<i>TP53</i> genomic alterations including targetable <i>TP53</i> Y220C mutation in clinically advanced breast cancer.

Abstract

1043 Background: Recent studies demonstrating the ability of drugs such as Rezatapopt to target the TP53 Y220C mutation motivated us to assess the TP53 mutation landscape in clinically advanced breast cancer (CABC). Methods: FFPE blocks of 23,760 CABC were analyzed by hybrid capture-based comprehensive genomic profiling that evaluated broad types of genomic alterations (GA) including mutations, amplifications, deletions, and fusions. MSI-high (MSI-H) status, tumor mutational burden (TMB), genomic ancestry, mutational signature, and homologous recombination deficiency signature (HRDsig) were determined from sequencing data. PD-L1 expression was determined by IHC (Dako 22C3, TPS scoring system). GA were compared using Fisher’s exact test with the Benjamini-Hochberg multiplicity adjustment. Results: Among analyzed cases of CABC, 12,653 (53%) had TP53 GA and 254 (1.1%) were the Y220C mutation. When compared with TP53 wild type (wt) cases, TP53 GA group were younger (56 vs 60 years; p &lt; .0001) and had a higher median GA (6 vs 5; p &lt; .0001). Both TP53 Y220C group (15.7% vs 11.2%; not significant [NS]) and TP53 non-Y220C group (18.3% vs 11.2%; p &lt; .0001) were more frequently of African genetic ancestry than TP53 wt group. The TP53 non-Y220C had significantly less European ( TP53 non-Y220C: 65.2% vs 74.7%; p &lt; .0001) genetic ancestries. MSI-H was rare in all groups, but slightly higher in TP53 Y220C than TP53 wt cases (1.7% vs 0.3%; p = .036). Median TMB was low for all groups (range 2.41-2.61; NS). An APOBEC genomic signature was more common in TP53 non-Y220C mutant than TP53 wt (6.2% vs 5.0%; p = .0002) but not in TP53 Y220C (4.3% vs 5.0%; NS). GA more frequent in TP53 Y220C and non-Y220C groups versus TP53 wt included BRCA1 , ERBB2 , PTEN, and RB1 . GA more frequent in the TP53 wt group included BRCA2 , CCND1 , CDH1 , ESR1, and PIK3CA . More TP53 Y220C than TP53 non-Y220C mutant cancers had CDH1 mutations (6.3% vs 2.8%; NS) suggesting the Y220C GA may be more frequent in lobular carcinomas. Conclusions: TP53 Y220C is a relatively rare event in CABC. The TP53 mutant group was associated with GA in tumor suppressor genes, including BRCA1 , PTEN , and RB1, whereas the TP53 wt group was associated with GA in pathways associated with endocrine resistance, including PIK3CA and ESR1. TP53 wt (N=11107) Y220Cmut (N=254) P-value † TP53 wt (N=11107) TP53 non-Y220Cmut (N=12399) P-value † TP53 Y220Cmut (N=254) TP53 non-Y220Cmut (N=12399) P-value † BRCA1 1.4% 7.5% &lt;.0001 1.4% 6.0% &lt;.0001 7.5% 6.0% NS BRCA2 5.2% 4.7% NS 5.2% 3.6% &lt;.0001 4.7% 3.6% NS CCND1 24.3% 7.5% &lt;.0001 24.3% 11.3% &lt;.0001 7.5% 11.3% NS CDH1 23.8% 2.8% &lt;.0001 23.8% 6.3% &lt;.0001 2.8% 6.3% NS ERBB2 10.1% 16.5% 0.003 10.1% 13.5% &lt;.0001 16.5% 13.5% NS ESR1 11.5% 3.1% &lt;.0001 11.5% 4.2% &lt;.0001 3.1% 4.2% NS PIK3CA 44.3% 23.6% &lt;.0001 44.3% 28.2% &lt;.0001 23.6% 28.2% NS PTEN 9.4% 18.9% &lt;.0001 9.4% 15.4% &lt;.0001 18.9% 15.4% NS RB1 2.6% 10.6% &lt;.0001 2.6% 11.8% &lt;.0001 10.6% 11.8% NS †Benjamini/Hochberg adjustment.