Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer
The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in p...
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| Veröffentlicht in: | Chest 2021-09, Vol.160 (3), p.1095-1107 |
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| creator | Roosan, Moom R. Mambetsariev, Isa Pharaon, Rebecca Fricke, Jeremy Husain, Hatim Reckamp, Karen L. Koczywas, Marianna Massarelli, Erminia Bild, Andrea H. Salgia, Ravi |
| description | The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).
How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?
We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.
A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.
Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC. |
| doi_str_mv | 10.1016/j.chest.2021.04.016 |
| format | Article |
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How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?
We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.
A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.
Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.</description><identifier>ISSN: 0012-3692</identifier><identifier>EISSN: 1931-3543</identifier><identifier>DOI: 10.1016/j.chest.2021.04.016</identifier><identifier>PMID: 33878340</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Biomarkers, Tumor - genetics ; Biopsy - methods ; Biopsy - statistics & numerical data ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - mortality ; Carcinoma, Non-Small-Cell Lung - pathology ; circulating tumor DNA ; Circulating Tumor DNA - genetics ; Class I Phosphatidylinositol 3-Kinases - genetics ; ErbB Receptors - genetics ; Female ; Humans ; Lung Neoplasms - genetics ; Lung Neoplasms - mortality ; Lung Neoplasms - pathology ; Male ; Molecular Targeted Therapy - methods ; Molecular Targeted Therapy - standards ; Mutation ; non-small cell lung cancer ; overall survival ; Precision Medicine - methods ; Precision Medicine - standards ; precision oncology ; Progression-Free Survival ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins p21(ras) - genetics ; Quality Improvement ; Thoracic Oncology: Original Research</subject><ispartof>Chest, 2021-09, Vol.160 (3), p.1095-1107</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2021 The Authors 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-90399d2ba900a67773301d05d2c19c58b5b1b7292eac3178f5ac762822b9357f3</citedby><cites>FETCH-LOGICAL-c459t-90399d2ba900a67773301d05d2c19c58b5b1b7292eac3178f5ac762822b9357f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33878340$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roosan, Moom R.</creatorcontrib><creatorcontrib>Mambetsariev, Isa</creatorcontrib><creatorcontrib>Pharaon, Rebecca</creatorcontrib><creatorcontrib>Fricke, Jeremy</creatorcontrib><creatorcontrib>Husain, Hatim</creatorcontrib><creatorcontrib>Reckamp, Karen L.</creatorcontrib><creatorcontrib>Koczywas, Marianna</creatorcontrib><creatorcontrib>Massarelli, Erminia</creatorcontrib><creatorcontrib>Bild, Andrea H.</creatorcontrib><creatorcontrib>Salgia, Ravi</creatorcontrib><title>Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer</title><title>Chest</title><addtitle>Chest</addtitle><description>The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).
How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?
We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.
A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.
Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.</description><subject>Aged</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biopsy - methods</subject><subject>Biopsy - statistics & numerical data</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - mortality</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>circulating tumor DNA</subject><subject>Circulating Tumor DNA - genetics</subject><subject>Class I Phosphatidylinositol 3-Kinases - genetics</subject><subject>ErbB Receptors - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - mortality</subject><subject>Lung Neoplasms - pathology</subject><subject>Male</subject><subject>Molecular Targeted Therapy - methods</subject><subject>Molecular Targeted Therapy - standards</subject><subject>Mutation</subject><subject>non-small cell lung cancer</subject><subject>overall survival</subject><subject>Precision Medicine - methods</subject><subject>Precision Medicine - standards</subject><subject>precision oncology</subject><subject>Progression-Free Survival</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Quality Improvement</subject><subject>Thoracic Oncology: Original Research</subject><issn>0012-3692</issn><issn>1931-3543</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uctu1DAUtRCITgtfgIS8ZJPUj7y8AKkKLVQaChJTsbQcx-l4SOxixyP1I_hnbjqlwIaNr3zvOec-DkKvKMkpodXpLtdbE-ecEUZzUuSQe4JWVHCa8bLgT9GKEMoyXgl2hI5j3BH4U1E9R0ecN3XDC7JCP6-jGdLoTIzYD7i1QadRzdbd4E2afMDvr86wdfiyN262w91S-OonQGj8Kc0QvYtYuR5vgtLf__DO935MS3VhfwEc8CP-ZuctvvIui5MaR9waeNYJSK1y2oQX6NmgxmhePsQTdH1xvmk_ZuvPHy7bs3Wmi1LMmSBciJ51ShCiqrquOSe0J2XPNBW6bLqyo13NBDNKc1o3Q6l0XbGGsU7wsh74CXp30L1N3WR6DbMFNcrbYCcV7qRXVv5bcXYrb_xeNkUBPSkIvHkQCP5HAhfkZKOGbZQzPkXJSloxVpWCA5QfoDr4GIMZHttQIhcj5U7eGykXIyUpJOSA9frvCR85v50DwNsDwMCd9tYEGTXcWJveBqNn2Xv73wa_AIUesf0</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Roosan, Moom R.</creator><creator>Mambetsariev, Isa</creator><creator>Pharaon, Rebecca</creator><creator>Fricke, Jeremy</creator><creator>Husain, Hatim</creator><creator>Reckamp, Karen L.</creator><creator>Koczywas, Marianna</creator><creator>Massarelli, Erminia</creator><creator>Bild, Andrea H.</creator><creator>Salgia, Ravi</creator><general>Elsevier Inc</general><general>American College of Chest Physicians</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210901</creationdate><title>Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer</title><author>Roosan, Moom R. ; 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How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?
We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.
A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.
Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33878340</pmid><doi>10.1016/j.chest.2021.04.016</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Biomarkers, Tumor - genetics Biopsy - methods Biopsy - statistics & numerical data Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - mortality Carcinoma, Non-Small-Cell Lung - pathology circulating tumor DNA Circulating Tumor DNA - genetics Class I Phosphatidylinositol 3-Kinases - genetics ErbB Receptors - genetics Female Humans Lung Neoplasms - genetics Lung Neoplasms - mortality Lung Neoplasms - pathology Male Molecular Targeted Therapy - methods Molecular Targeted Therapy - standards Mutation non-small cell lung cancer overall survival Precision Medicine - methods Precision Medicine - standards precision oncology Progression-Free Survival Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) - genetics Quality Improvement Thoracic Oncology: Original Research |
| title | Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer |
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