TP53 Genomic Alterations Including Targetable Y220C Mutation in Advanced Breast Cancer

Abstract

TP53 Y220C is a rare genomic alteration (GA) with emerging targeted therapies. However, its prevalence in breast cancer remains undefined. We evaluated the prevalence of the Y220C alteration and association with other GAs. A total of 23,760 patients with advanced breast cancer were analyzed by hybrid capture-based comprehensive genomic profiling that included GAs, microsatellite instability-high (MSI-H) status, tumor mutational burden, genomic ancestry, mutational signature, and homologous recombination deficiency. PD-L1 expression was determined by immunohistochemistry. GAs were compared using Fisher exact test with Benjamini-Hochberg multiplicity adjustment. Among the 12,653 (53%) patients with TP53 GA, 254 (1.1%) had the Y220C mutation. When compared with TP53 wildtype (wt), patients with TP53 GA were younger (56 v 60 years; P < .0001) and had a higher median number of GAs (6 v 5; P < .0001). The patients with TP53 non-Y220C GA were more frequently of African genetic ancestry than those with TP53 wt (18.3% v 11.2%; P < .0001). MSI-H was more frequent in patients with TP53 Y220C than those with TP53 wt (1.7% v 0.3%; P = .036). GAs more frequent in TP53 GA versus patients with TP53 wt included BRCA1 , ERBB2 , PTEN , RB1 , AKT2 , KRAS , MTAP , NTRK1 , and VEGFA . GAs more frequent in patients with TP53 wt included BRCA2 , CCND1 , CDH1 , ESR1 , PIK3CA , and AKT1 . TP53 GAs were common, seen in 53% of patients. However, TP53 Y220C was only seen in 1.1% of patients with advanced breast cancer. The TP53 GA group was associated with GA in other tumor suppressor genes, including BRCA1 , PTEN , and RB1 , whereas the TP53 wt group was most often associated with GA in pathways of endocrine resistance, including PIK3CA and ESR1 .