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Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different
Karama Asleh1,2,3, Rodney J Ouellette2,3,4,5
1Department of Pathology and Laboratory Medicine, Halifax, NS B3H 1V8, Canada.
Cancers
|February 24, 2024
Summary
Copy number alteration burden predicts poor survival in advanced cancer patients receiving immune checkpoint blockade. Combining copy number alteration burden with tumor mutational burden improves patient stratification for immunotherapy response.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Immune checkpoint blockade (ICB) response varies among advanced cancer patients.
- Predictive biomarkers are crucial for optimizing ICB efficacy.
- Copy number alteration (CNA) burden is a potential biomarker for ICB resistance.
Purpose of the Study:
- To evaluate the association between CNA burden and overall survival in ICB-treated patients.
- To investigate if combining CNA burden with tumor mutational burden (TMB) improves patient stratification.
- To explore the genomic and immune landscape of distinct patient subsets.
Main Methods:
- Retrospective analysis of 1661 ICB-treated patients with MSK-IMPACT profiling.
- Multivariate analysis to assess the impact of CNA burden on overall survival.
- Stratification of patients using combined TMB and CNA burden biomarkers.
Main Results:
- Increased CNA burden was significantly associated with poor overall survival in ICB-treated patients (HR = 1.52, p = 0.04).
- The combination of TMB and CNA burden identified four distinct patient subsets with significantly different survival outcomes (p < 0.0001).
- The "LowTMB/HighCNA" subset exhibited the worst survival.
- Distinct CNA profiles and enriched pathways were observed across the four subsets, correlating with immune signaling and CD8+ T-cell abundance.
Conclusions:
- CNA burden is a significant predictor of poor overall survival in patients undergoing ICB.
- Integrating CNA burden with TMB enhances patient stratification for immunotherapy.
- These findings can inform patient selection for ICB or alternative treatment strategies.
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