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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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/4/732 |
| _version_ | 1797298701892321280 |
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| author | Karama Asleh Rodney J. Ouellette |
| author_facet | Karama Asleh Rodney J. Ouellette |
| author_sort | Karama Asleh |
| collection | DOAJ |
| 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% (<i>n</i> = 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (<i>n</i> = 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), <i>p</i> = 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 (<i>p</i> < 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. |
| first_indexed | 2024-03-07T22:38:46Z |
| format | Article |
| id | doaj.art-8c62a2cf7c5749b8ae54a867ca8e1f38 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-07T22:38:46Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8c62a2cf7c5749b8ae54a867ca8e1f382024-02-23T15:10:43ZengMDPI AGCancers2072-66942024-02-0116473210.3390/cancers16040732Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer TypesKarama Asleh0Rodney J. Ouellette1Department of Pathology and Laboratory Medicine, Halifax, NS B3H 1V8, CanadaBeatrice Hunter Cancer Research Institute, Halifax, NS B3H 0A2, CanadaImmune 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% (<i>n</i> = 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (<i>n</i> = 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), <i>p</i> = 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 (<i>p</i> < 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.https://www.mdpi.com/2072-6694/16/4/732copy number alteration burdentumor mutational burdenimmune checkpoint blockadenext-generation sequencingMSK-IMPACT assaypredictive biomarkers |
| spellingShingle | Karama Asleh Rodney J. Ouellette Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types Cancers copy number alteration burden tumor mutational burden immune checkpoint blockade next-generation sequencing MSK-IMPACT assay predictive biomarkers |
| title | Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types |
| title_full | Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types |
| title_fullStr | Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types |
| title_full_unstemmed | Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types |
| title_short | Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types |
| title_sort | tumor copy number alteration burden as a predictor for resistance to immune checkpoint blockade across different cancer types |
| topic | copy number alteration burden tumor mutational burden immune checkpoint blockade next-generation sequencing MSK-IMPACT assay predictive biomarkers |
| url | https://www.mdpi.com/2072-6694/16/4/732 |
| work_keys_str_mv | AT karamaasleh tumorcopynumberalterationburdenasapredictorforresistancetoimmunecheckpointblockadeacrossdifferentcancertypes AT rodneyjouellette tumorcopynumberalterationburdenasapredictorforresistancetoimmunecheckpointblockadeacrossdifferentcancertypes |