The Experts below are selected from a list of 7812 Experts worldwide ranked by ideXlab platform
Richard L Schilsky - One of the best experts on this subject based on the ideXlab platform.
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Circulating Tumor DNA analysis in patients with cancer american society of clinical oncology and college of american pathologists joint review
Archives of Pathology & Laboratory Medicine, 2018Co-Authors: Jason D Merker, Maximilian Diehn, Geoffrey R Oxnard, Carolyn C Compton, Patricia Hurley, Alexander J Lazar, Neal I Lindeman, Christina M Lockwood, Alex J Rai, Richard L SchilskyAbstract:Purpose.— Clinical use of analytical tests to assess genomic variants in Circulating Tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the Colleg...
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Circulating Tumor DNA analysis in patients with cancer american society of clinical oncology and college of american pathologists joint review
Journal of Clinical Oncology, 2018Co-Authors: Jason D Merker, Maximilian Diehn, Geoffrey R Oxnard, Carolyn C Compton, Patricia Hurley, Alexander J Lazar, Neal I Lindeman, Christina M Lockwood, Alex J Rai, Richard L SchilskyAbstract:PurposeClinical use of analytical tests to assess genomic variants in Circulating Tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research.MethodsAn Expert Panel conducted a literature review on the use of ctDNA assays for solid Tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility.ResultsThe literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion.ConclusionThe evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, the...
Matti Annala - One of the best experts on this subject based on the ideXlab platform.
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Circulating Tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer
Cancer Discovery, 2018Co-Authors: Gillian Vandekerkhove, Matti Annala, Kevin Beja, Daniel Khalaf, Sinja Taavitsainen, Evan W Warner, Katherine Sunderland, Christian K Kollmannsberger, Bernhard J EiglAbstract:Primary resistance to androgen receptor (AR) directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 treatment-naive mCRPC patients to abiraterone or enzalutamide, and performed whole exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and Circulating Tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced Tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR directed therapy in mCRPC and identify potential minimally-invasive biomarkers.
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Circulating Tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer
Cancer Discovery, 2018Co-Authors: Gillian Vandekerkhove, Matti Annala, Kevin Beja, Daniel Khalaf, Sinja Taavitsainen, Evan W Warner, Katherine Sunderland, Christian K Kollmannsberger, Bernhard J EiglAbstract:Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naive mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and Circulating Tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced Tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common Circulating Tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444-57. ©2018 AACR.See related commentary by Jayaram et al., p. 392This article is highlighted in the In This Issue feature, p. 371.
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concordance of Circulating Tumor DNA and matched metastatic tissue biopsy in prostate cancer
Journal of the National Cancer Institute, 2017Co-Authors: Alexander W Wyatt, Matti Annala, Kevin Beja, Rahul Aggarwal, Felix Y Feng, Jack Youngren, Adam Foye, Paul Lloyd, Matti Nykter, Tomasz M BeerAbstract:Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma Circulating Tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the Tumor genome. However, no systematic comparisons of matched “liquid” and “solid” biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. Methods: We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Results: Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in Tumor suppressors TP53, PTEN, RB1, APC, CDKN1B, BRCA2, and PIK3R1. In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Conclusions: Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.
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Circulating Tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer
Clinical Cancer Research, 2017Co-Authors: Gillian Vandekerkhove, Tilman Todenhofer, Matti Annala, Werner J Struss, Amanda Wong, Kevin Beja, Elie Ritch, Sonal BrahmbhattAbstract:Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical Tumor molecular stratification. Circulating Tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the Tumor genome in real-time, but is critically underexplored in bladder cancer.Experimental Design: We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease.Results: The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to TP53, RB1, or MDM2, and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1 A novel FGFR3 gene fusion was identified in consecutive samples from one patient.Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. Clin Cancer Res; 23(21); 6487-97. ©2017 AACR.
Jason D Merker - One of the best experts on this subject based on the ideXlab platform.
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Circulating Tumor DNA analysis in patients with cancer american society of clinical oncology and college of american pathologists joint review
Archives of Pathology & Laboratory Medicine, 2018Co-Authors: Jason D Merker, Maximilian Diehn, Geoffrey R Oxnard, Carolyn C Compton, Patricia Hurley, Alexander J Lazar, Neal I Lindeman, Christina M Lockwood, Alex J Rai, Richard L SchilskyAbstract:Purpose.— Clinical use of analytical tests to assess genomic variants in Circulating Tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the Colleg...
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Circulating Tumor DNA analysis in patients with cancer american society of clinical oncology and college of american pathologists joint review
Journal of Clinical Oncology, 2018Co-Authors: Jason D Merker, Maximilian Diehn, Geoffrey R Oxnard, Carolyn C Compton, Patricia Hurley, Alexander J Lazar, Neal I Lindeman, Christina M Lockwood, Alex J Rai, Richard L SchilskyAbstract:PurposeClinical use of analytical tests to assess genomic variants in Circulating Tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research.MethodsAn Expert Panel conducted a literature review on the use of ctDNA assays for solid Tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility.ResultsThe literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion.ConclusionThe evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, the...
Maximilian Diehn - One of the best experts on this subject based on the ideXlab platform.
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Circulating Tumor DNA analysis in patients with cancer american society of clinical oncology and college of american pathologists joint review
Archives of Pathology & Laboratory Medicine, 2018Co-Authors: Jason D Merker, Maximilian Diehn, Geoffrey R Oxnard, Carolyn C Compton, Patricia Hurley, Alexander J Lazar, Neal I Lindeman, Christina M Lockwood, Alex J Rai, Richard L SchilskyAbstract:Purpose.— Clinical use of analytical tests to assess genomic variants in Circulating Tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the Colleg...
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Circulating Tumor DNA analysis in patients with cancer american society of clinical oncology and college of american pathologists joint review
Journal of Clinical Oncology, 2018Co-Authors: Jason D Merker, Maximilian Diehn, Geoffrey R Oxnard, Carolyn C Compton, Patricia Hurley, Alexander J Lazar, Neal I Lindeman, Christina M Lockwood, Alex J Rai, Richard L SchilskyAbstract:PurposeClinical use of analytical tests to assess genomic variants in Circulating Tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research.MethodsAn Expert Panel conducted a literature review on the use of ctDNA assays for solid Tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility.ResultsThe literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion.ConclusionThe evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, the...
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capturing genomic evolution of lung cancers through liquid biopsy for Circulating Tumor DNA
Journal of Oncology, 2017Co-Authors: Michael Offin, Jacob J Chabon, Pedram Razavi, James M Isbell, Charles M Rudin, Maximilian Diehn, Bob T LiAbstract:Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the Tumor’s dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intraTumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of Circulating Tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of Tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intraTumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid Tumors.
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noninvasive cancer classification using diverse genomic features in Circulating Tumor DNA
International Conference on Bioinformatics, 2016Co-Authors: Mohammad Shahrokh Esfahani, Maximilian Diehn, Aaron M Newman, Florian Scherer, Robert Tibshirani, Ash A AlizadehAbstract:Circulating Tumor DNA (ctDNA) has the potential to revolutionize cancer care, through detection of somatic lesions over time, as relevant for therapy selection, response monitoring, and early detection. Our group previously described cancer personalized profiling with deep sequencing (CAPP-Seq) [2], a ctDNA detection method targeting recurrent point mutations and structural variations within a given Tumor. However, two unmet challenges for ctDNA are its utility for noninvasive histology classification and for copy number variation (CNV) at low ctDNA levels. Here, we tackle both challenges as related problems. We describe a simple CNV detection algorithm for ctDNA. To correct for systematic/biological noise, we map depth data into corresponding z-statistics in healthy subjects. Then, we estimate parameters of a multivariate Gaussian governing z-statistics of the contributing regions. Finally, we employ a polished signal to assign a score to each gene. CNVs are then called based on predetermined performance metrics. We benchmarked performance via synthetic and empirical CAPP-Seq data, achieving 95% sensitivity/specificity for ctDNA levels 3-5% in actionable CNVs involving ERBB2, MET, and EGFR. We also successfully detected CNVs for ctDNA level as low as 3% in patients with non-small cell lung cancer or diffuse large B-cell lymphoma (DLBCL). We separately describe a Bayesian Tumor histology classifier using prior probabilities from existing knowledge regarding CNVs, single nucleotide variants, and gene fusions in public Tumor sequencing data. Prior probabilities were constructed within an optimization framework using maximum entropy. When applied to noninvasive classification of DLBCL subtypes (i.e. germinal center B-cell like (GCB) and activated B-cell like (ABC) [1]) using pretreatment plasma, this method showed ~ 80% concordance with routine clinical classification (Hans Algorithm). We conclude that Tumor subtype classification and CNV detection with ctDNA is feasible and robust using CAPP-Seq.
Razelle Kurzrock - One of the best experts on this subject based on the ideXlab platform.
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Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening
'MDPI AG', 2021Co-Authors: Jacob J. Adashek, Filip Janku, Razelle KurzrockAbstract:With the addition of molecular testing to the oncologist’s diagnostic toolbox, patients have benefitted from the successes of gene- and immune-directed therapies. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. An important advance in the application of molecular testing is the liquid biopsy, wherein Circulating Tumor DNA (ctDNA) is analyzed for point mutations, copy number alterations, and amplifications by polymerase chain reaction (PCR) and/or next-generation sequencing (NGS). The advantages of evaluating ctDNA over tissue DNA include (i) ctDNA requires only a tube of blood, rather than an invasive biopsy, (ii) ctDNA can plausibly reflect DNA shedding from multiple metastatic sites while tissue DNA reflects only the piece of tissue biopsied, and (iii) dynamic changes in ctDNA during therapy can be easily followed with repeat blood draws. Tissue biopsies allow comprehensive assessment of DNA, RNA, and protein expression in the Tumor and its microenvironment as well as functional assays; however, Tumor tissue acquisition is costly with a risk of complications. Herein, we review the ways in which ctDNA assessment can be leveraged to understand the dynamic changes of molecular landscape in cancers
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Clinical implications of plasma Circulating Tumor DNA in gynecologic cancer patients
'Wiley', 2021Co-Authors: Lindsey M. Charo, Richard B Lanman, Shumei Kato, Ramez N. Eskander, Ryosuke Okamura, Sandip P. Patel, Mina Nikanjam, David E. Piccioni, Michael T. Mchale, Razelle KurzrockAbstract:Molecular characterization of cancers is important in dictating prognostic factors and directing therapy. Next‐generation sequencing of plasma Circulating Tumor DNA (ctDNA) offers less invasive, more convenient collection, and a more real‐time representation of a Tumor and its molecular heterogeneity than tissue. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We describe the molecular landscape identified on ctDNA, ctDNA concordance with tissue‐based analysis, and factors associated with overall survival (OS) in gynecologic cancer patients with ctDNA analysis. We reviewed clinicopathologic and genomic information for 105 consecutive gynecologic cancer patients with ctDNA analysis, including 78 with tissue‐based sequencing, enrolled in the Profile‐Related Evidence Determining Individualized Cancer Therapy (NCT02478931) trial at the University of California San Diego Moores Cancer Center starting July 2014. Tumors included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvovaginal (2.9%), and unknown gynecologic primary (1.9%). Most ovarian and uterine cancers (86%) were high grade. 34% (N = 17) of ovarian cancers had BRCA alterations, and 22% (N = 11) were platinum sensitive. Patients received median 2 (range 0–13) lines of therapy prior to ctDNA collection. Most (75.2%) had at least one characterized alteration on ctDNA analysis, and the majority had unique genomic profiles on ctDNA. Most common alterations were TP53 (N = 59, 56.2% of patients), PIK3CA (N = 26, 24.8%), KRAS (N = 14, 13.3%), BRAF (N = 10, 9.5%), ERBB2 (N = 8, 7.6%), and MYC (N = 8, 7.6%). Higher ctDNA maximum mutation allele frequency was associated with worse OS [hazard ratio (HR): 1.91, P = 0.03], while therapy matched to ctDNA alterations (N = 33 patients) was independently associated with improved OS (HR: 0.34, P = 0.007) compared to unmatched therapy (N = 28 patients) in multivariate analysis. Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer
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the mutational landscape of gastrointestinal malignancies as reflected by Circulating Tumor DNA
Molecular Cancer Therapeutics, 2018Co-Authors: Paul Riviere, Paul T Fanta, Sadakatsu Ikeda, Joel M Baumgartner, Gregory M Heestand, Razelle KurzrockAbstract:We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived Circulating Tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N = 55; 26%), appendiceal adenocarcinoma (N = 46; 22%), hepatocellular carcinoma (N = 31; 15%), and pancreatic ductal adenocarcinoma (N = 25; 12%). The majority of patients (58%) had ≥1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had ≥1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal Tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297-305. ©2017 AACR.
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utility of genomic analysis in Circulating Tumor DNA from patients with carcinoma of unknown primary
Cancer Research, 2017Co-Authors: Shumei Kato, Kimberly C Banks, Richard B Lanman, Nithya Krishnamurthy, Kirstin Williams, Casey Williams, Brian Leylandjones, Scott M Lippman, Razelle KurzrockAbstract:Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing of Circulating Tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) ≥1 characterized alteration(s), excluding variants of unknown significance. TP53 -associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor–based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238–46. ©2017 AACR .
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the mutational landscape of gastrointestinal malignancies as reflected by Circulating Tumor DNA
Journal of Clinical Oncology, 2017Co-Authors: Paul Riviere, Paul T Fanta, Sadakatsu Ikeda, Joel M Baumgartner, Gregory M Heestand, Razelle KurzrockAbstract:11574Background: Liquid biopsy of Circulating Tumor DNA (ctDNA) is a novel method of detecting genetic alterations in cancer patients without tissue acquisition. Methods: Our analysis surveyed the ...