TP53 Y220C mutation in esophageal adenocarcinoma: A genomic landscape study.

Abstract

442 Background: Although an uncommon variant, the TP53 Y220C base substitution mutation has gained significant attention as novel drugs emerge that can revert this mutant non-cell cycle regulating protein to wild-type–like TP53 function, representing a promising therapeutic strategy. Defining the genomic and immune-oncology biomarker landscape of TP53 Y220C–mutant esophageal adenocarcinoma (EAC) may inform clinical development of targeted therapies. Methods: Comprehensive genomic profiling (CGP) was conducted on 12,246 esophageal adenocarcinoma (EAC) samples using hybrid-capture sequencing to identify all classes of genomic alterations (GA). Microsatellite instability (MSI) and tumor mutational burden (TMB) were derived from sequencing data. Programmed death-ligand 1 (PD-L1) expression was evaluated by immunohistochemistry (IHC) using the Dako 22C3 assay and tumor proportion score (TPS) criteria: 0% as negative, 1–49% as low, and 50% or greater as high. Results: A total of 129 EAC (1.1%) harbored the TP53 Y220C short variation mutation (TP53 Y220C+). Age (mean 64.4 vs. 64.9 years) and sex distribution (13.2% vs. 13.4% female) were similar between TP53 Y220C+ and TP53 Y220C– cohorts. Biomarkers predictive of immune checkpoint inhibitor response were similarly at low levels in both groups: MSI high status (0.8% vs. 2.8%), TMB ≥10 mutations/Mb (4.7% vs. 8.5%), and PD-L1 low-positive expression (7.7% vs. 12.2%). Non-Y220C TP53 genomic alterations co-occurred in 17.9% of TP53 Y220C+ tumors vs. 85.8% of TP53 Y220C– tumors. The prevalence of other genomic alterations was similar between groups, including ERBB2 (20.9% vs. 21.3%), KRAS (24.0% vs. 24.1%), ARID1A (17.1% vs. 14.6%), APC (12.4% vs. 8.2%), CDKN2B (11.6% vs. 12.8%), CCND1 (10.9% vs. 10.4%), EGFR (10.1% vs. 10.0%), MTAP (7.7% vs. 9.3%), PIK3CA (7.0% vs. 8.9%), NOTCH1 (7.0% vs. 5.2%), MET (6.2% vs. 5.5%), and PTEN (6.2% vs. 5.1%). Conclusions: The TP53 Y220C mutation defines a distinct but rare subset of esophageal adenocarcinoma (EAC), occurring in only 1.1% of cases. This small subgroup may benefit from novel therapeutics that restore TP53 function. The results support the rationale for ongoing and future clinical trials investigating TP53 reactivator drugs in TP53 Y220C–mutant EAC. Selected genomic alterations in TP53 Y220C+ vs. TP53 Y220C– EAC. Genomic alteration TP53 Y220C+ (%) TP53 Y220C– (%) ERBB2 20.9 21.3 KRAS 24.0 24.1 ARID1A 17.1 14.6 APC 12.4 8.2 CDKN2B 11.6 12.8 CCND1 10.9 10.4 EGFR 10.1 10.0 MTAP 7.7 9.3 PIK3CA 7.0 8.9