Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma
Abstract Background The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions. Methods We pr...
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| Veröffentlicht in: | Clinical chemistry (Baltimore, Md.) Md.), 2024-03, Vol.70 (3), p.516-527 |
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| creator | Fietz, Simon Diekmann, Eric de Vos, Luka Zarbl, Romina Hunecke, Alina Glosch, Ann-Kathrin Färber, Moritz Sirokay, Judith Hoffmann, Friederike Fröhlich, Anne Franzen, Alina Strieth, Sebastian Landsberg, Jennifer Dietrich, Dimo |
| description | Abstract
Background
The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions.
Methods
We prospectively assessed circulating cell-free SHOX2 DNA methylation (SHOX2 ccfDNAm) levels and their dynamic changes in blood plasma of melanoma patients by quantitative methylation-specific polymerase chain reaction. Patients were treated with either palliative (n = 42) or adjuvant (n = 55) anti-PD-1 immunotherapy. Moreover, we included n = 126 control patients without evidence of malignant disease. We analyzed SHOX2 ccfDNAm status prior to and 4 weeks after palliative treatment initiation with regard to outcome [objective response, progression-free survival (PFS), and overall survival (OS)]. In the adjuvant setting, we associated longitudinal SHOX2 ccfDNAm status with disease recurrence.
Results
Sensitivity was 60% with 25/42 melanoma patients showing increased SHOX2 ccfDNAm levels, whereas specificity was 98% with 123/126 (P < 0.001) control patients having SHOX2 ccfDNAm levels below cut-off. Pretreatment SHOX2 ccfDNAm status did not correlate with outcome; however, SHOX2 ccfDNAm negativity 4 weeks after palliative treatment initiation was strongly associated with improved survival [PFS: hazard ratio (HR) = 0.25, P = 0.002; OS: HR = 0.12, P = 0.007]. Pretreatment positive patients who reached SHOX2 ccfDNAm clearance after 4 weeks of immunotherapy showed an exceptionally beneficial outcome. SHOX2 ccfDNAm testing allowed for an early detection of distant metastases in adjuvant-treated melanoma patients.
Conclusions
Our study suggests SHOX2 ccfDNAm to be an early predictor of outcome in anti-PD-1 treated melanoma patients. SHOX2 ccfDNAm testing may aid individualized treatment decision-making. |
| doi_str_mv | 10.1093/clinchem/hvad230 |
| format | Article |
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Background
The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions.
Methods
We prospectively assessed circulating cell-free SHOX2 DNA methylation (SHOX2 ccfDNAm) levels and their dynamic changes in blood plasma of melanoma patients by quantitative methylation-specific polymerase chain reaction. Patients were treated with either palliative (n = 42) or adjuvant (n = 55) anti-PD-1 immunotherapy. Moreover, we included n = 126 control patients without evidence of malignant disease. We analyzed SHOX2 ccfDNAm status prior to and 4 weeks after palliative treatment initiation with regard to outcome [objective response, progression-free survival (PFS), and overall survival (OS)]. In the adjuvant setting, we associated longitudinal SHOX2 ccfDNAm status with disease recurrence.
Results
Sensitivity was 60% with 25/42 melanoma patients showing increased SHOX2 ccfDNAm levels, whereas specificity was 98% with 123/126 (P < 0.001) control patients having SHOX2 ccfDNAm levels below cut-off. Pretreatment SHOX2 ccfDNAm status did not correlate with outcome; however, SHOX2 ccfDNAm negativity 4 weeks after palliative treatment initiation was strongly associated with improved survival [PFS: hazard ratio (HR) = 0.25, P = 0.002; OS: HR = 0.12, P = 0.007]. Pretreatment positive patients who reached SHOX2 ccfDNAm clearance after 4 weeks of immunotherapy showed an exceptionally beneficial outcome. SHOX2 ccfDNAm testing allowed for an early detection of distant metastases in adjuvant-treated melanoma patients.
Conclusions
Our study suggests SHOX2 ccfDNAm to be an early predictor of outcome in anti-PD-1 treated melanoma patients. SHOX2 ccfDNAm testing may aid individualized treatment decision-making.</description><identifier>ISSN: 0009-9147</identifier><identifier>EISSN: 1530-8561</identifier><identifier>DOI: 10.1093/clinchem/hvad230</identifier><identifier>PMID: 38300881</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Biomarkers ; Cell-Free Nucleic Acids ; DNA Methylation ; Homeodomain Proteins - genetics ; Humans ; Melanoma - drug therapy ; Melanoma - genetics ; Neoplasm Recurrence, Local ; Prognosis</subject><ispartof>Clinical chemistry (Baltimore, Md.), 2024-03, Vol.70 (3), p.516-527</ispartof><rights>Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2024</rights><rights>Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c377t-b87ce0618ae6ccd0a2814d5963d607755b7a73d5eb81f52a4dc70e1aba65dcec3</citedby><cites>FETCH-LOGICAL-c377t-b87ce0618ae6ccd0a2814d5963d607755b7a73d5eb81f52a4dc70e1aba65dcec3</cites><orcidid>0000-0001-8334-5458 ; 0000-0003-3745-9125</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38300881$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fietz, Simon</creatorcontrib><creatorcontrib>Diekmann, Eric</creatorcontrib><creatorcontrib>de Vos, Luka</creatorcontrib><creatorcontrib>Zarbl, Romina</creatorcontrib><creatorcontrib>Hunecke, Alina</creatorcontrib><creatorcontrib>Glosch, Ann-Kathrin</creatorcontrib><creatorcontrib>Färber, Moritz</creatorcontrib><creatorcontrib>Sirokay, Judith</creatorcontrib><creatorcontrib>Hoffmann, Friederike</creatorcontrib><creatorcontrib>Fröhlich, Anne</creatorcontrib><creatorcontrib>Franzen, Alina</creatorcontrib><creatorcontrib>Strieth, Sebastian</creatorcontrib><creatorcontrib>Landsberg, Jennifer</creatorcontrib><creatorcontrib>Dietrich, Dimo</creatorcontrib><title>Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma</title><title>Clinical chemistry (Baltimore, Md.)</title><addtitle>Clin Chem</addtitle><description>Abstract
Background
The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions.
Methods
We prospectively assessed circulating cell-free SHOX2 DNA methylation (SHOX2 ccfDNAm) levels and their dynamic changes in blood plasma of melanoma patients by quantitative methylation-specific polymerase chain reaction. Patients were treated with either palliative (n = 42) or adjuvant (n = 55) anti-PD-1 immunotherapy. Moreover, we included n = 126 control patients without evidence of malignant disease. We analyzed SHOX2 ccfDNAm status prior to and 4 weeks after palliative treatment initiation with regard to outcome [objective response, progression-free survival (PFS), and overall survival (OS)]. In the adjuvant setting, we associated longitudinal SHOX2 ccfDNAm status with disease recurrence.
Results
Sensitivity was 60% with 25/42 melanoma patients showing increased SHOX2 ccfDNAm levels, whereas specificity was 98% with 123/126 (P < 0.001) control patients having SHOX2 ccfDNAm levels below cut-off. Pretreatment SHOX2 ccfDNAm status did not correlate with outcome; however, SHOX2 ccfDNAm negativity 4 weeks after palliative treatment initiation was strongly associated with improved survival [PFS: hazard ratio (HR) = 0.25, P = 0.002; OS: HR = 0.12, P = 0.007]. Pretreatment positive patients who reached SHOX2 ccfDNAm clearance after 4 weeks of immunotherapy showed an exceptionally beneficial outcome. SHOX2 ccfDNAm testing allowed for an early detection of distant metastases in adjuvant-treated melanoma patients.
Conclusions
Our study suggests SHOX2 ccfDNAm to be an early predictor of outcome in anti-PD-1 treated melanoma patients. SHOX2 ccfDNAm testing may aid individualized treatment decision-making.</description><subject>Biomarkers</subject><subject>Cell-Free Nucleic Acids</subject><subject>DNA Methylation</subject><subject>Homeodomain Proteins - genetics</subject><subject>Humans</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - genetics</subject><subject>Neoplasm Recurrence, Local</subject><subject>Prognosis</subject><issn>0009-9147</issn><issn>1530-8561</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1qGzEUhUVpadw0-66KloVEjTR_0ixd5xeSxtAEuhvuSNex0rHkShpDnqSvG7l2ui0IJKHvfKB7CPkk-FfB2_JUD9bpJa5OlxswRcnfkImoS85U3Yi3ZMI5b1krKnlAPsT4lK-VVM17clCqknOlxIT8mdmgxwGSdY90hsPALgIi_XF197OgZ9-n9BbT8nn77h29jhToPKCxOtkNnuSzf3Q-JqtPKDhDb72zyYet65v1Kwi_MFDr6NQ8jRtw6S80h2GwsBXQqUuWzc-YYPcBIWE24AAuJz-SdwsYIh7t90PycHF-P7tiN3eX17PpDdOllIn1SmrkjVCAjdaGQ6FEZeq2KU3DpazrXoIsTY29Eou6gMpoyVFAD01tNOrykHzZedfB_x4xpm5lo85zAId-jF3RFq3Iq1IZ5TtUBx9jwEW3Djb_8bkTvNvW0b3W0e3ryJHPe_vYr9D8C7zOPwPHO8CP6__rXgCaj5k5</recordid><startdate>20240302</startdate><enddate>20240302</enddate><creator>Fietz, Simon</creator><creator>Diekmann, Eric</creator><creator>de Vos, Luka</creator><creator>Zarbl, Romina</creator><creator>Hunecke, Alina</creator><creator>Glosch, Ann-Kathrin</creator><creator>Färber, Moritz</creator><creator>Sirokay, Judith</creator><creator>Hoffmann, Friederike</creator><creator>Fröhlich, Anne</creator><creator>Franzen, Alina</creator><creator>Strieth, Sebastian</creator><creator>Landsberg, Jennifer</creator><creator>Dietrich, Dimo</creator><general>Oxford University Press</general><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><orcidid>https://orcid.org/0000-0001-8334-5458</orcidid><orcidid>https://orcid.org/0000-0003-3745-9125</orcidid></search><sort><creationdate>20240302</creationdate><title>Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma</title><author>Fietz, Simon ; Diekmann, Eric ; de Vos, Luka ; Zarbl, Romina ; Hunecke, Alina ; Glosch, Ann-Kathrin ; Färber, Moritz ; Sirokay, Judith ; Hoffmann, Friederike ; Fröhlich, Anne ; Franzen, Alina ; Strieth, Sebastian ; Landsberg, Jennifer ; Dietrich, Dimo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c377t-b87ce0618ae6ccd0a2814d5963d607755b7a73d5eb81f52a4dc70e1aba65dcec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Biomarkers</topic><topic>Cell-Free Nucleic Acids</topic><topic>DNA Methylation</topic><topic>Homeodomain Proteins - genetics</topic><topic>Humans</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - genetics</topic><topic>Neoplasm Recurrence, Local</topic><topic>Prognosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fietz, Simon</creatorcontrib><creatorcontrib>Diekmann, Eric</creatorcontrib><creatorcontrib>de Vos, Luka</creatorcontrib><creatorcontrib>Zarbl, Romina</creatorcontrib><creatorcontrib>Hunecke, Alina</creatorcontrib><creatorcontrib>Glosch, Ann-Kathrin</creatorcontrib><creatorcontrib>Färber, Moritz</creatorcontrib><creatorcontrib>Sirokay, Judith</creatorcontrib><creatorcontrib>Hoffmann, Friederike</creatorcontrib><creatorcontrib>Fröhlich, Anne</creatorcontrib><creatorcontrib>Franzen, Alina</creatorcontrib><creatorcontrib>Strieth, Sebastian</creatorcontrib><creatorcontrib>Landsberg, Jennifer</creatorcontrib><creatorcontrib>Dietrich, Dimo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical chemistry (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fietz, Simon</au><au>Diekmann, Eric</au><au>de Vos, Luka</au><au>Zarbl, Romina</au><au>Hunecke, Alina</au><au>Glosch, Ann-Kathrin</au><au>Färber, Moritz</au><au>Sirokay, Judith</au><au>Hoffmann, Friederike</au><au>Fröhlich, Anne</au><au>Franzen, Alina</au><au>Strieth, Sebastian</au><au>Landsberg, Jennifer</au><au>Dietrich, Dimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma</atitle><jtitle>Clinical chemistry (Baltimore, Md.)</jtitle><addtitle>Clin Chem</addtitle><date>2024-03-02</date><risdate>2024</risdate><volume>70</volume><issue>3</issue><spage>516</spage><epage>527</epage><pages>516-527</pages><issn>0009-9147</issn><eissn>1530-8561</eissn><abstract>Abstract
Background
The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions.
Methods
We prospectively assessed circulating cell-free SHOX2 DNA methylation (SHOX2 ccfDNAm) levels and their dynamic changes in blood plasma of melanoma patients by quantitative methylation-specific polymerase chain reaction. Patients were treated with either palliative (n = 42) or adjuvant (n = 55) anti-PD-1 immunotherapy. Moreover, we included n = 126 control patients without evidence of malignant disease. We analyzed SHOX2 ccfDNAm status prior to and 4 weeks after palliative treatment initiation with regard to outcome [objective response, progression-free survival (PFS), and overall survival (OS)]. In the adjuvant setting, we associated longitudinal SHOX2 ccfDNAm status with disease recurrence.
Results
Sensitivity was 60% with 25/42 melanoma patients showing increased SHOX2 ccfDNAm levels, whereas specificity was 98% with 123/126 (P < 0.001) control patients having SHOX2 ccfDNAm levels below cut-off. Pretreatment SHOX2 ccfDNAm status did not correlate with outcome; however, SHOX2 ccfDNAm negativity 4 weeks after palliative treatment initiation was strongly associated with improved survival [PFS: hazard ratio (HR) = 0.25, P = 0.002; OS: HR = 0.12, P = 0.007]. Pretreatment positive patients who reached SHOX2 ccfDNAm clearance after 4 weeks of immunotherapy showed an exceptionally beneficial outcome. SHOX2 ccfDNAm testing allowed for an early detection of distant metastases in adjuvant-treated melanoma patients.
Conclusions
Our study suggests SHOX2 ccfDNAm to be an early predictor of outcome in anti-PD-1 treated melanoma patients. SHOX2 ccfDNAm testing may aid individualized treatment decision-making.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>38300881</pmid><doi>10.1093/clinchem/hvad230</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-8334-5458</orcidid><orcidid>https://orcid.org/0000-0003-3745-9125</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current) |
| subjects | Biomarkers Cell-Free Nucleic Acids DNA Methylation Homeodomain Proteins - genetics Humans Melanoma - drug therapy Melanoma - genetics Neoplasm Recurrence, Local Prognosis |
| title | Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma |
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