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Boscolo Bielo L, Trapani D, Repetto M, Crimini E, Valenza C, Belli C, Criscitiello C, Marra A, Subbiah V, Curigliano G. Variant allele frequency: a decision-making tool in precision oncology? Trends Cancer 2023; 9:1058-1068. [PMID: 37704501 DOI: 10.1016/j.trecan.2023.08.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/15/2023]
Abstract
Precision oncology requires additional predictive biomarkers for targeted therapy selection. Variant allele frequency (VAF), measuring the proportion of variant alleles within a genomic locus, provides insights into tumor clonality in somatic genomic testing, yielding a strong rationale for targeting dominant cancer cell populations. The prognostic and predictive roles of VAF have been evaluated across different studies. Yet, the absence of validated VAF thresholds and a lack of standardization between sequencing assays currently hampers its clinical utility. Therefore, analytical and clinical validation must be further examined. This Review summarizes the evidence regarding the use of VAF as a predictive biomarker and discusses challenges and opportunities for its clinical implementation as a decision-making tool for targeted therapy selection.
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Affiliation(s)
- Luca Boscolo Bielo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Matteo Repetto
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Early Drug Development service, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - Edoardo Crimini
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmen Belli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Antonio Marra
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
| | - Vivek Subbiah
- Drug Development Unit, Sarah Cannon Research Institute, Nashville, TN, USA
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
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Doleschal B, Petzer A, Rumpold H. Current concepts of anti-EGFR targeting in metastatic colorectal cancer. Front Oncol 2022; 12:1048166. [PMID: 36465407 PMCID: PMC9714621 DOI: 10.3389/fonc.2022.1048166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/26/2022] [Indexed: 11/07/2023] Open
Abstract
Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
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Affiliation(s)
- Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
- Johannes Kepler University Linz, Medical Faculty, Linz, Austria
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3
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Gouda MA, Duose DY, Lapin M, Zalles S, Huang HJ, Xi Y, Zheng X, Aldesoky AI, Alhanafy AM, Shehata MA, Wang J, Kopetz S, Meric-Bernstam F, Wistuba II, Luthra R, Janku F. Mutation-Agnostic Detection of Colorectal Cancer Using Liquid Biopsy-Based Methylation-Specific Signatures. Oncologist 2022; 28:368-372. [PMID: 36200910 PMCID: PMC10078907 DOI: 10.1093/oncolo/oyac204] [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: 06/09/2022] [Accepted: 08/29/2022] [Indexed: 11/12/2022] Open
Abstract
Detection of methylation patterns in circulating tumor DNA (ctDNA) can offer a novel approach for cancer diagnostics given the unique signature for each tumor type. We developed a next-generation sequencing (NGS)-based assay targeting 32 CpG sites to detect colorectal cancer-specific ctDNA. NGS was performed on bisulfite-converted libraries and status dichotomization was done using median methylation ratios at all targets. We included plasma samples from patients with metastatic colorectal (n = 20) and non-colorectal cancers (n = 8); and healthy volunteers (n = 4). Median methylation ratio was higher in colorectal cancer compared with non-colorectal cancers (P = .001) and normal donors (P = .005). The assay detected ctDNA in 85% of patients with colorectal cancer at a specificity of 92%. Notably, we were able to detect methylated ctDNA in 75% of patients in whom ctDNA was not detected by other methods. Detection of methylated ctDNA was associated with shorter median progression-free survival compared to non-detection (8 weeks versus 54 weeks; P = .027).
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Affiliation(s)
- Mohamed A Gouda
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.,Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA.,Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Egypt
| | - Dzifa Y Duose
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Morten Lapin
- Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Stephanie Zalles
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Helen J Huang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Yuanxin Xi
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Xiaofeng Zheng
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Amira I Aldesoky
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Egypt
| | - Alshimaa M Alhanafy
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Egypt
| | - Mohamed A Shehata
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Egypt
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Rajyalakshmi Luthra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
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4
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Gouda MA, Huang HJ, Piha-Paul SA, Call SG, Karp DD, Fu S, Naing A, Subbiah V, Pant S, Dustin DJ, Tsimberidou AM, Hong DS, Rodon J, Meric-Bernstam F, Janku F. Longitudinal Monitoring of Circulating Tumor DNA to Predict Treatment Outcomes in Advanced Cancers. JCO Precis Oncol 2022; 6:e2100512. [PMID: 35834760 PMCID: PMC9307306 DOI: 10.1200/po.21.00512] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/24/2022] [Accepted: 05/31/2022] [Indexed: 12/22/2022] Open
Abstract
PURPOSE The response to cancer therapies is typically assessed with radiologic imaging 6-10 weeks after treatment initiation. Circulating tumor DNA (ctDNA), however, has a short half-life, and dynamic changes in ctDNA quantity may allow for earlier assessment of the therapeutic response. METHODS Patients with advanced solid tumors referred to the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center were invited to participate in a liquid biopsy protocol for which serial blood samples were collected before, during, and after systemic therapy. We isolated ctDNA from serially collected plasma samples at baseline, mid-treatment, and first restaging. Genomically informed droplet digital polymerase chain reaction (ddPCR) was performed, and ctDNA quantities were reported as aggregate variant allele frequencies for all detected molecular aberrations. RESULTS We included 204 patients receiving 260 systemic therapies. The ctDNA detection rate was higher in progressors (patients with progressive disease) compared with nonprogressors (patients with stable disease, partial responses, or complete responses) at all time points (P < .009). Moreover, ctDNA detection was associated with a shorter median time-to-treatment failure (P ≤ .001). Positive delta and slope values for changes in ctDNA quantity were more frequent in progressors (P ≤ .03 and P < .001, respectively) and were associated with a shorter median time-to-treatment failure (P ≤ .014 and P < .001, respectively). Increasing ctDNA quantity was predictive of clinical and/or radiologic progressive disease in 73% of patients (median lead time, 23 days). CONCLUSION Detection of ctDNA and early dynamic changes in its quantity can predict the clinical outcomes of systemic therapies in patients with advanced solid tumors.
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Affiliation(s)
- Mohamed A. Gouda
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Clinical Oncology, Faculty of Medicine, Menoufia University. Shebin Al-Kom, Egypt
| | - Helen J. Huang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sarina A. Piha-Paul
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - S. Greg Call
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Daniel D. Karp
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shubham Pant
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Derek J. Dustin
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Apostolia M. Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - David S. Hong
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
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Goyal G, Tazi A, Go RS, Rech KL, Picarsic JL, Vassallo R, Young JR, Cox CW, Van Laar J, Hermiston ML, Cao XX, Makras P, Kaltsas G, Haroche J, Collin M, McClain KL, Diamond EL, Girschikofsky M. International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults. Blood 2022; 139:2601-2621. [PMID: 35271698 PMCID: PMC11022927 DOI: 10.1182/blood.2021014343] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 02/24/2022] [Indexed: 11/20/2022] Open
Abstract
Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.
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Affiliation(s)
- Gaurav Goyal
- Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL
| | - Abdellatif Tazi
- Université de Paris, INSERM UMR 976, Saint Louis Research Institute, Paris, France
- French National Reference Center for Histiocytoses, Department of Pulmonology, Saint-Louis Teaching Hospital, Assistance Publique-Hôpiaux de Paris, Paris, France
| | | | - Karen L. Rech
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Jennifer L. Picarsic
- Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | | | | | | | - Jan Van Laar
- Department of Internal Medicine
- Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michelle L. Hermiston
- Division of Pediatric Hematology-Oncology, University of California, San Francisco, San Francisco, CA
| | - Xin-Xin Cao
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Polyzois Makras
- LCH Adult Clinic
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force and VA General Hospital, Athens, Greece
| | - Gregory Kaltsas
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Greece
| | - Julien Haroche
- Service de médecine interne 2, Centre de Référence des Histiocytoses, Hôpital Pitié-Salpêtrière, Assistance Publique des Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France
| | - Matthew Collin
- Newcastle University and Newcastle Upon Tyne Hospitals, Newcastle Upon Tyne, United Kingdom
| | - Kenneth L. McClain
- Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Eli L. Diamond
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael Girschikofsky
- Internal Medicine I (Hemostasis, Hematology and Stem, Cell Transplantation and Medical Oncology), Ordensklinikum Linz Elisabethinen, Linz, Austria
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6
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Jia J, Howard L, Liu Y, Starr MD, Brady JC, Niedzwiecki D, Strickler JH, Nixon AB. Cabozantinib with or without Panitumumab for RAS wild-type metastatic colorectal cancer: impact of MET amplification on clinical outcomes and circulating biomarkers. Cancer Chemother Pharmacol 2022; 89:413-422. [PMID: 35171350 DOI: 10.1007/s00280-022-04404-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/29/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE Acquired resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC) remains a hurdle for effective treatment. MET amplification has been indicated as a driver of acquired resistance. Clinical activity has been demonstrated for the combination of EGFR and MET inhibitors in mCRC. But the impact of this regimen on angiogenesis and inflammation remains largely unknown. METHODS In this non-randomized, open-label phase Ib/II study, four patients were treated with cabozantinib alone and 25 patients received the combination of cabozantinib and panitumumab. MET amplification was detected in blood in all four patients treated with cabozantinib monotherapy and 5/25 patients treated with cabozantinib and panitumumab combination therapy. Plasma samples from 28 patients were available for biomarker analysis. RESULTS A panel of circulating protein biomarkers was assessed in patient plasma at baseline and on-treatment. Baseline marker levels were analyzed for prognostic value for clinical outcomes, including MET amplification as a covariate. HGF and OPN were prognostic for both progression-free survival (PFS) and overall survival (OS), while six markers (IL-6, VCAM-1, VEGF-R1, TSP-2, TIMP-1, ICAM-1) were prognostic only for OS. In patients with MET amplification, baseline PDGF-AA, PDGF-BB, TGF-β1, and VEGF-C levels were significantly higher, whereas baseline TGFβ-R3 levels were significantly lower than MET non-amplified patients. On-treatment change of four markers (CD73, PlGF, PDGF-BB, VEGF) were significantly different between MET amplified and non-amplified subpopulations. CONCLUSION This study identified circulating HGF and several inflammatory and angiogenic proteins as prognostic biomarkers. Furthermore, MET amplification status is associated with both baseline expression and on-treatment modulation of members of angiogenesis and TGF-β pathway proteins. CLINICAL TRIALS REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT02008383.
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Affiliation(s)
- Jingquan Jia
- Duke Cancer Institute, Durham, NC, USA.,Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Lauren Howard
- Duke Department of Biostatistics and Bioinformatics, Durham, NC, USA
| | - Yingmiao Liu
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Mark D Starr
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - John C Brady
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Donna Niedzwiecki
- Duke Department of Biostatistics and Bioinformatics, Durham, NC, USA
| | - John H Strickler
- Duke Cancer Institute, Durham, NC, USA.,Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Andrew B Nixon
- Duke Cancer Institute, Durham, NC, USA. .,Department of Medicine, Duke University Medical Center, Durham, NC, USA.
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Ye P, Cai P, Xie J, Zhang J. Reliability of BRAF mutation detection using plasma sample: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e28382. [PMID: 34941166 PMCID: PMC8701458 DOI: 10.1097/md.0000000000028382] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/10/2021] [Accepted: 12/01/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Testing of B-Raf proto-oncogene (BRAF) mutation in tumor is necessary before targeted therapies are given. When tumor samples are not available, plasma samples are commonly used for the testing of BRAF mutation. The aim of this study was to investigate the diagnostic accuracy of BRAF mutation testing using plasma sample of cancer patients. METHODS Databases of Pubmed, Embase, and Cochrane Library were searched for eligible studies investigating BRAF mutation in paired tissue and plasma samples of cancer patients. A total of 798 publications were identified after database searching. After removing 229 duplicated publications, 569 studies were screened using the following exclusion criteria: (1) BRAF mutation not measured in plasma or in tumor sample; (2) lacking BRAF-wildtype or BRAF-mutated samples; (3) tissue and plasma samples not paired; (4) lacking tumor or plasma samples; (5) not plasma sample; (6) not cancer; (7) un-interpretable data. Accuracy data and relevant information were extracted from each eligible study by 2 independent researchers and analyzed using statistical software. RESULTS After pooling the accuracy data from 3943 patients of the 53 eligible studies, the pooled sensitivity, specificity, and diagnostic odds ratio of BRAF mutation testing using plasma sample were 69%, 98%, and 55.78, respectively. Area under curve of summary receiver operating characteristic curve was 0.9435. Subgroup analysis indicated that BRAF mutation testing using plasma had overall higher accuracy (diagnostic odds ratio of 89.17) in colorectal cancer, compared to melanoma and thyroid carcinoma. In addition, next-generation sequencing had an overall higher accuracy in detecting BRAF mutation using plasma sample (diagnostic odds ratio of 63.90), compared to digital polymerase chain reaction (PCR) and conventional PCR, while digital PCR showed the highest sensitivity (74%) among the 3 techniques. CONCLUSION BRAF testing using plasma sample showed an overall high accuracy compared to paired tumor tissue sample, which could be used for cancer genotyping when tissue sample is not available. Large prospective studies are needed to further investigate the accuracy of BRAF mutation testing in plasma sample.
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Affiliation(s)
- Peng Ye
- Department of Anatomy and Histology, School of Preclinical Medicine, Chengdu University, Chengdu, P.R. China
| | - Peiling Cai
- Department of Anatomy and Histology, School of Preclinical Medicine, Chengdu University, Chengdu, P.R. China
| | - Jing Xie
- Department of Pathology and Clinical Laboratory, Sichuan Provincial Fourth People's Hospital, Chengdu, P.R. China
| | - Jie Zhang
- Adverse Drug Reaction Monitoring Center, Chengdu, P.R. China
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8
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Dumbrava EE, Call SG, Huang HJ, Stuckett AL, Madwani K, Adat A, Hong DS, Piha-Paul SA, Subbiah V, Karp DD, Fu S, Naing A, Tsimberidou AM, Moulder SL, Koenig KH, Barcenas CH, Kee BK, Fogelman DR, Kopetz ES, Meric-Bernstam F, Janku F. PIK3CA mutations in plasma circulating tumor DNA predict survival and treatment outcomes in patients with advanced cancers. ESMO Open 2021; 6:100230. [PMID: 34479035 PMCID: PMC8414046 DOI: 10.1016/j.esmoop.2021.100230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/08/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Background Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations. Patients and methods We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14). Results quantified as variant allele frequencies (VAFs) were compared with previous testing of archival tumor tissue and with patient outcomes. Results Of 68 patients, 58 (85%) had PIK3CA mutations in tumor tissue and 43 (74%) PIK3CA mutations in ctDNA with an overall concordance of 72% (49/68, κ = 0.38). In a subset analysis, which excluded samples from 26 patients known not to have disease progression at the time of sample collection, we found an overall concordance of 91% (38/42; κ = 0.74). PIK3CA-mutated ctDNA VAF of ≤8.5% (5% trimmed mean) showed a longer median survival compared with patients with a higher VAF (15.9 versus 9.4 months; 95% confidence interval 6.7-17.1 months; P = 0.014). Longitudinal analysis of ctDNA in 18 patients with serial plasma collections (range 2-22 time points, median 5) showed that those with a decrease in PIK3CA VAF had a longer time to treatment failure (TTF) compared with patients with an increase or no change (10.7 versus 2.6 months; P = 0.048). Conclusions Detection of PIK3CA mutations in ctDNA is concordant with testing of archival tumor tissue. Low quantity of PIK3CA-mutant ctDNA is associated with longer survival and a decrease in PIK3CA-mutant ctDNA on therapy is associated with longer TTF.
Testing for PIK3CA mutations in ctDNA is concordant with testing of tumor tissue. High PIK3CA-mutant abundance in ctDNA was associated with shorter survival. Increasing PIK3CA-mutant abundance in serial blood samples was associated with shorter TTF. Longitudinal monitoring of PIK3CA-mutant ctDNA tracked with cancer clinical course.
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Affiliation(s)
- E E Dumbrava
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S G Call
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - H J Huang
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A L Stuckett
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - K Madwani
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A Adat
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - D S Hong
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S A Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - V Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - D D Karp
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Fu
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A Naing
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A M Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S L Moulder
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - K H Koenig
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - C H Barcenas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - B K Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - D R Fogelman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - E S Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - F Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - F Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA.
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9
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Gao J, Xi L, Yu R, Xu H, Wu M, Huang H. Differential Mutation Detection Capability Through Capture-Based Targeted Sequencing in Plasma Samples in Hepatocellular Carcinoma. Front Oncol 2021; 11:596789. [PMID: 33996539 PMCID: PMC8120297 DOI: 10.3389/fonc.2021.596789] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 04/09/2021] [Indexed: 12/30/2022] Open
Abstract
Circulating tumor DNA (ctDNA) is a promising biomarker for accurate monitoring and less invasive assessment of tumor burden and treatment response. Here, targeted next-generation sequencing (NGS) with a designed gene panel of 176 cancer-relevant genes was used to assess mutations in 90 ctDNA samples from 90 patients with multiple types of liver disease and 10 healthy donor samples for control. Using our ctDNA detection panel, we identified mutations in 98.89% (89/90) of patient plasma biopsy samples, and 19 coding variants located in 10 cancer-related genes [ACVR2A, PCLO, TBCK, adhesion G protein-coupled receptor (ADGRV1), COL1A1, GABBR1, MUC16, MAGEC1, FASLG, and JAK1] were identified in 96.7% of patients (87/90). The 10 top mutated genes were tumor protein p53 (TP53), ACVR2A, ADGRV1, MUC16, TBCK, PCLO, COL11A1, titin (TTN), DNAH9, and GABBR1. TTN and TP53 and TTN and DNAH9 mutations tended to occur together in hepatocellular carcinoma samples. Most importantly, we found that most of those variants were insertions (frameshift insertions) and deletions (frameshift deletions and in-frame deletions), such as insertion variants in ACVR2A, PCLO, and TBCK; such mutations were detected in almost 95% of patients. Our study demonstrated that the targeted NGS-based ctDNA mutation profiling was a useful tool for hepatocellular carcinoma (HCC) monitoring and could potentially be used to guide treatment decisions in HCC.
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Affiliation(s)
- Jian Gao
- Department of Life Sciences and Technology, Yangtze Normal University, Fuling, China
| | - Lei Xi
- College of Biological Science and Technology, Hubei Minzu University, Enshi, China
| | - Rentao Yu
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Department of Infectious Diseases, The General Hospital of Western Theater Command, Chengdu, China
| | - Huailong Xu
- Chongqing Precision Biotech Co., Ltd., Chongqing, China
| | - Min Wu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing (Army Medical University), Chongqing, China
| | - Hong Huang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing (Army Medical University), Chongqing, China
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10
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Ballhausen A, Wheler JJ, Karp DD, Piha-Paul SA, Fu S, Pant S, Tsimberidou AM, Hong DS, Subbiah V, Holley VR, Huang HJ, Brewster AM, Koenig KB, Ibrahim NK, Meric-Bernstam F, Janku F. Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors. Clin Cancer Res 2021; 27:1247-1255. [PMID: 33115815 DOI: 10.1158/1078-0432.ccr-20-2878] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/15/2020] [Accepted: 10/23/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity. PATIENTS AND METHODS This first-in-human dose-escalation study (NCT02152943) enrolled patients with hormone receptor- positive, HER2-positive (defined by amplification, overexpression, or mutation) treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21), and intravenous trastuzumab (day 1) every 21 days to determine dose-limiting toxicities (DLT) and MTD or recommended phase II dose (RP2D). RESULTS A total of 32 patients with hormone receptor-positive, HER2-positive (amplification, n = 27; overexpression, n = 1; and mutation, n = 4) advanced breast cancer (n = 26) or other cancers (n = 6) were enrolled. The most frequent grade ≥3 adverse events included hyperglycemia (n = 4), anemia (n = 3), thrombocytopenia (n = 2), and mucositis (n = 2). DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8 mg/kg loading dose on day 1 of cycle 1 followed by a 6 mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five patients with breast cancer (four with HER2 amplification and one with HER2 mutation) had partial responses. HER2 amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (P < 0.05). CONCLUSIONS Everolimus, letrozole, and trastuzumab have a favorable safety profile and elicit encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor- and HER2-positive advanced cancers.
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Affiliation(s)
- Alexej Ballhausen
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.,Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jennifer J Wheler
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel D Karp
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sarina A Piha-Paul
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Siqing Fu
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shubham Pant
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Apostolia M Tsimberidou
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David S Hong
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vivek Subbiah
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Veronica R Holley
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Helen J Huang
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Abenaa M Brewster
- Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kimberly B Koenig
- Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nuhad K Ibrahim
- Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Funda Meric-Bernstam
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Filip Janku
- Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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11
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Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood 2021; 135:1929-1945. [PMID: 32187362 DOI: 10.1182/blood.2019003507] [Citation(s) in RCA: 237] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 03/04/2020] [Indexed: 01/18/2023] Open
Abstract
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
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12
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Velimirovic M, Juric D, Niemierko A, Spring L, Vidula N, Wander SA, Medford A, Parikh A, Malvarosa G, Yuen M, Corcoran R, Moy B, Isakoff SJ, Ellisen LW, Iafrate A, Chabner B, Bardia A. Rising Circulating Tumor DNA As a Molecular Biomarker of Early Disease Progression in Metastatic Breast Cancer. JCO Precis Oncol 2020; 4:1246-1262. [PMID: 35050782 DOI: 10.1200/po.20.00117] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Accurate monitoring of therapeutic response remains an important unmet need for patients with metastatic breast cancer (MBC). Analysis of tumor genomics obtained via circulating tumor DNA (ctDNA) can provide a comprehensive overview of tumor evolution. Here, we evaluated ctDNA change as an early prognostic biomarker of subsequent radiologic progression and survival in MBC. PATIENTS AND METHODS Paired blood samples from patients with MBC were analyzed for levels of ctDNA, carcinoembryonic antigen, and cancer antigen 15-3 at baseline and during treatment. A Clinical Laboratory Improvement Amendments–certified sequencing panel of 73 genes was used to quantify tumor-specific point mutations in ctDNA. Multivariable logistic regression analysis was conducted to evaluate the association between ctDNA rise from baseline to during-treatment (genomic progression) and subsequent radiologic progression and progression-free survival (PFS). RESULTS Somatic mutations were detected in 76 baseline samples (90.5%) and 71 during-treatment samples (84.5%). Patients with genomic progression were more than twice as likely to have subsequent radiologic progression (odds ratio, 2.04; 95% CI, 1.74 to 2.41; P < .0001), with a mean lead time of 5.8 weeks. Genomic assessment provided a high positive predictive value of 81.8% and a negative predictive value of 89.7%. The subset of patients with genomic progression also had shorter PFS (median, 4.2 v 8.3 months; hazard ratio, 2.97; 95% CI, 1.75 to 5.04; log-rank P < .0001) compared with those without genomic progression. CONCLUSION Genomic progression, as assessed by early rise in ctDNA, is an independent biomarker of disease progression before overt radiologic or clinical progression becomes evident in patients with MBC.
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Affiliation(s)
- Marko Velimirovic
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Dejan Juric
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Andrzej Niemierko
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Laura Spring
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Neelima Vidula
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Seth A. Wander
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Arielle Medford
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Aparna Parikh
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | | | - Megan Yuen
- Massachusetts General Hospital Cancer Center, Boston, MA
| | - Ryan Corcoran
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Beverly Moy
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Steven J. Isakoff
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Leif W. Ellisen
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Anthony Iafrate
- Harvard Medical School, Boston, MA
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Bruce Chabner
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Aditya Bardia
- Massachusetts General Hospital Cancer Center, Boston, MA
- Harvard Medical School, Boston, MA
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13
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Limited Practical Utility of Liquid Biopsy in the Treated Patients with Advanced Breast Cancer. Diagnostics (Basel) 2020; 10:diagnostics10080523. [PMID: 32731384 PMCID: PMC7460238 DOI: 10.3390/diagnostics10080523] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/24/2020] [Indexed: 12/16/2022] Open
Abstract
Recently, liquid biopsy has emerged as a tool to monitor oncologic disease progression and the effects of treatment. In this study we aimed to determine the clinical utility of liquid biopsy relative to conventional oncological post-treatment surveillance. Plasma cell-free (cf) DNA was collected from six healthy women and 37 patients with breast cancer (18 and 19 with stage III and IV tumors, respectively). CfDNA was assessed using the Oncomine Pan-Cancer Cell-Free Assay. In cfDNA samples from patients with BC, 1112 variants were identified, with only a few recurrent or hotspot mutations within specific regions of cancer genes. Of 65 potentially pathogenic variants detected in tumors, only 19 were also discovered in at least one blood sample. The allele frequencies of detected variants (VAFs) were <1% in cfDNA from all controls and patients with stage III BC, and 24/85 (28.2%) variants had VAFs > 1% in only 8 of 25 (32%) patients with stage IV BC. Copy number variations (CNVs) spanning CDK4, MET, FGFR1, FGFR2, ERBB2, MYC, and CCND3 were found in 1 of 12 (8%) and 8 of 25 (32%) patients with stage III and IV tumors, respectively. In healthy controls and patients without BC progression after treatment, VAFs were <1%, while in patients with metastatic disease and/or more advanced genomic alterations, VAFs > 1% and/or CNV were detected in approximately 30%. Therefore, most patients with stage IV BC could not be distinguished from those with stage III disease following therapy, based on liquid biopsy results.
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14
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Said R, Guibert N, Oxnard GR, Tsimberidou AM. Circulating tumor DNA analysis in the era of precision oncology. Oncotarget 2020; 11:188-211. [PMID: 32010431 PMCID: PMC6968778 DOI: 10.18632/oncotarget.27418] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.
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Affiliation(s)
- Rabih Said
- Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Oncology, St. George Hospital University Medical Center, University of Balamand, Beirut, Lebanon
- Co-authorship
| | - Nicolas Guibert
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Thoracic Oncology, Toulouse University Hospital, Toulouse, France
- Co-authorship
| | - Geoffrey R. Oxnard
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Apostolia M. Tsimberidou
- Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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15
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Sánchez NS, Kahle MP, Bailey AM, Wathoo C, Balaji K, Demirhan ME, Yang D, Javle M, Kaseb A, Eng C, Subbiah V, Janku F, Raymond VM, Lanman RB, Mills Shaw KR, Meric-Bernstam F. Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA. JCO Precis Oncol 2019; 3:PO.19.00017. [PMID: 32923868 PMCID: PMC7448805 DOI: 10.1200/po.19.00017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2019] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer. PATIENTS AND METHODS Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications. RESULTS We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96). CONCLUSION cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course.
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Affiliation(s)
- Nora S. Sánchez
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | - Chetna Wathoo
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kavitha Balaji
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Dong Yang
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Milind Javle
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ahmed Kaseb
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Cathy Eng
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Vivek Subbiah
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Filip Janku
- The University of Texas MD Anderson Cancer Center, Houston, TX
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16
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Afrang N, Honardoost M. Cell cycle regulatory markers in melanoma: New strategies in diagnosis and treatment. Med J Islam Repub Iran 2019; 33:96. [PMID: 31696090 PMCID: PMC6825388 DOI: 10.34171/mjiri.33.96] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Melanoma has been known as an aggressive type of skin cancer in recent years. Reports have distributed the spread rate of melanoma among white skin populations. Also, many studies have mentioned several causes of melanoma. Ultraviolet radiation was represented to be the most important reason for occurrence of melanoma. However, recent studies have found that a combination of factors, such as environmental and genetic factors, can contribute to occurrence of various cancers, specifically melanoma. Methods: Different studies have been conducted on the efficacy of genetic disorders in melanoma. These surveys marked the key role of specific biomarkers in molecular and cellular processes, and investigations have found the expression of several genes in these processes. In addition, aberrant expression of these genes due to mutation and methylation can affect the whole process. Results: The expression process of these genes is regulated by microRNAs. These new biomolecules have been considered as negative regulators because of managing molecular and cellular processes. MicroRNAs are small conserved regulators attached to their targets leading to rearrangement of gene expression. Adherence of these noncoding RNAs can cause mRNA degradation or inhibit its translation. Conclusion: Recently, the application of specific genes in melanoma has been studied. In this review, the way melanoma is regulated because of these biomarkers and their demand through cell cycle in diagnosis, prognosis, and therapeutic periods was considered. Keywords: Melanoma, Biomarkers, Cell cycle, Biomolecules
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Affiliation(s)
- Negin Afrang
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Honardoost
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
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17
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Herrmann S, Zhan T, Betge J, Rauscher B, Belle S, Gutting T, Schulte N, Jesenofsky R, Härtel N, Gaiser T, Hofheinz RD, Ebert MP, Boutros M. Detection of mutational patterns in cell-free DNA of colorectal cancer by custom amplicon sequencing. Mol Oncol 2019; 13:1669-1683. [PMID: 31254442 PMCID: PMC6670011 DOI: 10.1002/1878-0261.12539] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 06/24/2019] [Accepted: 06/27/2019] [Indexed: 12/12/2022] Open
Abstract
Monitoring the mutational patterns of solid tumors during cancer therapy is a major challenge in oncology. Analysis of mutations in cell-free (cf) DNA offers a noninvasive approach to detect mutations that may be prognostic for disease survival or predictive for primary or secondary drug resistance. A main challenge for the application of cfDNA as a diagnostic tool is the diverse mutational landscape of cancer. Here, we developed a flexible end-to-end experimental and bioinformatic workflow to analyze mutations in cfDNA using custom amplicon sequencing. Our approach relies on open-software tools to select primers suitable for multiplex PCR using minimal cfDNA as input. In addition, we developed a robust linear model to identify specific genetic alterations from sequencing data of cfDNA. We used our workflow to design a custom amplicon panel suitable for detection of hotspot mutations relevant for colorectal cancer and analyzed mutations in serial cfDNA samples from a pilot cohort of 34 patients with advanced colorectal cancer. Using our method, we could detect recurrent and patient-specific mutational patterns in the majority of patients. Furthermore, we show that dynamic changes of mutant allele frequencies in cfDNA correlate well with disease progression. Finally, we demonstrate that sequencing of cfDNA can reveal mechanisms of resistance to anti-Epidermal Growth Factor Receptor(EGFR) antibody treatment. Thus, our approach offers a simple and highly customizable method to explore genetic alterations in cfDNA.
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Affiliation(s)
- Simon Herrmann
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Germany.,Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Tianzuo Zhan
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Germany.,Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Betge
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Germany.,Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Benedikt Rauscher
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Germany
| | - Sebastian Belle
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Tobias Gutting
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nadine Schulte
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ralf Jesenofsky
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nicolai Härtel
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Timo Gaiser
- Medical Faculty Mannheim, Institute of Pathology, Heidelberg University, Mannheim, Germany
| | - Ralf-Dieter Hofheinz
- Medical Faculty Mannheim, Interdisciplinary Tumor Centre, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Michael Boutros
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
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18
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Janku F, Diamond EL, Goodman AM, Raghavan VK, Barnes TG, Kato S, Abdel-Wahab O, Durham BH, Meric-Bernstam F, Kurzrock R. Molecular Profiling of Tumor Tissue and Plasma Cell-Free DNA from Patients with Non-Langerhans Cell Histiocytosis. Mol Cancer Ther 2019; 18:1149-1157. [PMID: 31015311 PMCID: PMC6548628 DOI: 10.1158/1535-7163.mct-18-1244] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/16/2018] [Accepted: 04/05/2019] [Indexed: 12/18/2022]
Abstract
The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.
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Affiliation(s)
- Filip Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
| | - Eli L Diamond
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Aaron M Goodman
- Center for Personalized Cancer Therapy, Division of Blood and Marrow Transplantation, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California
| | - Vaijayanthi Kandadai Raghavan
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Tamara G Barnes
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Shumei Kato
- Center for Personalized Cancer Therapy, Division of Blood and Marrow Transplantation, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California
| | - Omar Abdel-Wahab
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benjamin H Durham
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, Division of Blood and Marrow Transplantation, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California
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19
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Yang X, Zhang K, Zhang C, Peng R, Sun C. Accuracy of analysis of cfDNA for detection of single nucleotide variants and copy number variants in breast cancer. BMC Cancer 2019; 19:465. [PMID: 31101027 PMCID: PMC6525451 DOI: 10.1186/s12885-019-5698-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/09/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Gene variants are dependable and sensitive biomarkers for target-specific therapies in breast cancer (BC). However, detection of mutations within tissues has many limitations. Plasma circulating free DNA (cfDNA) has been reported in many studies as an alternative tool for detection of mutations. But the diagnostic accuracy of cfDNA for most mutations in BC needs to be reviewed. This study was designed to perform comparative assessment of the diagnostic performance of cfDNA and DNA extracted from tissues for detection of single nucleotide variants (SNV) and copy number variants (CNV). METHODS True-positive (TP), false-positive (FP), false-negative (FN), and true-negative (TN) values were extracted from each selected study. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated. Subgroup analysis and single study omitted analysis were performed to quantify and explain the study heterogeneity. RESULTS Twenty eligible studies that involved 1055 cases were included in this meta-analysis. SNV studies in early breast cancer (EBC) subgroup are not suitable for meta-analysis owing to high heterogeneity. However, in advanced breast cancer (ABC) subgroup, the pooled sensitivity and specificity of detection of SNVs were 0.78 (0.71-0.84) and 0.92 (0.87-0.95), respectively. The summary receiver operative curve (SROC) exhibited an area under the curve (AUC) of 0.91(0.88-0.93). The pooled results of studies involving subgroups of PIK3CA, TP53, and ESR1 indicate that the diagnostic value of different genes is different, such as AUC for PIK3CA and TP53 were reported to be 0.96 (0.94-0.98) and 0.94 (0.91-0.95), respectively, and ESR1 had the lowest diagnostic value of 0.80 (0.76-0.83). Owing to the low sensitivity and AUC in the cases of CNV, there is no value for cfDNA-based detection of CNV based on insufficient amount of CNV data. CONCLUSION This meta-analysis suggests that the detection of gene mutations in cfDNA have adequate diagnostic accuracy and can be used as an alternative to the tumor tissue for detection of SNV but not for CNV in BC yet.
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Affiliation(s)
- Xin Yang
- Department of Clinical Lab, Yantai Yuhuangding Hospital, 20 Yudong Road, Yantai, Shandong Province, 264000, People's Republic of China.
| | - Kuo Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, 100730, People's Republic of China
| | - Caiji Zhang
- Department of Clinical Lab, Yantai Yuhuangding Hospital, 20 Yudong Road, Yantai, Shandong Province, 264000, People's Republic of China
| | - Rongxue Peng
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, 100730, People's Republic of China
| | - Chengming Sun
- Department of Clinical Lab, Yantai Yuhuangding Hospital, 20 Yudong Road, Yantai, Shandong Province, 264000, People's Republic of China.
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20
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Abbou SD, Shulman DS, DuBois SG, Crompton BD. Assessment of circulating tumor DNA in pediatric solid tumors: The promise of liquid biopsies. Pediatr Blood Cancer 2019; 66:e27595. [PMID: 30614191 PMCID: PMC6550461 DOI: 10.1002/pbc.27595] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/04/2018] [Accepted: 12/07/2018] [Indexed: 12/29/2022]
Abstract
Circulating tumor DNA can be detected in the blood and body fluids of patients using ultrasensitive technologies, which have the potential to improve cancer diagnosis, risk stratification, noninvasive tumor profiling, and tracking of treatment response and disease recurrence. As we begin to apply "liquid biopsy" strategies in children with cancer, it is important to tailor our efforts to the unique genomic features of these tumors and address the technical and logistical challenges of integrating biomarker testing. This article reviews the literature demonstrating the feasibility of applying liquid biopsy to pediatric solid malignancies and suggests new directions for future studies.
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Affiliation(s)
- Samuel D. Abbou
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA,Department of Oncology for Children and Adolescents, Gustave Roussy, Villejuif, France
| | - David S. Shulman
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA
| | - Steven G. DuBois
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA
| | - Brian D. Crompton
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA,Broad Institute, Cambridge, MA, USA
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21
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Möhrmann L, Janku F. Liquid Biopsies Using Plasma Exosomal Nucleic Acids. Oncoscience 2019; 6:296-297. [PMID: 31106231 PMCID: PMC6508195 DOI: 10.18632/oncoscience.478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/21/2018] [Indexed: 11/25/2022] Open
Affiliation(s)
- Lino Möhrmann
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Filip Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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22
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Huang M, Wei S. Overview of Molecular Testing of Cytology Specimens. Acta Cytol 2019; 64:136-146. [PMID: 30917368 DOI: 10.1159/000497187] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 01/23/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Utilizing cytology specimens for molecular testing has attracted increasing attention in the era of personalized medicine. Cytology specimens are clinically easier to access. The samples can be quickly and completely fixed in a very short time of fixation before tissue degradation occurs, compared to hours or days of fixation in surgical pathology specimens. In addition, cytology specimens can be fixed without formalin, which can significantly damage DNA and RNA. All these factors contribute to the superb quality of DNA and RNA in cytology specimens for molecular tests. STUDY DESIGN We summarize the most pertinent information in the literature regarding molecular testing in the field of cytopathology. RESULTS The first part focuses on the types of cytological specimens that can be used for molecular testing, including the advantages and limitations. The second section describes the common molecular tests and their clinical application. CONCLUSION Various types of cytology specimens are suitable for many molecular tests, which may require additional clinical laboratory validation.
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Affiliation(s)
- Min Huang
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Shuanzeng Wei
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA,
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23
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Potential Utility of Liquid Biopsy as a Diagnostic and Prognostic Tool for the Assessment of Solid Tumors: Implications in the Precision Oncology. J Clin Med 2019; 8:jcm8030373. [PMID: 30889786 PMCID: PMC6463095 DOI: 10.3390/jcm8030373] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/24/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
Abstract
Liquid biopsy is a technique that utilizes circulating biomarkers in the body fluids of cancer patients to provide information regarding the genetic landscape of the cancer. It is emerging as an alternative and complementary diagnostic and prognostic tool to surgical biopsy in oncology. Liquid biopsy focuses on the detection and isolation of circulating tumor cells, circulating tumor DNA and exosomes, as a source of genomic and proteomic information in cancer patients. Liquid biopsy is expected to provide the necessary acceleratory force for the implementation of precision oncology in clinical settings by contributing an enhanced understanding of tumor heterogeneity and permitting the dynamic monitoring of treatment responses and genomic variations. However, widespread implementation of liquid biopsy based biomarker-driven therapy in the clinical practice is still in its infancy. Technological advancements have resolved many of the hurdles faced in the liquid biopsy methodologies but sufficient clinical and technical validation for specificity and sensitivity has not yet been attained for routine clinical implementation. This article provides a comprehensive review of the clinical utility of liquid biopsy and its effectiveness as an important diagnostic and prognostic tool in colorectal, breast, hepatocellular, gastric and lung carcinomas which were the five leading cancer related mortalities in 2018.
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24
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Soria-Comes T, Palomar-Abril V, Ureste MM, Guerola MT, Maiques ICM. Real-World Data of the Correlation between EGFR Determination by Liquid Biopsy in Non-squamous Non-small Cell Lung Cancer (NSCLC) and the EGFR Profile in Tumor Biopsy. Pathol Oncol Res 2019; 26:845-851. [PMID: 30847713 DOI: 10.1007/s12253-019-00628-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 02/28/2019] [Indexed: 12/22/2022]
Abstract
EGFR-mutated non-small cell lung cancer (NSCLC) has significant improved outcomes when treated with EGFR-tyrosine kinase inhibitors (TKI). Thus, EGFR-mutational status should be assessed at diagnosis and in the course of treatment with TKI. However, tissue samples are not always evaluable, and molecular profiling has been increasingly performed in cell-free tumor DNA (ctDNA) from blood samples. Our objective is to evaluate the reliability of ctDNA profiling in plasma samples in a real-world setting. We retrospectively analyzed the patients diagnosed with non-squamous NSCLC from May 2016 to December 2017 at Hospital Universitario Doctor Peset who had been tested for EGFR mutations in tissue and plasma samples. Both samples were sent to an external laboratory to perform the analysis by the cobas® EGFR assay. Percentage of agreement and concordance were calculated by kappa statistic. Of 102 patients reviewed, 89 were eligible. The overall EGFR mutation frequency was 18.6% for the evaluable tissue samples and 19.6% for evaluable plasma samples. Mutation status concordance between matched samples was 87.4%. Cohen's kappa index (κ) = 0.6 (sensitivity 70.6%, specificity 91.7%, positive predictive value 66.7%, negative predictive value 93%). When concordance was stablished only in stage IV tumors κ = 0.7, suggesting a higher agreement in advanced disease. This real-world data suggest that plasma is a feasible sample for ctDNA EGFR mutation assessment. Results of ctDNA molecular profiling are reliable when using a validated technique such as the cobas® EGFR assay, especially in patients that cannot undergo a tissue biopsy.
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Affiliation(s)
- Teresa Soria-Comes
- Department of Medical Oncology, Hospital Universitario Doctor Peset, 46017, Comunitat Valenciana, Valencia, Spain.
| | | | - María Martín Ureste
- Department of Medical Oncology, Hospital Universitario Doctor Peset, 46017, Comunitat Valenciana, Valencia, Spain
| | - Mónica Tallón Guerola
- Department of Medical Oncology, Hospital Universitario Doctor Peset, Comunitat Valenciana, Valencia, Spain
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25
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Bhatty M, Kato S, Piha-Paul SA, Naing A, Subbiah V, Huang HJ, Karp DD, Tsimberidou AM, Zinner RG, Hwu WJ, Javle M, Patel SP, Hu MI, Varadhachary GR, Conley AP, Ramzanali NM, Holley VR, Kurzrock R, Meric-Bernstam F, Chae YK, Kim KB, Falchook GS, Janku F. Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies. Cancer 2019; 125:463-472. [PMID: 30383888 PMCID: PMC6340722 DOI: 10.1002/cncr.31812] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 08/22/2018] [Accepted: 08/28/2018] [Indexed: 11/11/2022]
Abstract
BACKGROUND BRAF inhibitors are effective against selected BRAFV600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity. METHODS Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). RESULTS Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045). CONCLUSIONS The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAFV600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.
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Affiliation(s)
- Minny Bhatty
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shumei Kato
- Division of Hematology & Oncology and Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Sarina A. Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aung Naing
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Helen J. Huang
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel D. Karp
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Apostolia M. Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Wen-Jen Hwu
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sapna P. Patel
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mimi I. Hu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gauri R. Varadhachary
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anthony P. Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nishma M. Ramzanali
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Veronica R. Holley
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Razelle Kurzrock
- Division of Hematology & Oncology and Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Young Kwang Chae
- Developmental Therapeutics Lurie Cancer Center and Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Kevin B. Kim
- California Pacific Medical Center Research Institute, San Francisco, California
| | | | - Filip Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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26
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Rohanizadegan M. Analysis of circulating tumor DNA in breast cancer as a diagnostic and prognostic biomarker. Cancer Genet 2018; 228-229:159-168. [PMID: 29572011 PMCID: PMC6108954 DOI: 10.1016/j.cancergen.2018.02.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 01/15/2018] [Accepted: 02/16/2018] [Indexed: 12/17/2022]
Abstract
Despite all the advances in diagnosis and treatment of breast cancer, a large number of patients suffer from late diagnosis or recurrence of their disease. Current available imaging modalities do not reveal micrometastasis and tumor biopsy is an invasive method to detect early stage or recurrent cancer, signifying the need for an inexpensive, non-invasive diagnostic modality. Cell-free tumor DNA (ctDNA) has been tried for early detection and targeted therapy of breast cancer, but its diagnostic and prognostic utility is still under investigation. This review summarizes the existing evidence on the use of ctDNA specifically in breast cancer, including detection methods, diagnostic accuracy, role in genetics and epigenetics evaluation of the tumor, and comparison with other biomarkers. Current evidence suggests that increasing levels of ctDNA in breast cancer can be of significant diagnostic value for early detection of breast cancer although the sensitivity and specificity of the methods is still suboptimal. Additionally, ctDNA allows for characterizing the tumor in a non-invasive way and monitor the response to therapy, although discordance of ctDNA results with direct biopsy (i.e. due to tumor heterogeneity) is still considered a notable limitation.
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Affiliation(s)
- Mersedeh Rohanizadegan
- Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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27
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Wills B, Gorse E, Lee V. Role of liquid biopsies in colorectal cancer. Curr Probl Cancer 2018; 42:593-600. [PMID: 30268335 DOI: 10.1016/j.currproblcancer.2018.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/27/2018] [Accepted: 08/08/2018] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, with a global incidence of over 1 million cases. In the era of personalized medicine, tumor sampling is essential for characterizing the molecular profile of individual tumors. This provides pivotal information regarding optimal sequencing of therapy and emergence of drug resistance, allowing for timely therapy adjustment. However, tumor tissue sampling offers static information in a single time point and area of disease at the time of biopsy, which may not entirely represent the heterogeneity of molecular alterations. Moreover, tumor biopsies often involve invasive procedures with potential risks to patients. Less invasive, safer, and real-time methods such as liquid biopsies have generated increasing interest as a surrogate of solid tumor biopsies. Liquid biopsy allows for noninvasive survey with detection of cell-free circulating tumor DNA (ctDNA) or circulating tumor cells. Blood-based assays are the most widely studied. Additionally, the quantity of ctDNA detected has been shown to correlate with tumor burden and enables assessment of tumor heterogeneity. In this article, we discuss the concept of liquid biopsies including ctDNA and circulating tumor cell, and their current application in the diagnosis and management of CRC. We suggest that liquid biopsies can be successfully used to characterize the molecular profile of CRC, monitor disease, detect minimal residual disease after surgery, and identify therapeutic targets and mechanisms of drug resistance. This strategy could potentially imply an early change in treatment, sparing unnecessary side effects, and minimizing health costs. Combined radiological and liquid biopsy assessments will likely become more standard in CRC oncology. However, large prospective studies are needed to definitively establish the role of liquid biopsy.
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Affiliation(s)
- Beatriz Wills
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD.
| | - Egal Gorse
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD
| | - Valerie Lee
- Department of GI Oncology, Johns Hopkins Hospital, Baltimore, MD
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28
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Jia J, Morse MA, Nagy RJ, Lanman RB, Strickler JH. Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer. Front Oncol 2018; 8:305. [PMID: 30211110 PMCID: PMC6121109 DOI: 10.3389/fonc.2018.00305] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 07/19/2018] [Indexed: 01/06/2023] Open
Abstract
MET amplification is rare in treatment-naïve metastatic colorectal cancer (CRC) tumors, but can emerge as a mechanism of resistance to anti-EGFR therapies. Preclinical and clinical data suggest that patients with MET amplified tumors benefit from MET-targeted therapy. Cabozantinib is an inhibitor of multiple tyrosine kinases, included c-MET. Panitumumab is an inhibitor of EGFR. This report describes a patient with KRAS, NRAS, and BRAF wild-type metastatic CRC who experienced disease progression on all standard chemotherapy and anti-EGFR antibody therapy. The patient was enrolled in a clinical trial evaluating the combination of cabozantinib plus panitumumab. After only 6 weeks of treatment, the patient experienced a significant anti-tumor response. Although tumor tissue was negative for MET amplification, molecular profiling of cell-free DNA (cfDNA) revealed MET amplification. This case represents the first report showing the activity of cabozantinib in combination with panitumumab in a patient with metastatic CRC, and suggests that MET amplification in cfDNA may be a biomarker of response. A clinical trial targeting MET amplified metastatic CRC is currently underway.
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Affiliation(s)
- Jingquan Jia
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Michael A. Morse
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | | | | | - John H. Strickler
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
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29
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Saluja H, Karapetis CS, Pedersen SK, Young GP, Symonds EL. The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers. Front Oncol 2018; 8:275. [PMID: 30087854 PMCID: PMC6066577 DOI: 10.3389/fonc.2018.00275] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 07/02/2018] [Indexed: 01/10/2023] Open
Abstract
Gastrointestinal cancers, including oesophageal, gastric and colorectal cancers (CRC) have high rates of disease recurrence despite curative resection. There are a number of recent studies that have investigated the use of circulating tumor DNA (ctDNA) for prognostic value in these cancers. We reviewed studies that had been published prior to March 2018 that assessed the prognostic values of ctDNA in patients with oesophageal and gastric cancers, gastrointestinal stromal tumors (GIST) and CRC. We identified 63 eligible clinical studies that focussed on recurrence and survival. Studies assessed investigated various ctDNA biomarkers in patients with different stages of cancer undergoing surgical resection, chemotherapy and no treatment. For oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, methylation of certain genes such as APC and DAPK have been highlighted as promising biomarkers for prognostication, but these studies are limited and more comprehensive research is needed. Studies focusing on gastric cancer patients showed that methylation of ctDNA in SOX17 and APC were independently associated with poor survival. Two studies demonstrated an association between ctDNA and recurrence and survival in GIST patients, but more studies are needed for this type of gastrointestinal cancer. A large proportion of the literature was on CRC which identified both somatic mutations and DNA methylation biomarkers to determine prognosis. ctDNA biomarkers that identified somatic mutations were more effective if they were personalized based on mutations found in the primary tumor tissue, but ctDNA methylation studies identified various biomarkers that predicted increased risk of recurrence, poor disease free survival and overall survival. While the use of non-invasive ctDNA biomarkers for prognosis is promising, larger studies are needed to validate the clinical utility for optimizing treatment and surveillance strategies to reduce mortality from gastrointestinal cancers.
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Affiliation(s)
- Hariti Saluja
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Department of Medicine, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Department of Oncology, Flinders Medical Centre, Bedford Park, SA, Australia
| | | | - Graeme P Young
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Erin L Symonds
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Bowel Health Service, Flinders Medical Centre, Bedford Park, SA, Australia
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Owonikoko TK, Busari AK, Kim S, Chen Z, Akintayo A, Lewis C, Carthon BC, Alese OB, El-Rayes BF, Ramalingam SS, Harvey RD. Race-, Age-, and Gender-Based Characteristics and Toxicities of Targeted Therapies on Phase I Trials. Oncology 2018; 95:138-146. [PMID: 29913438 PMCID: PMC6113074 DOI: 10.1159/000488763] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 03/12/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND The impact of age-, gender-, and race-based differences on safety and efficacy in phase I clinical trials has not been well studied. METHODS We analyzed data from phase I clinical trials evaluating targeted biologic agents in patients with advanced solid malignancies. Race and gender distribution of enrolled patients was compared to the referral population demographics at the city, metro, and state levels. The association between age, gender, and race with type, frequency, and severity of treatment-emergent toxicities and clinical benefit was assessed using univariate and multivariable models. RESULTS Data from 117 eligible patients - Blacks/Caucasians/Others (27/85/5); male/female (66/51) - were obtained. Blacks were younger than Caucasian patients (median age of 56 vs. 62 years, p = 0.004). Nausea/vomiting was more frequent in female patients (43 vs. 24%, p = 0.03), while hematologic toxicity was more likely in Whites. While median time on treatment was comparable (113 vs. 91; p = 0.840), the median overall survival was significantly shorter for Blacks versus Caucasians (7.4 vs. 11.4 months; p = 0.0227). Black race (HR 2.11; 95% CI 1.24-3.60; p = 0.006) and older age (HR 1.03; 95% CI 1.00-1.06; p = 0.029) were associated with an increased risk of death. CONCLUSIONS Age-, gender-, and race-based disparities were observed with specific toxicity and survival outcomes on phase I clinical trials of anticancer agents.
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Affiliation(s)
- Taofeek K. Owonikoko
- Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta GA
- Winship Cancer Institute of Emory University, Atlanta, GA
| | | | - Sungjin Kim
- Winship Cancer Institute of Emory University, Atlanta, GA
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zhengjia Chen
- Winship Cancer Institute of Emory University, Atlanta, GA
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta GA, USA
| | | | - Colleen Lewis
- Winship Cancer Institute of Emory University, Atlanta, GA
| | - Bradley C. Carthon
- Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta GA
| | - Olatunji B. Alese
- Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta GA
| | - Bassel F. El-Rayes
- Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta GA
- Winship Cancer Institute of Emory University, Atlanta, GA
| | - Suresh S. Ramalingam
- Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta GA
- Winship Cancer Institute of Emory University, Atlanta, GA
| | - R. Donald Harvey
- Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta GA
- Winship Cancer Institute of Emory University, Atlanta, GA
- Department of Pharmacology, Emory University School of Medicine, Atlanta GA
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Baumgartner JM, Raymond VM, Lanman RB, Tran L, Kelly KJ, Lowy AM, Kurzrock R. Preoperative Circulating Tumor DNA in Patients with Peritoneal Carcinomatosis is an Independent Predictor of Progression-Free Survival. Ann Surg Oncol 2018; 25:2400-2408. [PMID: 29948422 DOI: 10.1245/s10434-018-6561-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Next-generation sequencing (NGS) is a useful tool for detecting genomic alterations in circulating tumor DNA (ctDNA). To date, most ctDNA tests have been performed on patients with widely metastatic disease. Patients with peritoneal carcinomatosis (metastases) present unique prognostic and therapeutic challenges. We therefore explored preoperative ctDNA in patients with peritoneal metastases undergoing surgery. METHODS Patients referred for surgical resection of peritoneal metastases underwent preoperative blood-derived ctDNA analysis (clinical-grade NGS [68-73 genes]). ctDNA was quantified as the percentage of altered circulating cell-free DNA (% cfDNA). RESULTS Eighty patients had ctDNA testing: 46 (57.5%) women; median age 55.5 years. The following diagnoses were included: 59 patients (73.8%), appendix cancer; 11 (13.8%), colorectal; five (6.3%), peritoneal mesothelioma; two (2.5%), small bowel; one (1.3%) each of cholangiocarcinoma, ovarian, and testicular cancer. Thirty-one patients (38.8%) had detectable preoperative ctDNA alterations, most frequently in the following genes: TP53 (25.8% of all alterations detected) and KRAS (11.3%). Among 15 patients with tissue DNA NGS, 33.3% also had ctDNA alterations (overall concordance = 96.7%). Patients with high ctDNA quantities (≥ 0.25% cfDNA, n = 25) had a shorter progression-free survival (PFS) than those with lower ctDNA quantities (n = 55; 7.8 vs. 15.0 months; hazard ratio 3.23, 95% confidence interval 1.43-7.28, p = 0.005 univariate, p = 0.044 multivariate). CONCLUSIONS A significant proportion of patients with peritoneal metastases referred for surgical intervention have detectable ctDNA alterations preoperatively. Patients with high levels of ctDNA have a worse prognosis independent of histologic grade.
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Affiliation(s)
- Joel M Baumgartner
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, La Jolla, CA, USA.
| | | | | | - Lisa Tran
- Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, CA, USA
| | - Kaitlyn J Kelly
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, La Jolla, CA, USA
| | - Andrew M Lowy
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, La Jolla, CA, USA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, CA, USA
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Liu L, Toung JM, Jassowicz AF, Vijayaraghavan R, Kang H, Zhang R, Kruglyak KM, Huang HJ, Hinoue T, Shen H, Salathia NS, Hong DS, Naing A, Subbiah V, Piha-Paul SA, Bibikova M, Granger G, Barnes B, Shen R, Gutekunst K, Fu S, Tsimberidou AM, Lu C, Eng C, Moulder SL, Kopetz ES, Amaria RN, Meric-Bernstam F, Laird PW, Fan JB, Janku F. Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification. Ann Oncol 2018; 29:1445-1453. [PMID: 29635542 PMCID: PMC6005020 DOI: 10.1093/annonc/mdy119] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially useful in early diagnosis. Patients and methods We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients' outcomes. Results Median methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016). Conclusions Comprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.
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Affiliation(s)
- L Liu
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA.
| | - J M Toung
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A F Jassowicz
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - R Vijayaraghavan
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - H Kang
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - R Zhang
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - K M Kruglyak
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - H J Huang
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - T Hinoue
- Van Andel Research Institute, Grand Rapids, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - H Shen
- Van Andel Research Institute, Grand Rapids, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - N S Salathia
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - D S Hong
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A Naing
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - V Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S A Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - M Bibikova
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - G Granger
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - B Barnes
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - R Shen
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - K Gutekunst
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Fu
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A M Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - C Lu
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - C Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S L Moulder
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - E S Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - R N Amaria
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - F Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
| | - P W Laird
- Van Andel Research Institute, Grand Rapids, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - J-B Fan
- Illumina, Inc., San Diego, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - F Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA.
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Arneth B. Update on the types and usage of liquid biopsies in the clinical setting: a systematic review. BMC Cancer 2018; 18:527. [PMID: 29728089 PMCID: PMC5935950 DOI: 10.1186/s12885-018-4433-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 04/25/2018] [Indexed: 12/23/2022] Open
Abstract
Background This systematic review aimed to gather evidence from research on the current state of liquid biopsy in medical practice, specifically focusing on mutation detection and monitoring. Methods A systematic search was performed via Medline. Results The results of this investigation indicate that liquid biopsy plays a critical role in the detection and management of tumors. This technique gives healthcare providers the ability to gather critical and reliable information that may potentially shape the diagnosis, treatment, and prognosis of a variety of cancers in the near future. This study further reveals that liquid biopsy has several potential shortcomings that may limit its application and use in the healthcare setting. Nevertheless, liquid biopsy remains a valuable tool that is gradually becoming a part of routine healthcare practice in oncology departments and hospitals worldwide. Conclusions The evidence described herein reveals the potential relevance of liquid biopsy as an important prognostic, diagnostic, and theranostic tool. This non-invasive procedure enables healthcare practitioners to detect and monitor genomic alterations and will likely replace tumor tissue biopsy as the standard method for detecting and monitoring mutations in the future. The information obtained herein can enable physicians to make informed decisions regarding current treatment options; however, liquid biopsy has not yet been incorporated into routine clinical diagnostics for cancer patients.
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Affiliation(s)
- Borros Arneth
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, University Hospital of the Universities of Giessen and Marburg UKGM, Justus Liebig University Giessen, Feulgenstr. 12, 35392, Giessen, Germany.
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Mansilla C, Soria E, Ramírez N. The identification and isolation of CTCs: A biological Rubik's cube. Crit Rev Oncol Hematol 2018; 126:129-134. [PMID: 29759554 DOI: 10.1016/j.critrevonc.2018.03.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 02/22/2018] [Accepted: 03/29/2018] [Indexed: 12/17/2022] Open
Abstract
Liquid biopsy represents an alternative to conventional biopsies for the evaluation of tumors mainly due to its easy sampling. One of the main applications is the enumeration of Circulating Tumor Cells (CTCs) to evaluate tumor progression or response to treatment. The analysis of the functional characteristics of CTCs could give us much more information about their role in order to establish a more personalized treatment for the patients. The major issue that has to be solved is the isolation of the CTC population. Multiple protocols have been developed, however none of them has demonstrated to be the definitive one. In fact, a combination of these techniques has often been performed in order to obtain a purer and viable population of CTCs. In this review we have summarized for the first time the different combinatorial approaches used in the last years to optimize the isolation of CTCs and their limitations.
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Affiliation(s)
- Cristina Mansilla
- Oncohematology Research Group, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Elena Soria
- Oncohematology Research Group, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Natalia Ramírez
- Oncohematology Research Group, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain.
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35
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36
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Ikeda S, Tsigelny IF, Skjevik ÅA, Kono Y, Mendler M, Kuo A, Sicklick JK, Heestand G, Banks KC, Talasaz A, Lanman RB, Lippman S, Kurzrock R. Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma. Oncologist 2018; 23:586-593. [PMID: 29487225 PMCID: PMC5947459 DOI: 10.1634/theoncologist.2017-0479] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 01/09/2018] [Indexed: 12/21/2022] Open
Abstract
This article reports unique aspects of the management of hepatocellular carcinoma. The study aimed to determine if next‐generation sequencing of blood‐derived circulating tumor DNA from patients with hepatocellular carcinoma could identify actionable somatic molecular alterations. Illustrative examples of treated patients and of in silico molecular dynamic simulation to reveal genomic variant function are included. Background. Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood‐derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. Materials and Methods. We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild‐type allele fraction was calculated. Results. All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1–8]); median mutant allele fraction, 0.29% (range, 0.1%–37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A‐inactivating and a CTNNB1‐activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX‐2/Wnt inhibitor); des‐gamma‐carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN‐inactivating and a MET‐activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0–15 ng/mL]). Conclusion. ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC. Implications for Practice. This study reports that blood‐derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy.
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Affiliation(s)
- Sadakatsu Ikeda
- Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
- Tokyo Medical and Dental University, Tokyo, Japan
| | - Igor F Tsigelny
- Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
- San Diego Supercomputer Center, University of California San Diego, La Jolla, California, USA
- Department of Neuroscience, University of California San Diego, La Jolla, California, USA
- CureMatch Inc., San Diego, California, USA
| | - Åge A Skjevik
- San Diego Supercomputer Center, University of California San Diego, La Jolla, California, USA
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Yuko Kono
- Division of Gastroenterology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
| | - Michel Mendler
- Division of Gastroenterology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
| | - Alexander Kuo
- Division of Gastroenterology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
| | - Jason K Sicklick
- Division of Surgical Oncology, Department of Surgery, University of California San Diego Moores Cancer Center, La Jolla, California, USA
| | - Gregory Heestand
- Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
| | | | | | | | - Scott Lippman
- Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA
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Addressing intra-tumoral heterogeneity and therapy resistance. Oncotarget 2018; 7:72322-72342. [PMID: 27608848 PMCID: PMC5342165 DOI: 10.18632/oncotarget.11875] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022] Open
Abstract
In the last several years, our appreciation of intra-tumoral heterogeneity has greatly increased due to accumulating evidence for the co-existence of genetically and epigenetically divergent cancer cells residing in different microenvironments within a tumor. Herein, we review recent literature discussing intra-tumoral heterogeneity in the context of therapy resistance mechanisms at the genetic, epigenetic and microenvironmental levels. We illustrate the influence of tumor microenvironment on therapy resistance and epigenetic states of cancer cells by highlighting the role of cancer stem cells in therapy resistance. We also summarize different strategies that have been employed to address various resistance mechanisms at genetic, epigenetic, and microenvironmental levels in preclinical and clinical studies. We propose that future personalized cancer therapy design needs to incorporate dynamic and comprehensive analyses of tumor heterogeneity landscape and multi-dimensional mechanisms of therapy resistance.
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38
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Bennett CW, Berchem G, Kim YJ, El-Khoury V. Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer. Oncotarget 2018; 7:71013-71035. [PMID: 27589834 PMCID: PMC5342606 DOI: 10.18632/oncotarget.11717] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 08/11/2016] [Indexed: 12/13/2022] Open
Abstract
Personalized medicine has emerged as the future of cancer care to ensure that patients receive individualized treatment specific to their needs. In order to provide such care, molecular techniques that enable oncologists to diagnose, treat, and monitor tumors are necessary. In the field of lung cancer, cell free DNA (cfDNA) shows great potential as a less invasive liquid biopsy technique, and next-generation sequencing (NGS) is a promising tool for analysis of tumor mutations. In this review, we outline the evolution of cfDNA and NGS and discuss the progress of using them in a clinical setting for patients with lung cancer. We also present an analysis of the role of cfDNA as a liquid biopsy technique and NGS as an analytical tool in studying EGFR and MET, two frequently mutated genes in lung cancer. Ultimately, we hope that using cfDNA and NGS for cancer diagnosis and treatment will become standard for patients with lung cancer and across the field of oncology.
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Affiliation(s)
- Catherine W Bennett
- Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
| | - Guy Berchem
- Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.,Centre Hospitalier de Luxembourg, L-1210 Luxembourg, Luxembourg
| | - Yeoun Jin Kim
- Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
| | - Victoria El-Khoury
- Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
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Chae YK, Davis AA, Carneiro BA, Chandra S, Mohindra N, Kalyan A, Kaplan J, Matsangou M, Pai S, Costa R, Jovanovic B, Cristofanilli M, Platanias LC, Giles FJ. Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA. Oncotarget 2018; 7:65364-65373. [PMID: 27588476 PMCID: PMC5323161 DOI: 10.18632/oncotarget.11692] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
Genomic analysis of tumor tissue is the standard technique for identifying DNA alterations in malignancies. Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a relatively non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance of genomic alterations between cfDNA and tissue biopsies in this retrospective study. Twenty-eight patients with advanced solid tumors with paired next-generation sequencing tissue and cfDNA biopsies were identified. Sixty-five genes were common to both assays. Concordance was defined as the presence or absence of the identical genomic alteration(s) in a single gene on both molecular platforms. Including all aberrations, the average number of alterations per patient for tissue and cfDNA analysis was 4.82 and 2.96, respectively. When eliminating alterations not detectable in the cfDNA assay, mean number of alterations for tissue and cfDNA was 3.21 and 2.96, respectively. Overall, concordance was 91.9–93.9%. However, the concordance rate decreased to 11.8–17.1% when considering only genes with reported genomic alterations in either assay. Over 50% of mutations detected in either technique were not detected using the other biopsy technique, indicating a potential complementary role of each assay. Across 5 genes (TP53, EGFR, KRAS, APC, CDKN2A), sensitivity and specificity were 59.1% and 94.8%, respectively. Potential explanations for the lack of concordance include differences in assay platform, spatial and temporal factors, tumor heterogeneity, interval treatment, subclones, and potential germline DNA contamination. These results highlight the importance of prospective studies to evaluate concordance of genomic findings between distinct platforms that ultimately may inform treatment decisions.
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Affiliation(s)
- Young Kwang Chae
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Andrew A Davis
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Benedito A Carneiro
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Sunandana Chandra
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Nisha Mohindra
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Aparna Kalyan
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Jason Kaplan
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Maria Matsangou
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Sachin Pai
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Ricardo Costa
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Borko Jovanovic
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Massimo Cristofanilli
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Leonidas C Platanias
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA
| | - Francis J Giles
- Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
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40
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Abraham J, Singh S, Joshi S. Liquid biopsy - emergence of a new era in personalized cancer care. ACTA ACUST UNITED AC 2018. [DOI: 10.1186/s41241-018-0053-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Yang X, Zhuo M, Ye X, Bai H, Wang Z, Sun Y, Zhao J, An T, Duan J, Wu M, Wang J. Quantification of mutant alleles in circulating tumor DNA can predict survival in lung cancer. Oncotarget 2018; 7:20810-24. [PMID: 26989078 PMCID: PMC4991494 DOI: 10.18632/oncotarget.8021] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 02/15/2016] [Indexed: 01/05/2023] Open
Abstract
Purpose We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the quantitative and dynamic detection of EGFR mutations and next generation sequencing (NGS) for screening EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance-relevant mutations in circulating tumor DNA (ctDNA) from advanced lung adenocarcinoma (ADC) patients. Results Detection limit of EGFR mutation in ctDNA by ddPCR was 0.04%. Taking the EGFR mutation in tumor tissue as the golden standard, the concordance of EGFR mutations detected in ctDNA was 74% (54/73). Patients with EGFR mutation in ctDNA (n = 54) superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P < 0.001) and overall survival (OS, median, 35.6 vs. 23.8 months, P = 0.028) compared to those with EGFR wild type in ctDNA (n = 19). Patients with high EGFR-mutated abundance in ctDNA (> 5.15%) showed better PFS compared to those with low EGFR mutated abundance (≤ 5.15%) (PFS, median, 15.4 vs. 11.1 months, P = 0.021). NGS results showed that 66.6% (8/12) total mutational copy number were elevated and 76.5% (26/34) mutual mutation frequency increased after disease progression. Methods Seventy-three advanced ADC patients with tumor tissues carrying EGFR mutations and their matched pre- and post-EGFR-TKIs plasma samples were enrolled in this study. Absolute quantities of plasma EGFR mutant and wild-type alleles were measured by ddPCR. Multi-genes testing was performed using NGS in 12 patients. Conclusions Dynamic and quantitative analysis of EGFR mutation in ctDNA could guide personalized therapy for advanced ADC. NGS shows good performance in multiple genes testing especially novel and uncommon genes.
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Affiliation(s)
- Xue Yang
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Minglei Zhuo
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xin Ye
- Asia and Emerging Markets Innovative Medicine of AstraZeneca R & D, Shanghai, China
| | - Hua Bai
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhijie Wang
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yun Sun
- Asia and Emerging Markets Innovative Medicine of AstraZeneca R & D, Shanghai, China
| | - Jun Zhao
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Tongtong An
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianchun Duan
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Meina Wu
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jie Wang
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
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Veldore VH, Choughule A, Routhu T, Mandloi N, Noronha V, Joshi A, Dutt A, Gupta R, Vedam R, Prabhash K. Validation of liquid biopsy: plasma cell-free DNA testing in clinical management of advanced non-small cell lung cancer. LUNG CANCER (AUCKLAND, N.Z.) 2018; 9:1-11. [PMID: 29379323 PMCID: PMC5757203 DOI: 10.2147/lctt.s147841] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Plasma cell-free tumor DNA, or circulating tumor DNA (ctDNA), from liquid biopsy is a potential source of tumor genetic material, in the absence of tissue biopsy, for EGFR testing. Our validation study reiterates the clinical utility of ctDNA next generation sequencing (NGS) for EGFR mutation testing in non-small cell lung cancer (NSCLC). A total of 163 NSCLC cases were included in the validation, of which 132 patients had paired tissue biopsy and ctDNA. We chose to validate ctDNA using deep sequencing with custom designed bioinformatics methods that could detect somatic mutations at allele frequencies as low as 0.01%. Benchmarking allele specific real time PCR as one of the standard methods for tissue-based EGFR mutation testing, the ctDNA NGS test was validated on all the plasma derived cell-free DNA samples. We observed a high concordance (96.96%) between tissue biopsy and ctDNA for oncogenic driver mutations in Exon 19 and Exon 21 of the EGFR gene. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the assay were 91.1%, 100% 100%, 95.6%, and 97%, respectively. A false negative rate of 3% was observed. A subset of mutations was also verified on droplet digital PCR. Sixteen percent EGFR mutation positivity was observed in patients where only liquid biopsy was available, thus creating options for targeted therapy. This is the first and largest study from India, demonstrating successful validation of circulating cell-free DNA as a clinically useful material for molecular testing in NSCLC.
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Affiliation(s)
| | | | | | | | | | - Amit Joshi
- Tata Memorial Centre, Parel, Mumbai, India
| | - Amit Dutt
- The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, India
| | - Ravi Gupta
- MedGenome Labs Private Ltd,, Bangalore, India
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Mamdani H, Ahmed S, Armstrong S, Mok T, Jalal SI. Blood-based tumor biomarkers in lung cancer for detection and treatment. Transl Lung Cancer Res 2017; 6:648-660. [PMID: 29218268 DOI: 10.21037/tlcr.2017.09.03] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The therapeutic landscape of lung cancer has expanded significantly over the past decade. Advancements in molecularly targeted therapies, strategies to discover and treat resistance mutations, and development of personalized cancer treatments in the context of tumor heterogeneity and dynamic tumor biology have made it imperative to obtain tumor samples on several different occasions through the course of patient treatment. While this approach is critical to the delivery of optimal cancer treatment, it is fraught with a number of barriers including the need for invasive procedures with associated complications, access to limited amount of tissue, logistical delays in obtaining the biopsy, high healthcare cost, and in many cases inability to obtain tissue because of technically difficult location of the tumor. Given multiple limitations of obtaining tissue samples, the use of blood-based biomarkers ("liquid biopsies") may enable earlier diagnosis of cancer, lower costs by avoiding complex invasive procedures, tailoring molecular targeted treatments, improving patient convenience, and ultimately supplement clinical oncologic decision-making. In this paper, we review various blood-based biomarkers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor derived exosomes, tumor educated platelets (TEPs), and microRNA; and highlight current evidence for their use in detection and treatment of lung cancer.
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Affiliation(s)
- Hirva Mamdani
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Shahid Ahmed
- Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
| | - Samantha Armstrong
- Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tony Mok
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
| | - Shadia I Jalal
- Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
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Falzone L, Salemi R, Travali S, Scalisi A, McCubrey JA, Candido S, Libra M. MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma. Aging (Albany NY) 2017; 8:933-44. [PMID: 27115178 PMCID: PMC4931845 DOI: 10.18632/aging.100951] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/19/2016] [Indexed: 12/13/2022]
Abstract
Tumor spreading is associated with the degradation of extracellular matrix proteins, mediated by the overexpression of matrix metalloproteinase 9 (MMP-9). Although, such overexpression was linked to epigenetic promoter methylation, the role of intragenic methylation was not clarified yet. Melanoma was used as tumor model to investigate the relationship between the DNA intragenic methylation of MMP9 gene and MMP-9 overexpression at transcriptional and protein levels. Computational analysis revealed DNA hypermethylation within the intragenic CpG-2 region of MMP9 gene in melanoma samples with high MMP-9 transcript levels. In vitro validation showed that CpG-2 hotspot region was hypermethylated in the A375 melanoma cell line with highest mRNA and protein levels of MMP-9, while low methylation levels were observed in the MEWO cell line where MMP-9 was undetectable. Concordant results were demonstrated in both A2058 and M14 cell lines. This correlation may give further insights on the role of MMP-9 upregulation in melanoma.
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Affiliation(s)
- Luca Falzone
- Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology and Functional Genomics, Section of General and Clinical Pathology and Oncology, University of Catania, 95124, Catania, Italy
| | - Rossella Salemi
- Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology and Functional Genomics, Section of General and Clinical Pathology and Oncology, University of Catania, 95124, Catania, Italy
| | - Salvatore Travali
- Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology and Functional Genomics, Section of General and Clinical Pathology and Oncology, University of Catania, 95124, Catania, Italy
| | | | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology and Functional Genomics, Section of General and Clinical Pathology and Oncology, University of Catania, 95124, Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology and Functional Genomics, Section of General and Clinical Pathology and Oncology, University of Catania, 95124, Catania, Italy
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Hovelson DH, Liu CJ, Wang Y, Kang Q, Henderson J, Gursky A, Brockman S, Ramnath N, Krauss JC, Talpaz M, Kandarpa M, Chugh R, Tuck M, Herman K, Grasso CS, Quist MJ, Feng FY, Haakenson C, Langmore J, Kamberov E, Tesmer T, Husain H, Lonigro RJ, Robinson D, Smith DC, Alva AS, Hussain MH, Chinnaiyan AM, Tewari M, Mills RE, Morgan TM, Tomlins SA. Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy. Oncotarget 2017; 8:89848-89866. [PMID: 29163793 PMCID: PMC5685714 DOI: 10.18632/oncotarget.21163] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 09/08/2017] [Indexed: 12/11/2022] Open
Abstract
Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.
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Affiliation(s)
- Daniel H. Hovelson
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Chia-Jen Liu
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yugang Wang
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Qing Kang
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - James Henderson
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Amy Gursky
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Scott Brockman
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nithya Ramnath
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - John C. Krauss
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - Moshe Talpaz
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - Malathi Kandarpa
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - Rashmi Chugh
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - Missy Tuck
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kirk Herman
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
| | - Catherine S. Grasso
- Division of Hematology-Oncology, University of California, Los Angeles and the Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
- The Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA
| | - Michael J. Quist
- Division of Hematology-Oncology, University of California, Los Angeles and the Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
- The Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA
| | - Felix Y. Feng
- Departments of Radiation Oncology, Urology, and Medicine, University of California at San Francisco, San Francisco, CA, USA
| | | | | | | | | | - Hatim Husain
- Medical Oncology, University of California, San Diego Moore's Cancer Center, San Diego, CA, USA
| | - Robert J. Lonigro
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Dan Robinson
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - David C. Smith
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ajjai S. Alva
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Maha H. Hussain
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
- Present address: Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Arul M. Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
- Division of Hematology-Oncology, University of California, Los Angeles and the Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Muneesh Tewari
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine (Hematology/Oncology), University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Biointerfaces Institute, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ryan E. Mills
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Todd M. Morgan
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Scott A. Tomlins
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
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Olmedillas-López S, Lévano-Linares DC, Alexandre CLA, Vega-Clemente L, Sánchez EL, Villagrasa A, Ruíz-Tovar J, García-Arranz M, García-Olmo D. Detection of KRAS G12D in colorectal cancer stool by droplet digital PCR. World J Gastroenterol 2017; 23:7087-7097. [PMID: 29093617 PMCID: PMC5656456 DOI: 10.3748/wjg.v23.i39.7087] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 09/15/2017] [Accepted: 09/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess KRAS G12D mutation detection by droplet digital PCR (ddPCR) in stool-derived DNA from colorectal cancer (CRC) patients.
METHODS In this study, tumor tissue and stool samples were collected from 70 patients with stage I-IV CRC diagnosed by preoperative biopsy. KRAS mutational status was determined by pyrosequencing analysis of DNA obtained from formalin-fixed paraffin-embedded (FFPE) tumor tissues. The KRAS G12D mutation was then analyzed by ddPCR in FFPE tumors and stool-derived DNA from patients with this point mutation. Wild-type (WT) tumors, as determined by pyrosequencing, were included as controls; analysis of FFPE tissue and stool-derived DNA by ddPCR was performed for these patients as well.
RESULTS Among the total 70 patients included, KRAS mutations were detected by pyrosequencing in 32 (45.71%), whereas 38 (54.29%) had WT tumors. The frequency of KRAS mutations was higher in left-sided tumors (11 located in the right colon, 15 in the left, and 6 in the rectum). The predominant point mutation was KRAS G12D (14.29%, n = 10), which was more frequent in early-stage tumors (I-IIA, n = 7). In agreement with pyrosequencing results, the KRAS G12D mutation was detected by ddPCR in FFPE tumor-derived DNA, and only a residual number of mutated copies was found in WT controls. The KRAS G12D mutation was also detected in stool-derived DNA in 80% of all fecal samples from CRC patients with this point mutation.
CONCLUSION ddPCR is a reliable and sensitive method to analyze KRAS G12D mutation in stool-derived DNA from CRC patients, especially at early stages. This non-invasive approach is potentially applicable to other relevant biomarkers for CRC management.
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Affiliation(s)
- Susana Olmedillas-López
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Dennis César Lévano-Linares
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Department of Surgery, Rey Juan Carlos University Hospital, Madrid 28933, Spain
| | | | - Luz Vega-Clemente
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Edurne León Sánchez
- Department of Biomedicine and Biotechnology, Universidad de Alcalá, Madrid 28805, Spain
| | - Alejandro Villagrasa
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Jaime Ruíz-Tovar
- Department of Surgery, Rey Juan Carlos University Hospital, Madrid 28933, Spain
| | - Mariano García-Arranz
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damián García-Olmo
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
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Möhrmann L, Huang HJ, Hong DS, Tsimberidou AM, Fu S, Piha-Paul SA, Subbiah V, Karp DD, Naing A, Krug A, Enderle D, Priewasser T, Noerholm M, Eitan E, Coticchia C, Stoll G, Jordan LM, Eng C, Kopetz ES, Skog J, Meric-Bernstam F, Janku F. Liquid Biopsies Using Plasma Exosomal Nucleic Acids and Plasma Cell-Free DNA Compared with Clinical Outcomes of Patients with Advanced Cancers. Clin Cancer Res 2017; 24:181-188. [PMID: 29051321 DOI: 10.1158/1078-0432.ccr-17-2007] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/14/2017] [Accepted: 10/10/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNAs) originate from living cells, which can better reflect underlying cancer biology.Experimental Design: Next-generation sequencing (NGS) was used to test exoNA, and droplet digital PCR (ddPCR) and BEAMing PCR were used to test cfDNA for BRAFV600, KRASG12/G13, and EGFRexon19del/L858R mutations in 43 patients with progressing advanced cancers. Results were compared with clinical testing of archival tumor tissue and clinical outcomes.Results: Forty-one patients had BRAF, KRAS, or EGFR mutations in tumor tissue. These mutations were detected by NGS in 95% of plasma exoNA samples, by ddPCR in 92% of cfDNA samples, and by BEAMing in 97% cfDNA samples. NGS of exoNA did not detect any mutations not present in tumor, whereas ddPCR and BEAMing detected one and two such mutations, respectively. Compared with patients with high exoNA mutation allelic frequency (MAF), patients with low MAF had longer median survival (11.8 vs. 5.9 months; P = 0.006) and time to treatment failure (7.4 vs. 2.3 months; P = 0.009). A low amount of exoNA was associated with partial response and stable disease ≥6 months (P = 0.006).Conclusions: NGS of plasma exoNA for common BRAF, KRAS, and EGFR mutations has high sensitivity compared with clinical testing of archival tumor and testing of plasma cfDNA. Low exoNA MAF is an independent prognostic factor for longer survival. Clin Cancer Res; 24(1); 181-8. ©2017 AACR.
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Affiliation(s)
- Lino Möhrmann
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Helen J Huang
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David S Hong
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel D Karp
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aung Naing
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anne Krug
- Exosome Diagnostics, Waltham, Massachusetts
| | | | | | | | - Erez Eitan
- Exosome Diagnostics, Waltham, Massachusetts
| | | | | | | | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - E Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Johan Skog
- Exosome Diagnostics, Waltham, Massachusetts
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Filip Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Duréndez-Sáez E, Azkárate A, Meri M, Calabuig-Fariñas S, Aguilar-Gallardo C, Blasco A, Jantus-Lewintre E, Camps C. New insights in non-small-cell lung cancer: circulating tumor cells and cell-free DNA. J Thorac Dis 2017; 9:S1332-S1345. [PMID: 29184672 DOI: 10.21037/jtd.2017.06.112] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Lung cancer is the second most frequent tumor and the leading cause of death by cancer in both men and women. Increasing knowledge about the cancer genome and tumor environment has led to a new setting in which morphological and molecular characterization is needed to treat patients in the most personalized way in order to achieve better outcomes. Since tumor products can be detected in body fluids, the liquid biopsy, particularly, peripheral blood, has emerged as a new source for lung cancer biomarker's analysis. A variety of tumor components can be used for this purpose. Among them, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) should be especially considered. Different detection methods for both CTCs and ctDNA have been and are being developed to improve the sensitivity and specificity of these tests. This would lead to better characterization and would solve some clinical doubts at different disease evolution times, e.g., intratumoral or temporal heterogeneity, difficulty in the obtaining a tumor sample, etc., and would also avoid the side effects of very expensive and complicated tumor obtaining interventions. CTCs and ctDNA are useful in different lung cancer settings. Their value has been shown for the early diagnosis, prognosis, prediction of treatment efficacy, monitoring responses and early detection of lung cancer relapse. CTCs have still not been validated for use in clinical settings in non-small-cell lung cancer (NSCLC), while ctDNA has been approved by the Food and Drug Administration (FDA) and European Medical Association (EMA), and the main clinical guidelines used for detect different epidermal growth factor receptor (EGFR) mutations and the monitoring and treatment choice of mutated patients with tyrosine kinase inhibitors (TKIs). This review, describes how ctDNA seem to be winning the race against CTCs from the laboratory bench to clinical practice due to easier obtaining methods, manipulation and its implementation into clinical practice.
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Affiliation(s)
- Elena Duréndez-Sáez
- Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain
| | - Aitor Azkárate
- Department of Oncology, University Hospital Son Espases, Palma de Mallorca, Spain
| | - Marina Meri
- Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain
| | - Silvia Calabuig-Fariñas
- Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.,Department of Pathology, Universitat de València, Valencia, Spain.,CIBERONC, Valencia, Spain
| | | | - Ana Blasco
- Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain.,CIBERONC, Valencia, Spain
| | - Eloisa Jantus-Lewintre
- Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.,CIBERONC, Valencia, Spain.,Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain
| | - Carlos Camps
- Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.,Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain.,CIBERONC, Valencia, Spain.,Department of Medicine, Universitat de València, Valencia, Spain
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Zhu L, Zhang S, Xun Y, Jiang Y, Xia B, Chen X, Wang L, Jiang H, Ma S. Comparison of the Amplification Refractory Mutation System, Super Amplification Refractory Mutation System, and Droplet Digital PCR for T790 M Mutation Detection in Non-small Cell Lung Cancer after Failure of Tyrosine Kinase Inhibitor Treatment. Pathol Oncol Res 2017; 24:843-851. [PMID: 28868565 DOI: 10.1007/s12253-017-0286-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 08/07/2017] [Indexed: 01/01/2023]
Abstract
Plasma mutation detection has the advantages of non-invasiveness and accessibility. Here, we evaluated three methods, the amplification refractory mutation system (ARMS), second-generation ARMS (SuperARMS), and droplet digital PCR (ddPCR), to assess their concordance and feasibility for the detection of mutations in plasma samples. Non-small lung cancer patients with stage IIIB/IV that were resistant to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment were enrolled. Blood samples were collected within 14 days after TKI resistance. Each sample was simultaneously assessed by the three methods. In total, 169 patients were enrolled; 54.4% were female, 72.2% were diagnosed with stage IV disease; and 97.6% had adenocarcinoma. T790 M mutations were detected in 42 (24.8%) of the 169 samples using ARMS, one of which carried the T790 M alone, 22 that also encoded exon 19 deletions, and 19 with L858R mutations. For the SuperARMS assay, 59 (34.9%) samples exhibited the T790 M mutation, and 110 (65.1%) showed no detectable T790 M mutation. ddPCR showed that 61 (36.1%) samples contained the T790 M mutation, whereas 108 (63.9%) were not positive. T790 M abundance ranged from 0.04% to 38.2%. The median T790 M abundance was 0.15% for total samples and 2.98% for T790 M mutation samples. The overall concordance was 78.7% (133/169) among ARMS, SuperARMS, and ddPCR. Compared with patients with stage III disease, patients with stage IV disease exhibited a higher T790 M mutation detection rate (28.7% vs. 14.9% by ARMS; 37.7% vs. 27.7% by SuperARMS; and 41.8% vs. 21.3% by ddPCR). Liquid biopsy showed promise and has the advantages of non-invasiveness and accessibility. T790 M detection based on circulating tumor DNA showed high concordance. Compared with non-digital platforms, ddPCR showed higher sensitivity and provided both frequency and abundance information, which might be important for treatment decisions.
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Affiliation(s)
- Lucheng Zhu
- Department of Oncology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261, Huansha Road, Shangcheng District, Hangzhou, 310006, People's Republic of China.,Department of Oncology, Hangzhou Cancer Hospital, Hangzhou, China
| | - Shirong Zhang
- Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Nanjing, China. .,Hangzhou First People's Hospital, Nanjing Medical University, No.6, Xiaonv Road, Shangcheng District, Hangzhou, 310006, People's Republic of China.
| | - Yanping Xun
- Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Nanjing, China
| | - Yanping Jiang
- Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Nanjing, China
| | - Bing Xia
- Department of Oncology, Hangzhou Cancer Hospital, Hangzhou, China
| | - Xueqin Chen
- Department of Oncology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261, Huansha Road, Shangcheng District, Hangzhou, 310006, People's Republic of China
| | - Limin Wang
- Department of Respiratory, Hangzhou First People's Hospital, Nanjing Medical University, Nanjing, China
| | - Hong Jiang
- Department of Thoracic Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Nanjing, China
| | - Shenglin Ma
- Hangzhou First People's Hospital, Nanjing Medical University, No.261, Huansha Road, Shangcheng District, Hangzhou, 310006, People's Republic of China.
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50
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Schwaederlé MC, Patel SP, Husain H, Ikeda M, Lanman RB, Banks KC, Talasaz A, Bazhenova L, Kurzrock R. Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma. Clin Cancer Res 2017; 23:5101-5111. [PMID: 28539465 PMCID: PMC5581668 DOI: 10.1158/1078-0432.ccr-16-2497] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 01/07/2017] [Accepted: 05/18/2017] [Indexed: 12/11/2022]
Abstract
Purpose: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes.Experimental Design: Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next-generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications.Results: Seventy-two patients (82%) had ≥1 ctDNA alteration(s); among these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in the TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% vs. 61.5%; ≤1 vs. >1 month between ctDNA and tissue tests; P = 0.04) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥1 ctDNA alteration(s); 72.3% (N = 16/22) of the evaluable matched patients achieved stable disease ≥6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥1 alteration with ≥5% variant allele fraction (vs. < 5%) had a significantly shorter median survival (P = 0.012).Conclusions: ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies. Clin Cancer Res; 23(17); 5101-11. ©2017 AACR.
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Affiliation(s)
- Maria C Schwaederlé
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California.
| | - Sandip P Patel
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California
| | - Hatim Husain
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California
| | - Megumi Ikeda
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California
| | - Richard B Lanman
- Department of Medical Affairs, Guardant Health, Inc., Redwood City, California
| | - Kimberly C Banks
- Department of Medical Affairs, Guardant Health, Inc., Redwood City, California
| | - AmirAli Talasaz
- Department of Medical Affairs, Guardant Health, Inc., Redwood City, California
| | - Lyudmila Bazhenova
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California
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