WDR49 mutation as a novel predictive biomarker in patients with non–small cell lung cancer with immune checkpoint inhibitors.

Authors

null

Zhihui Shi

The Second Xiangya Hospital of Central South University, Changsha, China

Zhihui Shi , Yaqin Liu , Lele Zhao , Lin Chen , Qidong Yang , Mingzhe Xiao

Organizations

The Second Xiangya Hospital of Central South University, Changsha, China, The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd; Nanjing Simcere Medical Laboratory Science Co., Ltd; The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China, Jiangsu Simcere Diagnostics Co., The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China, The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China

Research Funding

No funding received

Background: Application of Immune Checkpoint Inhibitors (ICIs) has become the first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). WDR49 gene belongs to the WDR (WD40-repeat) protein family which participates in a wide range of biological processes, including DNA damage repair and immune regulation, etc. However, the correlation between WDR49 mutation and immune efficacy is unclear. Methods: A total of three independent cohorts of NSCLC patients treated with immunotherapy were analyzed in this study: the Miao cohort (n = 56), the Rizvi cohort (n = 34), the Hellmann cohort (n = 75). Survival was estimated by Kaplan-Meier curves, with the p value determined by a log-rank test. HR was determined through the univariable and multivariable Cox regression. The CIBERSORT analysis relied on RNA-seq data in The Cancer Genome Atlas (TCGA) database. Two-sided P value < 0.05 was considered statistically significant. All the statistical analyses were conducted with R version 4.0.3. Results: In this merged cohort, the frequency of WDR49 mutation (WDR49-mut) was 10.30% (17 in 165), and most patients with WDR49 mutation were lung adenocarcinoma (LUAD) (11.85%, 16 in 135). Meanwhile, the frequency of WDR49-mut in TCGA database was 7.05 % and 3.84% in LUAD and lung squamous cell carcinoma (LUSC), respectively. The Kaplan-Meier curves survival analysis indicated that WDR49-mut was associated with longer progression free survival (PFS) (median PFS 23 months vs 5.2 months, hazard ratio [HR] = 0.17 [95% CI, 0.06–0.47], P < 0.001) and higher objective response rate (ORR) (76% vs 27%, P < 0.001). Furtherly, WDR49-mut was significantly related to higher tumor mutational burden (TMB) (median TMB 495 vs 149, P < 0.001), but it had nothing to do with the expression of PD-L1 (Proportion of PD-L1 positive 72.7% vs 68.5%, P = 1). The CIBERSORT analysis revealed that CD8+ T cell infiltration was significantly higher in WDR49-mut group than WDR49 wildtype group (p < 0.05). Conclusions: Better treatment response and survival benefit in the mutant group suggest that the WDR49 mutation may serve as a novel predictive biomarker in NSCLC patients with ICIs. The significantly higher TMB and CD8+ T cell infiltration in WDR49-mut group may be the potential mechanism.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics—Immunotherapy

Sub Track

Tissue-Based Biomarkers

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr 2615)

DOI

10.1200/JCO.2022.40.16_suppl.2615

Abstract #

2615

Poster Bd #

270

Abstract Disclosures

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