Clinical characteristics and management of Li-Fraumeni syndrome-associated lung cancer

Li-Fraumeni syndrome (LFS), caused by pathogenic germline TP53 variants, is increasingly recognized as a predisposition to lung adenocarcinoma (LUAD); however, its clinical features remain insufficiently defined. Patients diagnosed with LFS at our institution between 2000 and 2025 were retrospectively reviewed, and five patients with primary LUAD were identified among 32 individuals with LFS. The median age at diagnosis was 34 years (range, 29-53 years), and four patients had never smoked. Three patients had a family history of lung cancer, and three had multiple synchronous lung lesions. Notably, activating EGFR alterations were identified in all four tested cases. The clinical course was heterogeneous: one patient with advanced disease achieved ongoing disease control with lazertinib plus amivantamab, whereas another patient achieved prolonged benefit from sequential EGFR tyrosine kinase inhibitors, with 34 months on gefitinib and 51 months on osimertinib after the acquisition of EGFR T790M. In contrast, surveillance of a patient with previously recognized LFS led to the detection of two early-stage lung cancers, followed by curative-intent surgery and a favorable postoperative course. Two of the five patients did not fulfill the 2015 Chompret criteria. These exploratory findings suggest that LFS-associated LUAD may be under-recognized and characterized by early-onset presentation and never-smoking status, multifocal disease, and frequent EGFR alterations, warranting validation in larger cohorts.