Pan-cancer analysis of YAP1 expression as a predictive biomarker for cancer immunotherapy

2629 Background: High YAP1 expression correlates with the ‘T-cell inflamed’ expression phenotype in small cell lung cancer (SCLC), but its association with other biomarkers of immune checkpoint vulnerability and in tumor types beyond SCLC is not known. We examined whether YAP1 expression correlates with other established markers of immune checkpoint blockade (ICB) efficacy (PDL1 expression and TMB) in a tumor agnostic manner to determine clinical relevance. Methods: Next-generation sequencing of DNA (592 gene panel or whole exome) and RNA (whole transcriptome) was performed for patient samples (n = 57,134), representing 13 cancer types, submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). The ‘T-cell inflamed’ signature (TIS) score was calculated as an 18-gene weighted coefficient composite value (Cristescu, 2018). PDL1 expression was assessed by immunohistochemistry (IHC) with cancer type-specific antibodies and thresholds, and high tumor mutational burden was defined as ≥10 mut/Mb. Patients were stratified into subgroups based on median YAP1 expression (YAP1-High/YAP-Low) within each cancer type. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: YAP1-High tumors were associated with significantly increased TIS scores compared to YAP1-Low across all 13 cancer types examined, with the largest fold increase observed in SCLC (1.33-fold, p < 0.0001), followed by pancreatic cancer (1.28-fold, p < 0.0001), while the smallest occurred in melanoma (1.13-fold, p < 0.0001). Spearman correlation strength (range 0.23-0.57) between YAP expression and TIS scores was consistent with increased TIS scores in YAP1-High samples. TMB-High rates were similar in YAP-High and YAP1-Low subgroups for most cancer types, with slightly lower rates in YAP1-High tumors observed for endometrial (23.0 vs 26.6%, p < 0.001) and esophageal (7.0 vs 9.5%, p < 0.05) cancers. YAP1 expression was not significantly increased in PDL1+ (IHC) tumors for most cancer types. However, significantly decreased YAP1 expression was associated with PDL1+ samples in RCC (Renal Cell Carcinoma) (0.91-fold change, P < 0.05), MM (0.90-fold change, P < 0.001), and ENCA (0.80-fold change, P < 0.0001) Conclusions: Our analyses provide confirmation that YAP1 expression positively correlates with the ‘T-cell inflamed’ phenotype across many cancer types, including those with approvals for (ICB) therapy. YAP1 expression was independent of established markers of ICB response, including TMB and PDL1. Further analysis of YAP1 expression as an additional tumor agnostic predictive biomarker is warranted.