Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types
Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data...
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| Veröffentlicht in: | Cancers 2024-02, Vol.16 (4), p.732 |
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| description | Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (
= 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (
= 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01-2.30),
= 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which "LowTMB/HighCNA" showed the worst survival (
< 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies. |
| doi_str_mv | 10.3390/cancers16040732 |
| format | Article |
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= 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (
= 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01-2.30),
= 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which "LowTMB/HighCNA" showed the worst survival (
< 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers16040732</identifier><identifier>PMID: 38398121</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Analysis ; B cells ; Biomarkers ; Cancer ; Care and treatment ; CD8 antigen ; Clinical medicine ; Clinical trials ; Copy number ; CTLA-4 protein ; DNA structure ; FDA approval ; Genes ; Genomes ; Hypotheses ; Immune checkpoint inhibitors ; Immune status ; Immunosuppressive agents ; Immunotherapy ; Lymphocytes T ; Mann-Whitney U test ; Medical research ; Medicine, Experimental ; Melanoma ; Multivariate analysis ; Mutation ; Patients ; PD-1 protein ; PD-L1 protein ; T cells ; Tumor microenvironment ; Tumors</subject><ispartof>Cancers, 2024-02, Vol.16 (4), p.732</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c387t-e7e6c0499f045add896a9a8a2ce4dc905096695cf9b9b252940d17621601ba5b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38398121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Asleh, Karama</creatorcontrib><creatorcontrib>Ouellette, Rodney J</creatorcontrib><title>Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (
= 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (
= 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01-2.30),
= 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which "LowTMB/HighCNA" showed the worst survival (
< 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies.</description><subject>Analysis</subject><subject>B cells</subject><subject>Biomarkers</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>CD8 antigen</subject><subject>Clinical medicine</subject><subject>Clinical trials</subject><subject>Copy number</subject><subject>CTLA-4 protein</subject><subject>DNA structure</subject><subject>FDA approval</subject><subject>Genes</subject><subject>Genomes</subject><subject>Hypotheses</subject><subject>Immune checkpoint inhibitors</subject><subject>Immune status</subject><subject>Immunosuppressive agents</subject><subject>Immunotherapy</subject><subject>Lymphocytes T</subject><subject>Mann-Whitney U test</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Melanoma</subject><subject>Multivariate analysis</subject><subject>Mutation</subject><subject>Patients</subject><subject>PD-1 protein</subject><subject>PD-L1 protein</subject><subject>T cells</subject><subject>Tumor microenvironment</subject><subject>Tumors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkc9PHSEQx0ljU4313FtD4sXLUxbYZTk-t79MTNs0r-cNC4Oiu7ACe3iH_u_lqW2tEUKGwGcm3_kOQu8qcsqYJGdaeQ0xVQ3hRDD6Ch1QIuiqaSTfe3LfR0cp3ZCyGKtEI96gfdYy2Va0OkC_NssUIu7CvMVfl2mAiNdjhqiyCx6fL9GAxyphhb9HME7nAttyfkByKe8E4BzwxTQtHnB3Dfp2Ds5nfD4GfasMYKVjSAl_cNZChPLT3avGm-0M6S16bdWY4OgxHqKfnz5uui-ry2-fL7r15UqzVuQVCGg04VJawmtlTCsbJVWrqAZutCQ1kaXRWls5yIHWVHJiSqe0OFMNqh7YITp5qDvHcLdAyv3kkoZxVB7CknoqGeWMS9oW9PgZehOW6Iu6HUWKcbWQ_6grNULvvA05Kr0r2q9FywkTvCaFOn2BKtvA5HTwYF15_y_h7CHh3rQItp-jm1Tc9hXpdzPvn828ZLx_lLsME5i__J8Js990uKbD</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Asleh, Karama</creator><creator>Ouellette, Rodney J</creator><general>MDPI AG</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20240201</creationdate><title>Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types</title><author>Asleh, Karama ; Ouellette, Rodney J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-e7e6c0499f045add896a9a8a2ce4dc905096695cf9b9b252940d17621601ba5b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Analysis</topic><topic>B cells</topic><topic>Biomarkers</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>CD8 antigen</topic><topic>Clinical medicine</topic><topic>Clinical trials</topic><topic>Copy number</topic><topic>CTLA-4 protein</topic><topic>DNA structure</topic><topic>FDA approval</topic><topic>Genes</topic><topic>Genomes</topic><topic>Hypotheses</topic><topic>Immune checkpoint inhibitors</topic><topic>Immune status</topic><topic>Immunosuppressive agents</topic><topic>Immunotherapy</topic><topic>Lymphocytes T</topic><topic>Mann-Whitney U test</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Melanoma</topic><topic>Multivariate analysis</topic><topic>Mutation</topic><topic>Patients</topic><topic>PD-1 protein</topic><topic>PD-L1 protein</topic><topic>T cells</topic><topic>Tumor microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Asleh, Karama</creatorcontrib><creatorcontrib>Ouellette, Rodney J</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Asleh, Karama</au><au>Ouellette, Rodney J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2024-02-01</date><risdate>2024</risdate><volume>16</volume><issue>4</issue><spage>732</spage><pages>732-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (
= 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (
= 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01-2.30),
= 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which "LowTMB/HighCNA" showed the worst survival (
< 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>38398121</pmid><doi>10.3390/cancers16040732</doi><oa>free_for_read</oa></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
| subjects | Analysis B cells Biomarkers Cancer Care and treatment CD8 antigen Clinical medicine Clinical trials Copy number CTLA-4 protein DNA structure FDA approval Genes Genomes Hypotheses Immune checkpoint inhibitors Immune status Immunosuppressive agents Immunotherapy Lymphocytes T Mann-Whitney U test Medical research Medicine, Experimental Melanoma Multivariate analysis Mutation Patients PD-1 protein PD-L1 protein T cells Tumor microenvironment Tumors |
| title | Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types |
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