KEY TAKEAWAYS
- An observational study explored global and local CNAs for predicting patient survival, correlating CNA status with tumor immune scores derived from gene expression data.
- The analysis highlighted that CNA signatures can potentially optimize cancer prognosis and immunotherapy, especially in lung cancer. HRD showed predictive value for ICI outcomes.
Copy number aberrations (CNAs), encompassing DNA segment amplifications or deletions, are widespread in cancer and present a promising alternative for predicting responses to immune checkpoint inhibitors (ICIs). This complements established biomarkers like tumor mutation burden (TMB).
In exploring the prognostic value of copy number aberrations (CNAs) on patient survival, the study investigated the correlation between CNA status and tumor immune scores derived from gene expression data. Real-world genomic data from the Oncology Research Information Exchange Network (ORIEN) Avatar project, comprising 1250 lung cancer patients (including 112 treated with immune checkpoint inhibitors), was analyzed.
Global CNA signatures, such as total copy number burden (TCB) and homologous recombination deficiency (HRD) score, were assessed. Immune states were determined through ESTIMATE, CIBERSORTx, and EcoTyper using matched gene expression data. Predictive signatures influencing survival outcomes were identified via Kaplan-Meier analysis, Cox regression, and the Xsurv R package.
In the entire cohort, an elevated total copy number burden (TCB) demonstrated a significant correlation with smoking history (P<0.001) and metastatic status (P<0.001). This heightened TCB was also notably associated with diminished overall survival (P<0.001). Noteworthy prognostic copy number aberration (CNA) genes were identified, particularly in 1q21.1 (gain) and 22q11.23 (loss).
Within the cohort treated with immune checkpoint inhibitors (ICIs), a higher homologous recombination deficiency (HRD) score, as opposed to TCB, exhibited a significant association with unfavorable survival (P=0.03). According to the univariable Cox model, the most impactful prognostic CNAs were FAM231C (1p36.13 gain) and OR4F5 (1p36.33 loss). Employing survival boosting (XSurv), the identified top prognostic aberrant genes included OR11H12 (14q11.2), SLC2A14 (12p13.31), POM121 (7q11.23), and NBPF1 (1p36.13). The final Xsurv-based predictive model achieved a robust C-index of approximately 0.8, signifying a strong predictive capability using local copy number variation (CNV) information.
In immune phenotyping analysis on matched gene expression data, higher TCB or HRD score demonstrated a significant association with lower overall immune infiltration scores as determined by ESTIMATE and suppressed immune states defined by Ecotyper.
The analysis collectively emphasized the potential of employing copy number aberration (CNA) signatures to enhance cancer prognosis and immunotherapeutic outcomes, particularly in lung cancer.
The data suggested that while both total copy number burden (TCB) and homologous recombination deficiency (HRD) are closely associated with tumor immune status, only HRD demonstrates predictive value in determining immune checkpoint inhibitor (ICI) survival outcomes.
Further scrutiny is warranted to assess the clinical applicability of these CNA signatures across diverse cancer types.
Source: https://jitc.bmj.com/content/11/Suppl_1/A209
Clinical Trial: https://clinicaltrials.gov/study/NCT03977402
Wang X, Li T, Shaw TI, et al185 Global and local copy number aberration signatures as prognostic and immunotherapeutic predictorsJournal for ImmunoTherapy of Cancer 2023;11:doi: 10.1136/jitc-2023-SITC2023.0185
