YAP1 mutation as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers.

Abstract

2604 Background: YAP1 is the main downstream target of the Hippo pathway and acts as a transcriptional coactivator to regulate development processes. YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored in nonsurgical esophageal squamous cell carcinoma (ESCC). YAP1 overexpression has been identified in multiple solid cancers, which consistently correlated with unfavorable clinical outcomes. Previous work suggested that YAP1 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of these findings in needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients, and the public database of TACG was also compared. Data from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 0.62 % (22 in 3547). Meanwhile, the frequency of YAP1 mutation in TCGA cohort was 0.90 % (99 in 10953). We further analyzed Kaplan-Meier curves from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In MSK-IMPACT cohort, mutation of YAP1 was associated with higher TMB (P = 0.022) and higher mutation count (P = 0.017) in pan-cancers. YAP1 mutation was associated with prolonged overall survival (OS) trend compared with YAP1 wt in pan-cancers (P = 0.15; HR, 2.209, 95% CI, 0.7109-6.8639). Conclusions: In our study, the frequency of YAP1 mutation was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. YAP1 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers via upregulating TMB and mutation count.