Abstract 5367: Distinct molecular characteristics and treatment implications of <i>TP53</i> gain-of-function mutations in non-small cell lung cancer

Abstract Background: TP53 gain-of-function (GOF) effects lead to cellular responses beyond the capabilities of wild-type TP53 and are known to promote cancer progression and tumor growth. Clinical studies linked TP53 GOF mutations to poorer outcomes in high-methylated metastatic colorectal cancer and advanced pancreatic ductal adenocarcinoma, while their impact on lung cancer remains unclear. Methods: A total of 486 patients diagnosed with non-small cell lung cancer (NSCLC) with baseline DNA sequencing data were enrolled. Clinical and sequencing data from external two NSCLC cohorts treated with immunotherapy, one treated with ROS1 tyrosine kinase inhibitors, and one with histological data were analyzed to assess relationships between TP53 GOF mutations and immunotherapy efficacy, TKI efficacy, and histological transformation. The TP53 GOF mutations are defined by the “The TP53 Database” (https://tp53.cancer.gov/). Results: Among all patients, 98 are with TP53 GOF mutations (20.2%), 189 with TP53 other mutations (38.9%), and 199 with TP53 wild-type (40.9%). Compared to TP53 non-GOF mutations, patients with TP53 GOF mutations show higher mutation rates in PIK3CA (P = 0.010), STK11 (P = 0.026), and CTNNB1 (P = 0.020) but lower in NTRK1 (P = 0.018); increased VEGFA (P = 0.010) but decreased DLL3 (P = 0.036) and HRAS (P = 0.036) amplification rates; and more frequent PI3K (P = 0.026) and WNT (P = 0.040) pathway alterations. Patients with TP53 GOF mutations have significantly higher tumor mutation burdens (TMB) than those with other TP53 statuses (P &amp;lt; 0.001). Moreover, TP53-mutated patients, both with GOF and other mutations, show significantly higher expression of immune checkpoints, including CD274, PDCD1, PDCD1LG2, CTLA4, and LAG3, compared to TP53 wild-type patients. GOF-mutated patients also have higher M1 macrophage and CD8+ T cell infiltration, alongside elevated B cell receptor signaling, whereas patients with other TP53 mutations display greater expression of inflammatory pathways. Notably, the ratio of TP53 GOF mutations in TP53-mutated patients decreases with higher histological grades (lepidic vs. acinar/papillary vs. solid/micropapillary: 40.0% vs. 31.7% vs. 30.8%). For treatment efficacy, TP53 GOF mutations are associated to improved outcomes with immunotherapy (mPFS: 5.37 months in GOF mutations vs. 3.03 in wild-type vs. 4.27 in non-GOF mutations) but poorer prognosis with ROS1-TKIs (mPFS: 10.65 months in GOF mutations vs. 19.60 in wild-type vs. 4.95 in non-GOF mutations). Conclusions: This study demonstrates that TP53 GOF mutations are associated with poorer TKI efficacy but improved immunotherapy outcomes in NSCLC. Patients with TP53 GOF mutations also exhibit elevated immune activities and distinct molecular profiles, marked by higher TMB, VEGFA amplification rates, and mutation rates in PIK3CA and the PI3K pathway. Citation Format: Hanlin Chen, Haimeng Tang, Xue Wu, Qiuxiang Ou. Distinct molecular characteristics and treatment implications of TP53 gain-of-function mutations in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5367.