Genomic landscape of <i>TP53</i> Y220C–mutated clinically advanced prostate carcinoma (CAPC).

Abstract

5044 Background: The TP53 Y220C base substitution mutation has become a significant therapeutic target with the development of reactivator drugs that restore TP53 function with a regulatory function in the cell cycle. However, its real-world prevalence and associated genomic landscape is not established in CAPC. Data on concurrent genomic alterations (GA) may guide the development of combinatorial therapeutic strategies. Methods: 26,156 cases of CAPC underwent hybrid capture-based comprehensive genomic profiling (CGP) to study all classes of GA including base substitutions, short insertions, deletions, copy number changes, rearrangements and fusions. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were determined from the sequencing data; comparisons utilized the Fisher Exact method. Results: 144 CAPC (0.6%) of CAPC cases featured TP53 Y220C mutation ( TP53 Y220C+). Patients with TP53 Y220C+ CAPC had slightly higher median age (70.0 vs 68.2; p = 0.020) and numerically lower frequency of TMPRSS2 GA (33.0% vs 39.4%; Not significant (NS)). GA potentially associated with CAPC primary hormonal-based therapy response more frequently found in TP53 Y220C+ cases included SPOP (10.5% vs 1.4%; p &lt; 0.0001) with AR GA (13.6% vs 11.3%; NS) being similar in both groups. GA linked to PARP inhibitor response slightly more frequent in TP53 Y220C+ cases included BRCA2 GA (8.7% vs 3.5%; p = 0.0003) and ATM GA (5.9% vs 4.2%; NS). GA in RAD21 were slightly higher in TP53 Y220C- CAPC (14.8% vs 8.3%; p = 0.029). GA in PIK3CA (6.6% vs 7.0%) and PTEN (32.4% vs 34.5%) were similar in the two groups. Biomarkers likely associated with benefit with anti-PD1/L1 agents were very low in both groups, included higher frequency of CDK12 GA (5.4% vs 0.7%; p &lt; 0.0001) in TP53 Y220C+ cases and higher frequencies of MSI-High status (2.7% vs 0.0%; p = 0.045), mean TMB (3.8 vs 2.1 mutations/Mb; p &lt; 0.0001) and TMB &gt; 10 mutations/MB (4.4% vs 0.0%; p = 0.010) in TP53 Y220C- cases. Conclusions: TP53 Y220C is a rare finding in CAPC, but it may offer a potential therapeutic avenue for these patients whose tumors feature such a mutation. In addition, TP53 Y220C+ cases appear to be genomically relatively distinct from TP53 Y220C- CAPC cases and may feature genomic signatures that could influence treatment selection and trial design. Study limitations include a retrospective, descriptive design, a lack of clinical data annotation, and selection and confounding biases, so our findings are hypothesis-generating. Selective GA in TP53 Y220C+ vs TP53 Y220C- in patients with CAPC. TP53 Y220C+ CAPC (144 cases) TP53 Y220C- CAPC (26,012 cases) P Value Median Age (yrs) 70 (46-89+) 68 (35-89+) TP53 (all) 100.0% 39.7% &lt;0.0001 TP53 (non-Y220C) 7.6% 39.7% &lt;0.0001 SPOP 10.5% 1.4% &lt;0.0001 BRCA2 8.7% 3.5% 0.0003 CDK12 5.4% 0.7% &lt;0.0001 APC 9.1% 4.2% 0.0004 MSI-High 0.0% 2.7% 0.045 Mean TMB 2.1 3.8 &lt;0.0001