Single-center retrospective review of 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 prediposition to lung adenocarcinoma (LUAD); however, it s clinical features are insufficiently defined. A retrospective review of patients at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (Tokyo) between 2000 and 2025 found five patients with primary LUAD among 32 individuals with LFS. The median age at diagnosis was 34 years (range 29-53), and four patients had never smoked. Three patients had a family history of lung cancer, and three had multiple synchronic lung lesions. Activating EGFR alterations were identified in all four tested cases. The clinical course was heterogeneous: one patients 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 patients 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. The authors conclude that 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.