James's Hospital, Surgical Oncology, St James's St, Dublin 8, Ireland
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Matsunaga M, Kaneta T, Miwa K, Ichikawa W, Fujita KI, Nagashima F, Furuse J, Kage M, Akagi Y, Sasaki Y. A comparison of four methods for detecting KRAS mutations in formalin-fixed specimens from metastatic colorectal cancer patients. Oncol Lett 2016; 12:150-156. [PMID: 27347117 DOI: 10.3892/ol.2016.4576] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 04/29/2016] [Indexed: 12/24/2022] Open
Abstract
There is currently no standard method for the detection of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status in colorectal tumors. In the present study, we compared the KRAS mutation detection ability of four methods: direct sequencing, Scorpion-ARMS assaying, pyrosequencing and multi-analyte profiling (Luminex xMAP). We evaluated 73 cases of metastatic colorectal cancer (mCRC) resistant to irinotecan, oxaliplatin and fluoropyrimidine that were enrolled in an all-case study of cetuximab. The KRAS mutation detection capacity of the four analytical methods was compared using DNA samples extracted from tumor tissue, and the detection success rate and concordance of the detection results were evaluated. KRAS mutations were detected by direct sequencing, Scorpion-ARMS assays, pyrosequencing and Luminex xMAP at success rates of 93.2%, 97.3%, 95.9% and 94.5%, respectively. The concordance rates of the detection results by Scorpion-ARMS, pyrosequencing and Luminex xMAP with those of direct sequencing were 0.897, 0.923 and 0.900 (κ statistics), respectively. The direct sequencing method could not determine KRAS mutation status in five DNA samples. Of these, Scorpion-ARMS, pyrosequencing and Luminex xMAP successfully detected three, two and one KRAS mutation statuses, respectively. Three cases demonstrated inconsistent results, whereby Luminex xMAP detected mutated KRAS in two samples while wild-type KRAS was detected by the other methods. In the remaining case, direct sequencing detected wild-type KRAS, which was identified as mutated KRAS by the other methods. In conclusion, we confirmed that Scorpion-ARMS, pyrosequencing and Luminex xMAP were equally reliable in detecting KRAS mutation status in mCRC. However, in rare cases, the KRAS status was differentially diagnosed using these methods.
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Affiliation(s)
- Mototsugu Matsunaga
- Multidisciplinary Treatment Cancer Center, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan
| | - Toshikado Kaneta
- Division of Medical Oncology, Department of Internal Medicine, Showa University Hospital, Hatanodai, Shinagawa, Tokyo 142-8666, Japan
| | - Keisuke Miwa
- Multidisciplinary Treatment Cancer Center, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan
| | - Wataru Ichikawa
- Division of Medical Oncology, Department of Internal Medicine, Showa University Hospital, Hatanodai, Shinagawa, Tokyo 142-8666, Japan
| | - Ken-Ichi Fujita
- Division of Medical Oncology, Department of Internal Medicine, Showa University Hospital, Hatanodai, Shinagawa, Tokyo 142-8666, Japan
| | - Fumio Nagashima
- Department of Medical Oncology, Kyorin University School of Medicine, Hinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, Hinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan
| | - Yoshito Akagi
- Department of Surgery, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan
| | - Yasutsuna Sasaki
- Division of Medical Oncology, Department of Internal Medicine, Showa University Hospital, Hatanodai, Shinagawa, Tokyo 142-8666, Japan
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Daoud MA, Aboelnaga EM, Mohamed WM. Second-line panitumumab as a triweekly dose for patients with wild-type KRAS exon 2 metastatic colorectal cancer: a single-institution experience. Cancer Biol Med 2016; 13:136-41. [PMID: 27144068 PMCID: PMC4850122 DOI: 10.28092/j.issn.2095-3941.2015.0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Panitumumab administered as monotherapy in colorectal cancer (CRC) has shown response and disease stabilization rates of approximately 30%. The current study aimed to evaluate the progression-free survival (PFS) and overall survival (OS) of patients with metastatic colorectal cancer (mCRC) treated with panitumumab every 3 weeks as a second line treatment. METHODS This study is a retrospective analysis of 18 patients, aged more than 18 years, with wild-type KRAS exon 2 mCRC treated with panitumumab as a second-line single agent after progression on first-line chemotherapy. RESULTS The median number of courses received was 10 (range, 4-29), and the median duration of treatment was 30 weeks (range, 12-96 weeks). After a median follow-up period of 13 months, the median PFS was 6 months (range, 4.3-7.7 months) and the median OS was 11 months (range, 7.4-14.5 months). The median PFS was 4 months for patients with < grade 2 skin toxicity and 6 months (range, 4.5-7.5 months) for patients with ≥grade 2 skin rash (P=0.05). The median OS was 9 months (range, 6.4-11.5 months) and 14 months (range, 11.6-16.3 months) for the two groups of patients (P=0.002). CONCLUSIONS Panitumumab given every 3 weeks is effective and well tolerated in patients with advanced CRC that progressed after standard chemotherapy.
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Affiliation(s)
- Mohamed A. Daoud
- Department of Radiation Oncology, Mansoura Faculty of Medicine, King Abdullah Medical City, Mecca 24246, Saudi Arabia
| | - Engy M. Aboelnaga
- Department of Radiation Oncology, Mansoura Faculty of Medicine, King Abdullah Medical City, Mecca 24246, Saudi Arabia
| | - Wael M. Mohamed
- Department of Radiation Oncology, Mansoura Faculty of Medicine, King Abdullah Medical City, Mecca 24246, Saudi Arabia
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Costa-Cabral S, Brough R, Konde A, Aarts M, Campbell J, Marinari E, Riffell J, Bardelli A, Torrance C, Lord CJ, Ashworth A. CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours. PLoS One 2016; 11:e0149099. [PMID: 26881434 PMCID: PMC4755568 DOI: 10.1371/journal.pone.0149099] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 01/27/2016] [Indexed: 12/11/2022] Open
Abstract
Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation.
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Affiliation(s)
- Sara Costa-Cabral
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Rachel Brough
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Asha Konde
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Marieke Aarts
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - James Campbell
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Eliana Marinari
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Jenna Riffell
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Alberto Bardelli
- IFOM—FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy
| | - Christopher Torrance
- Horizon Discovery, 7100 Cambridge Research Park, Waterbeach, Cambridge, CB25 9TL, United Kingdom
| | - Christopher J. Lord
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
| | - Alan Ashworth
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
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29
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Huang S, Peter Rodemann H, Harari PM. Molecular Targeting of Growth Factor Receptor Signaling in Radiation Oncology. Recent Results Cancer Res 2016; 198:45-87. [PMID: 27318681 DOI: 10.1007/978-3-662-49651-0_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Ionizing radiation has been shown to activate and interact with multiple growth factor receptor pathways that can influence tumor response to therapy. Among these receptor interactions, the epidermal growth factor receptor (EGFR) has been the most extensively studied with mature clinical applications during the last decade. The combination of radiation and EGFR-targeting agents using either monoclonal antibody (mAb) or small-molecule tyrosine kinase inhibitor (TKI) offers a promising approach to improve tumor control compared to radiation alone. Several underlying mechanisms have been identified that contribute to improved anti-tumor capacity after combined treatment. These include effects on cell cycle distribution, apoptosis, tumor cell repopulation, DNA damage/repair, and impact on tumor vasculature. However, as with virtually all cancer drugs, patients who initially respond to EGFR-targeted agents may eventually develop resistance and manifest cancer progression. Several potential mechanisms of resistance have been identified including mutations in EGFR and downstream signaling molecules, and activation of alternative member-bound tyrosine kinase receptors that bypass the inhibition of EGFR signaling. Several strategies to overcome the resistance are currently being explored in preclinical and clinical models, including agents that target the EGFR T790 M resistance mutation or target multiple EGFR family members, as well as agents that target other receptor tyrosine kinase and downstream signaling sites. In this chapter, we focus primarily on the interaction of radiation with anti-EGFR therapies to summarize this promising approach and highlight newly developing opportunities.
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Affiliation(s)
- Shyhmin Huang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA
- Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, WIMR 3136, 1111 Highland Ave Madison, Madison, WI, 53705, USA
| | - H Peter Rodemann
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Röntgenweg, 72076, Tübingen, Germany
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA.
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Trojan J, Mineur L, Tomášek J, Rouleau E, Fabian P, de Maglio G, García-Alfonso P, Aprile G, Taylor A, Kafatos G, Downey G, Terwey JH, van Krieken JH. Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review. PLoS One 2015; 10:e0140717. [PMID: 26491871 PMCID: PMC4619650 DOI: 10.1371/journal.pone.0140717] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 09/28/2015] [Indexed: 11/27/2022] Open
Abstract
Background From 2008–2013, the European indication for panitumumab required that patients’ tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported. Methods The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists’ survey. Results In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients’ tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme. Conclusions There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients’ tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.
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Affiliation(s)
- Jörg Trojan
- University Hospital, Frankfurt, Germany
- * E-mail:
| | | | - Jiří Tomášek
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | | | - Pavel Fabian
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
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31
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Wason JMS, Abraham JE, Baird RD, Gournaris I, Vallier AL, Brenton JD, Earl HM, Mander AP. A Bayesian adaptive design for biomarker trials with linked treatments. Br J Cancer 2015; 113:699-705. [PMID: 26263479 PMCID: PMC4559835 DOI: 10.1038/bjc.2015.278] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 06/15/2015] [Accepted: 07/02/2015] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Response to treatments is highly heterogeneous in cancer. Increased availability of biomarkers and targeted treatments has led to the need for trial designs that efficiently test new treatments in biomarker-stratified patient subgroups. METHODS We propose a novel Bayesian adaptive randomisation (BAR) design for use in multi-arm phase II trials where biomarkers exist that are potentially predictive of a linked treatment's effect. The design is motivated in part by two phase II trials that are currently in development. The design starts by randomising patients to the control treatment or to experimental treatments that the biomarker profile suggests should be active. At interim analyses, data from treated patients are used to update the allocation probabilities. If the linked treatments are effective, the allocation remains high; if ineffective, the allocation changes over the course of the trial to unlinked treatments that are more effective. RESULTS Our proposed design has high power to detect treatment effects if the pairings of treatment with biomarker are correct, but also performs well when alternative pairings are true. The design is consistently more powerful than parallel-groups stratified trials. CONCLUSIONS This BAR design is a powerful approach to use when there are pairings of biomarkers with treatments available for testing simultaneously.
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Affiliation(s)
- James M S Wason
- MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge, UK
| | - Jean E Abraham
- Department of Oncology, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
| | - Richard D Baird
- Department of Oncology, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
| | - Ioannis Gournaris
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
| | - Anne-Laure Vallier
- Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - James D Brenton
- Department of Oncology, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
| | - Helena M Earl
- Department of Oncology, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
| | - Adrian P Mander
- MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge, UK
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C/EBP-β-activated microRNA-223 promotes tumour growth through targeting RASA1 in human colorectal cancer. Br J Cancer 2015; 112:1491-500. [PMID: 25867276 PMCID: PMC4453668 DOI: 10.1038/bjc.2015.107] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 02/19/2015] [Indexed: 01/02/2023] Open
Abstract
Background: Evidences have shown that the RAS signalling pathway plays an important role in colorectal cancer (CRC). Moreover, RAS-GTPase-activating proteins (RASGAPs) as RAS signalling terminators are associated with tumourigenicity and tumour progression. In this study, we used bioinformatics analysis to predict and study important miRNAs that could target RAS p21 GTPase-activating protein 1 (RASA1), an important member of RASGAPs. Methods: The levels of RASA1 and miR-223 were analysed by real-time PCR, western blotting or in situ immunofluorescence analyses. The functional effects of miR-223 and the effects of miR-223-targeted inhibitors were examined in vivo using established assays. Results: Upregulation of miR-223 was detected in CRC tissues (P<0.01) and was involved in downregulation of RASA1 in CRC tissues. Furthermore, the direct inhibition of RASA1 translation by miR-223 and the activation of miR-223 by CCAAT/enhancer binding protein-β (C/EBP-β) were evaluated in CRC cells. An in vivo xenograft model of CRC suggested that the upregulation of miR-223 could promote tumour growth and that the inhibition of miR-223 might prevent solid tumour growth. Conclusions: These results identify that C/EBP-β-activated miR-223 contributes to tumour growth by targeting RASA1 in CRC and miR-223-targeted inhibitors may have clinical promise for CRC treatment via suppression of miR-223.
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Association between KRAS mutation and lung metastasis in advanced colorectal cancer. Br J Cancer 2014; 112:424-8. [PMID: 25535726 PMCID: PMC4453646 DOI: 10.1038/bjc.2014.619] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 10/27/2014] [Accepted: 11/26/2014] [Indexed: 12/16/2022] Open
Abstract
Background: KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development. Methods: We retrospectively evaluated data from patients with mCRC whose tumour was tested for KRAS mutation from 2008 to 2010. The relationships of KRAS mutational status with time-to-lung metastasis (TTLM) and overall survival (OS) were analysed. Results: Of the 494 patients identified, 202 (41%) had tumours with KRAS mutation. KRAS mutations were associated with a shorter TTLM (median 15.2 vs 22.4 months; hazard ratio=1.40; P=0.002) and a two-fold greater odds of developing lung metastases during the disease course in patients with liver-limited mCRC at diagnosis (72 vs 56%, P=0.007). Overall survival did not differ by KRAS status. Conclusions: Lung metastasis was more likely to develop during the disease course in patients whose tumour had a KRAS mutation than in those whose tumour did not have a KRAS mutation. This finding may have an impact on decision making for surgical resection of metastatic disease.
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Kothari N, Schell MJ, Teer JK, Yeatman T, Shibata D, Kim R. Comparison of KRAS mutation analysis of colorectal cancer samples by standard testing and next-generation sequencing. J Clin Pathol 2014; 67:764-7. [PMID: 25004944 DOI: 10.1136/jclinpath-2014-202405] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
AIMS Based on KRAS testing, the subset of patients with metastatic colorectal cancer (CRC) that could benefit from anti-EGFR therapy can be better delineated. Though KRAS testing has become significantly more prevalent over the last few years, methods for testing remain heterogeneous and discordance has been reported between methods. METHODS In this study, we examined a CRC patient population and compared KRAS testing done in Clinical Laboratory Improvement Amendments (CLIA) approved laboratories as part of standard clinical care and by next-generation sequencing (NGS) using the Illumina platform. Discordances were further evaluated with manual review of the NGS testing. RESULTS Out of 468 CRC patient samples, 77 had KRAS testing done by both CLIA assay and NGS. There were concordant results between testing methodologies in 74 out of 77 patients, or 96% (95% CI 89% to 99%). There were three patient samples that showed discordant results between the two methods of testing. Upon further investigation of the NGS results for the three discordant cases, one sample showed a low level of the mutation seen in the standard testing, one sample showed low tumour fraction and a third did not show any evidence of the mutation that was found with the standard assay. Five patients had KRAS mutations not typically tested with standard testing. CONCLUSIONS Overall there was a high concordance rate between NGS and standard testing for KRAS. However, NGS revealed mutations that are not tested for with standard KRAS assays that might have clinical impact with regards to the role for anti-EGFR therapy.
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Kircher SM, Mohindra N, Nimeiri H. Cost estimates and economic implications of expanded RAS testing in metastatic colorectal cancer. Oncologist 2014; 20:14-8. [PMID: 25410095 DOI: 10.1634/theoncologist.2014-0252] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND In colorectal cancer (CRC), evidence shows that expanding RAS testing to analyze more mutations may better predict benefit from anti-EGFR therapy. The economic implications of expanding RAS testing for metastatic CRC were analyzed. MATERIALS AND METHODS Estimates of standard KRAS exon 2 testing were based on the Centers for Medicare and Medicaid Services (CMS) 2014 Diagnostic Laboratory Fee Schedule, and expanded RAS testing was estimated using a sensitivity analysis done with various potential cost scenarios (1, 2, 10, and 30 times the cost of the standard KRAS test). The cost estimates for cetuximab and panitumumab were based on the CMS payment allowance limits for Medicare Part B. RESULTS A total of 28,692 patients with metastatic CRC were estimated to be eligible annually for RAS testing. For cetuximab, the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $816 million if the cost of the tests were the same. If the cost of the expanded RAS test were 30 times the cost of the standard test, then the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $980 million, a continued savings of more than $184 million annually. Similar savings were seen with panitumumab. CONCLUSION The increased societal cost of expanded RAS testing versus standard approved KRAS exon 2 testing was inconsequential when compared with the amount of money saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti-EGFR therapy.
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Affiliation(s)
- Sheetal M Kircher
- Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Nisha Mohindra
- Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Halla Nimeiri
- Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Nrdp1 inhibits metastasis of colorectal cancer cells by EGFR signaling-dependent MMP7 modulation. Tumour Biol 2014; 36:1129-33. [PMID: 25330950 DOI: 10.1007/s13277-014-2726-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 10/07/2014] [Indexed: 01/09/2023] Open
Abstract
The molecular mechanism underlying cancer invasiveness and metastasis of colorectal cancer (CRC) remains elusive. Here we reported a strong correlation of the levels of neuregulin receptor degradation protein-1 (Nrdp1) and matrix metalloproteinase-7 (MMP7) in CRC from the patients. We then used a human CRC line, Caco-2, to study the underlying molecular basis. We found that Nrdp1 inhibited the phosphorylation of ErB3, a key player in epidermal growth factor receptor (EGFR) signaling in Caco-2 cells, which is required for activation of MMP7 to promote cell invasion. Our findings thus reveal Nrdp1, EGFR signaling, and MMP7 as promising therapeutic targets for preventing the metastasis of CRC.
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Jürgensmeier JM, Eder JP, Herbst RS. New strategies in personalized medicine for solid tumors: molecular markers and clinical trial designs. Clin Cancer Res 2014; 20:4425-35. [PMID: 25183480 PMCID: PMC5369358 DOI: 10.1158/1078-0432.ccr-13-0753] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The delineation of signaling pathways to understand tumor biology combined with the rapid development of technologies that allow broad molecular profiling and data analysis has led to a new era of personalized medicine in oncology. Many academic institutions now routinely profile patients and discuss their cases in meetings of personalized medicine tumor boards before making treatment recommendations. Clinical trials initiated by pharmaceutical companies often require specific markers for enrollment or at least explore multiple options for future markers. In addition to the still small number of targeted agents that are approved for the therapy of patients with histological and molecularly defined tumors, a broad range of novel targeted agents in development are undergoing clinical studies with companion profiling to determine the best-responding patient population. Although the present focus of profiling lies in genetic analyses, additional tests of RNA, protein, and immune parameters are being developed and incorporated in clinical research, and these methods are likely to contribute significantly to future patient selection and treatment approaches. As the advances in tumor biology and human genetics have identified promising tumor targets, the ongoing clinical evaluation of novel agents will now need to show if the promise can be translated into benefit for patients.
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Affiliation(s)
| | - Joseph P Eder
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Roy S Herbst
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
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Abstract
OBJECTIVES To identify common signaling pathways that control cancer growth and discuss the mechanism of action of cancer targeted therapies. DATA SOURCES Medical and nursing literature, research articles, published clinical guidelines. CONCLUSION Understanding the signaling pathways and genetic mutations that control cancer cell growth elucidates an understanding of the mechanism of targeted therapies. IMPLICATIONS FOR NURSING PRACTICE To understand the mechanism of action of targeted therapies, oncology nurses must first be familiar with the most common signaling pathways. Adding to this foundation, the nurse can easily learn about the classes of targeted therapies and the strategies to minimize and manage common side effects.
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Ewara E, Zaric G, Welch S, Sarma S. Cost-effectiveness of first-line treatments for patients with KRAS wild-type metastatic colorectal cancer. Curr Oncol 2014; 21:e541-50. [PMID: 25089105 PMCID: PMC4117621 DOI: 10.3747/co.21.1837] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Combinations of chemotherapy regimens and monoclonal antibodies have been demonstrated to improve clinical outcomes in patients with metastatic colorectal cancer (mcrc). Although these combination treatment strategies are safe and effective in first-line treatment for mcrc, little is known about their economic consequences and resource allocation implications. In the present study, we evaluated the cost-effectiveness of bevacizumab plus folfiri, cetuximab plus folfiri, and panitumumab plus folfiri for patients with KRAS wild-type mcrc. METHODS A Markov model simulated the lifetime patient outcomes and costs of each first-line treatment strategy and subsequent lines of treatment from the perspective of the health care payer in Ontario. The model was parameterized using data from the Ontario Cancer Registry, Ontario health administrative databases, and published randomized control trials. Patient outcomes were measured in quality-adjusted life years (qalys), and costs were measured in monetary terms. Costs and outcomes were both discounted at 5% and expressed in 2012 Canadian dollars. RESULTS For mcrc patients with KRAS wild-type disease, the treatment strategy of bevacizumab plus folfiri was found to dominate the other two first-line treatment strategies. Sensitivity analyses revealed that the incremental cost-effectiveness ratio values were sensitive to the effectiveness of treatment, the costs of bevacizumab and cetuximab, and health utility values. CONCLUSIONS Evidence from Ontario showed that bevacizumab plus folfiri is the cost-effective first-line treatment strategy for patients with KRAS wild-type mcrc. The panitumumab plus folfiri and cetuximab plus folfiri options were both dominated, but the cetuximab plus folfiri strategy must be further investigated given that, in the sensitivity analyses, the cost-effectiveness of that strategy was found to be superior to that of bevacizumab plus folfiri under certain ranges of parameter values.
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Affiliation(s)
- E.M. Ewara
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON
| | - G.S. Zaric
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON
- Richard Ivey School of Business, Western University, London, ON
| | - S. Welch
- Division of Medical Oncology, Department of Oncology, Western University, London, ON
| | - S. Sarma
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON
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40
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A PNA-mediated clamping PCR for routine detection of KRAS mutations in colorectal carcinoma. Int J Biol Markers 2014; 29:e55-61. [PMID: 24242294 DOI: 10.5301/jbm.5000052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2013] [Indexed: 12/23/2022]
Abstract
The detection of somatic mutations in a tumor represents a valuable tool for tumor characterization and provides the clinicians with information for setting up the most appropriate therapy. KRAS mutations in codons 12 and 13 are important biomarkers routinely analyzed in the clinic for the management of anti-EGFR treatment in colorectal carcinoma (CRC). Here we report a sensitive and inexpensive assay for KRAS mutations based on a PNA-mediated PCR clamping. The assay displays very high sensitivity (0.7%) and specificity (96.7%) when compared to traditional sequencing (SS) and pyrosequencing (PS), two of the most commonly and routinely used methods employed today by diagnostic laboratories. Furthermore, the PNA assay requires only basic and low-cost laboratory equipment, in contrast with all the most recent PCR-based technologies, which are highly sensitive but also much more expensive. Finally, despite the PNA assay does not allow for the definition of specific mutations, it is the cheapest and easiest screening method to firstly stratify wild-type and mutated patients, information that is strictly necessary to clinicians for the management of CRC and anti-EGFR treatment.
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41
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Tong JHM, Lung RWM, Sin FMC, Law PPY, Kang W, Chan AWH, Ma BBY, Mak TWC, Ng SSM, To KF. Characterization of rare transforming KRAS mutations in sporadic colorectal cancer. Cancer Biol Ther 2014; 15:768-76. [PMID: 24642870 PMCID: PMC4049792 DOI: 10.4161/cbt.28550] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
KRAS mutational status has been shown to be a predictive biomarker of resistance to anti-EGFR monoclonal antibody (mAb) therapy in patients with metastatic colorectal cancer. We report the spectrum of KRAS mutation in 1506 patients with colorectal cancer and the identification and characterization of rare insertion mutations within the functional domain of KRAS. KRAS mutations are found in 44.5% (670/1506) of the patients. Two cases are found to harbor double mutations involving both codons 12 and 13. The frequencies of KRAS mutations at its codons 12, 13, 61, and 146 are 75.1%, 19.3%, 2.5%, and 2.7%, respectively. The most abundant mutation of codon 12 is G12D, followed by G12V and G12C while G13D is the predominant mutation in codon 13. Mutations in other codons are rare. The KRAS mutation rate is significantly higher in women (48%, 296/617) than in men (42.1%, 374/889, P = 0.023). Tumors on the right colon have a higher frequency of KRAS mutations than those on the left (57.3% vs. 40.4%, P < 0.0001). Two in-frame insertion mutations affect the phosphate-binding loop (codon 10–16) of KRAS are identified. One of them has never been reported before. Compared with wild-type protein, the insertion variants enhance the cellular accumulation of active RAS (RAS-GTP) and constitutively activate the downstream signaling pathway. NIH3T3 cells transfected with the insertion variants show enhanced anchorage-independent growth and in vivo tumorigenicity. Potentially these mutations contribute to primary resistance to anti-EGFR mAb therapy but the clinical implication requires further validation.
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Affiliation(s)
- Joanna H M Tong
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China
| | - Raymond W M Lung
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China
| | - Frankie M C Sin
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China
| | - Peggy P Y Law
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China
| | - Anthony W H Chan
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China
| | - Brigette B Y Ma
- Sir Y.K. Pao Cancer Center; Hong Kong SAR, PR China; Department of Clinical Oncology; The Chinese University of Hong Kong; Hong Kong SAR, PR China
| | - Tony W C Mak
- Department of Surgery; The Chinese University of Hong Kong; Hong Kong SAR, PR China
| | - Simon S M Ng
- Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China; Department of Surgery; The Chinese University of Hong Kong; Hong Kong SAR, PR China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China
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42
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KRAS mutations: analytical considerations. Clin Chim Acta 2014; 431:211-20. [PMID: 24534449 DOI: 10.1016/j.cca.2014.01.049] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 01/20/2014] [Accepted: 01/22/2014] [Indexed: 12/27/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer death globally. Significant improvements in survival have been made in patients with metastasis by new therapies. For example, Cetuximab and Panitumumab are monoclonal antibodies that inhibit the epidermal growth receptor (EGFR). KRAS mutations in codon 12 and 13 are the recognized biomarkers that are analyzed in clinics before the administration of anti-EGFR therapy. Genetic analyses have revealed that mutations in KRAS predict a lack of response to Panitumumab and Cetuximab in patients with metastatic CRC (mCRC). Notably, it is estimated that 35-45% of CRC patients harbor KRAS mutations. Therefore, KRAS mutation testing should be performed in all individuals with the advanced CRC in order to identify the patients who will not respond to the monoclonal EGFR antibody inhibitors. New techniques for KRAS testing have arisen rapidly, and each technique has advantages and disadvantages. Herein, we review the latest published literature specific to KRAS mutation testing techniques. Since reliability and feasibility are important issues in clinical analyses. Therefore, this review also summarizes the effectiveness and limitations of numerous KRAS mutation testing techniques.
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EGFR, HER-2 and KRAS in canine gastric epithelial tumors: a potential human model? PLoS One 2014; 9:e85388. [PMID: 24454858 PMCID: PMC3893207 DOI: 10.1371/journal.pone.0085388] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 11/26/2013] [Indexed: 12/26/2022] Open
Abstract
Epidermal growth factor receptor (EGFR or HER-1) and its analog c-erbB-2 (HER-2) are protein tyrosine kinases correlated with prognosis and response to therapy in a variety of human cancers. KRAS mediates the transduction of signals between EGFR and the nucleus, and its mutation has been identified as a predictor of resistance to anti-EGFR drugs. In human oncology, the importance of the EGFR/HER-2/KRAS signalling pathway in gastric cancer is well established, and HER-2 testing is required before initiating therapy. Conversely, this pathway has never been investigated in canine gastric tumours. A total of 19 canine gastric epithelial neoplasms (5 adenomas and 14 carcinomas) were retrospectively evaluated for EGFR/HER-2 immunohistochemical expression and KRAS mutational status. Five (35.7%) carcinomas were classified as intestinal-type and 9 (64.3%) as diffuse-type. EGFR was overexpressed (≥1+) in 8 (42.1%) cases and HER-2 (3+) in 11 (57.9%) cases, regardless of tumour location or biological behaviour. The percentage of EGFR-positive tumours was significantly higher in the intestinal-type (80%) than in the diffuse-type (11.1%, p = 0.023). KRAS gene was wild type in 18 cases, whereas one mucinous carcinoma harboured a point mutation at codon 12 (G12R). EGFR and HER-2 may be promising prognostic and therapeutic targets in canine gastric epithelial neoplasms. The potential presence of KRAS mutation should be taken into account as a possible mechanism of drug resistance. Further studies are necessary to evaluate the role of dog as a model for human gastric cancer.
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Molinari F, Frattini M. KRASmutational test for metastatic colorectal cancer patients: not just a technical problem. Expert Rev Mol Diagn 2014; 12:123-6. [DOI: 10.1586/erm.11.94] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abstract
The use of biomarkers to identify patients who can benefit from treatment with a specific anticancer agent has the potential to both improve patient care and accelerate drug development. The development of targeted agents and their accompanying biomarkers frequently occurs contemporaneously, and confidence in a putative biomarker's performance might, therefore, be insufficient to restrict the definitive testing of a new agent to the subgroup of biomarker-positive patients. This Review considers which clinical trial designs and analysis strategies are appropriate for use in phase III, biomarker-driven, randomized clinical trials, on the basis of pre-existing evidence that the biomarker can successfully identify patients who will respond to the treatment in question. The types of interim monitoring that are appropriate for these trials are also discussed. In addition, enrichment strategies based on the use of prognostic biomarkers to separate a population into subgroups with better and worse outcomes, regardless of treatment, are described. Finally, the possibility of formally using a biomarker during phase II drug development, to select what type of biomarker-driven strategy should be used in the phase III trial, is discussed.
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46
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Patel GS, Karapetis CS. Personalized treatment for advanced colorectal cancer: KRAS and beyond. Cancer Manag Res 2013; 5:387-400. [PMID: 24294007 PMCID: PMC3839845 DOI: 10.2147/cmar.s35025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Targeted therapies have improved the survival of patients with advanced colorectal cancer (CRC). However, further improvements in patient outcomes may be gained by the development of predictive biomarkers in order to select individuals who are most likely to benefit from treatment, thus personalizing treatment. Using the epidermal growth-factor receptor (EGFR) pathway, we discuss the existing and potential predictive biomarkers in clinical development for use with EGFR-targeted agents in metastatic CRC. The data and technological issues surrounding such biomarkers as expression of EGFR or its family members or ligands, KRAS-, NRAS-, and BRAF-mutation status, PI3K/PTEN expression, and imaging and clinical biomarkers, such as rash and hypomagnesemia, are summarized. Although the discovery of KRAS mutations has improved patient selection for EGFR-targeted treatments, further biomarkers are required, especially for those patients who exhibit KRAS mutations rather than the wild-type gene.
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Affiliation(s)
- Gargi Surendra Patel
- Department of Medical Oncology, Flinders Medical Centre, Flinders University, Bedford Park, Adelaide, SA, Australia
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47
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Harris JN, Liljestrand P, Alexander GL, Goddard KAB, Kauffman T, Kolevska T, McCarty C, O'Neill S, Pawloski P, Rahm A, Williams A, Somkin CP. Oncologists' attitudes toward KRAS testing: a multisite study. Cancer Med 2013; 2:881-8. [PMID: 24403261 PMCID: PMC3892392 DOI: 10.1002/cam4.135] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 08/12/2013] [Accepted: 08/13/2013] [Indexed: 01/18/2023] Open
Abstract
Recent discoveries promise increasingly to help oncologists individually tailor anticancer therapy to their patients’ molecular tumor characteristics. One such promising molecular diagnostic is Kirsten ras (KRAS) tumor mutation testing for metastatic colorectal cancer (mCRC) patients. In the current study, we examined how and why physicians adopt KRAS testing and how they subsequently utilize the information when discussing treatment strategies with patients. We conducted 34 semi-structured in-person or telephone interviews with oncologists from seven different health plans. Each interview was audiotaped, transcribed, and coded using qualitative research methods. Information and salient themes relating to the research questions were summarized for each interview. All of the oncologists in this study reported using the KRAS test at the time of the interview. Most appeared to have adopted the test rapidly, within 6 months of the publication of National Clinical Guidelines. Oncologists chose to administer the test at various time points, although the majority ordered the test at the time their patient was diagnosed with mCRC. While oncologists expressed a range of opinions about the KRAS test, there was a general consensus that the test was useful and provided benefits to mCRC patients. The rapid adoption and enthusiasm for KRAS suggests that these types of tests may be filling an important informational need for oncologists when making treatment decisions. Future research should focus on the informational needs of patients around this test and whether patients feel informed or confident with their physicians’ use of these tests to determine treatment access.
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Affiliation(s)
- Julie N Harris
- Division of Research, Kaiser Permanente Northern California, Oakland, California
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Meguerditchian AN, Bullard Dunn K. Biomarkers and Targeted Therapeutics in Colorectal Cancer. Surg Oncol Clin N Am 2013; 22:841-55. [DOI: 10.1016/j.soc.2013.07.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Zhou J, Zheng S. Colorectal Cancer: Basic and Translational Research. Gastrointest Tumors 2013; 1:18-24. [PMID: 26675004 PMCID: PMC4645573 DOI: 10.1159/000354994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) still accounts for high mortality and morbidity of cancer patients worldwide. Early detection screening and therapeutic management of CRC are still traditional, with some important progress including cetuximab, microsatellite instability and the concept of CRC intrinsic subtypes. SUMMARY Most achievements are derived from translational cancer research. Translational cancer research attempts to better understand the heterogeneity of human cancer and further turn discoveries into benefits for cancer patients. The four basic strategies of translational research can be depicted as (a) biomarker discovery, (b) identification in xenografts, (c) population-based verification and (d) clinical validation.
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Affiliation(s)
| | - S. Zheng
- Department of Surgical Oncology, Second Affiliated Hospital, and The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China
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50
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Gutiérrez C, Rodriguez J, Patiño-García A, García-Foncillas J, Salgado J. KRAS mutational status analysis of peripheral blood isolated circulating tumor cells in metastatic colorectal patients. Oncol Lett 2013; 6:1343-1345. [PMID: 24179521 PMCID: PMC3813698 DOI: 10.3892/ol.2013.1544] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 07/23/2013] [Indexed: 11/08/2022] Open
Abstract
The present study describes an optimized method for isolating peripheral blood circulating tumor cells (CTCs) and performing KRAS mutation analysis. The approach combines isolation of peripheral blood mononuclear cells and immunomagnetic labeling with CD45 and CD326 human microbeads with KRAS analysis performed with a Therascreen KRAS kit by quantitative PCR. KRAS mutations were detected in the CTCs of patients with metastatic colorectal cancer (mCRC). CTCs may represent an alternative to invasive procedures and their analysis may be representative of the current disease status of the patient. This proposed analysis may be performed in a daily clinical practice.
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Affiliation(s)
- Cristina Gutiérrez
- Clinical Genetics Unit, University Clinic of Navarra, Pamplona, Navarra 31008, Spain
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