Clinical outcomes and cumulative cost of preventive surveillance versus treatment in Li–Fraumeni syndrome: Results from the European PREVENTABLE project.

10553 Background: Li-Fraumeni syndrome (LFS), caused by TP53 pathogenic variants, is one of the most severe hereditary cancer predisposition syndromes, characterized by very early cancer onset, broad tumor spectrum, and a high lifetime risk of multiple cancers. At the European level, no large-scale health economics study has compared LFS proactive cancer preventive management including intensive multiorgan surveillance and early cancer detection, with treatment approaches initiated after the first tumor occurs in individuals at high cancer risk. To address this gap, and within the European PREVENTABLE project, we evaluated healthcare pathways and cumulative costs of proactive prevention versus treatment in LFS European families. Methods: We retrospectively collected clinical data from 866 individuals from seven European countries (ERN GENTURIS centers), including 505 TP53 gene carriers (27% of whom were children) and 361 non-carrier family members. Based on multidisciplinary expertise, we developed a structured LFS care matrix, mapping patient clinical trajectories and clinical procedures across diagnosis, risk reduction strategies, surveillance and treatments. Costs were estimated using standardized French hospital tariffs, and data were collected via a GDPR-compliant digital tool interface developed by the PREVENTABLE consortium. Results: From 866 individuals, 155 were TP53 carriers without a prior cancer diagnosis at the time of genetic testing, defining the preventive arm. During follow-up (median 75 months; range 6–267), 20 individuals developed one or more cancers.The mean prevention cost per patient was €6,046.8 (range €451–€71,854.76). Among the 273 patients with a history of cancer prior to genetic testing, 109 had early-stage disease and 164 had advanced-stage disease (median follow-up 83 months; range 2–468). The mean treatment cost per patient was €53,906 (range €385.50–€440,760.93). Overall cumulative costs were €937,258 for prevention and €15,103,188 for treatment, including €5,245,915 for early-stage cancers and €9,857,273 for advanced-stage cancers. Preventive mastectomy was performed in 24% of women in either prevention or treatment groups. Conclusions: This first European cumulative cost analysis demonstrates that treatment costs for LFS far exceed prevention costs (9-fold), providing strong economic evidence in favor of early genetic diagnosis and preventive surveillance. These findings support public health decision-making and the harmonization of care pathways within the framework of precision medicine in Europe. Preventable is funded by the European Union (EU) under Grant nº 101095483.