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Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
EPHA7 mutation as a predictive biomarker for immune checkpoint inhibitors in multiple cancers
Zhen Zhang1,2, Hao-Xiang Wu1,2, Wu-Hao Lin1,2
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
Background:
A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking.
Methods:
Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis.
Results:
Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor.
Conclusions:
EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.
Insights
Ephrin A7 (EPHA7) gene mutations predict a better response to immune checkpoint inhibitors (ICIs) in cancer patients. This finding highlights EPHA7 mutations as a potential biomarker for improving ICI therapy efficacy.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Identifying patients who benefit from immune checkpoint inhibitors (ICIs) is crucial for effective cancer immunotherapy.
- Eph receptors play a role in tumor immunity, but their association with ICI response remains unclear.
- Predictive biomarkers are needed to optimize clinical outcomes for patients receiving ICIs.
Purpose of the Study:
- To investigate the association between EPH gene mutations and the efficacy of immune checkpoint inhibitor (ICI) therapy.
- To identify potential predictive biomarkers for ICI treatment response.
Main Methods:
- Consolidated clinical and whole-exome sequencing (WES) data from published studies to form a discovery cohort.
- Utilized an independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) for validation.
- Performed anti-tumor immunity and pathway enrichment analysis using The Cancer Genome Atlas (TCGA) cohort.
Main Results:
- EPHA7 gene mutations (EPHA7-MUT) were significantly enriched in patients responding to ICI therapy (FDR adjusted P < 0.05).
- EPHA7-MUT patients showed improved objective response rate (ORR) and durable clinical benefit (DCB) in the discovery cohort.
- EPHA7-MUT was associated with improved overall survival in the validation cohort, independent of tumor mutational burden (TMB) and copy number alteration (CNA).
- EPHA7-MUT tumors exhibited enhanced anti-tumor immunity.
Conclusions:
- EPHA7-MUT serves as a potential predictive biomarker for immune checkpoint inhibitor (ICI) therapy.
- EPHA7-MUT is associated with better clinical outcomes in patients treated with ICIs across various cancer types.
- The findings suggest EPHA7 mutations can help stratify patients for immunotherapy.
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