Fibrolamellar Carcinoma in the Molecular Era: From DNAJB1::PRKACA Biology to Precision Therapeutic Strategies.
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PURPOSE: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of adolescents and young adults that arises in a non-cirrhotic liver and was long treated as a variant of hepatocellular carcinoma (HCC). The 2014 discovery of the recurrent DNAJB1::PRKACA gene fusion as a near-universal event reframed FLC as a distinct, fusion-driven malignancy with specific diagnostic and therapeutic consequences. This review focuses on advances in systemic and precision therapies for FLC. METHODS: PubMed/MEDLINE and ClinicalTrials.gov were searched from inception through 16 September 2026 to inform a narrative synthesis of clinical and translational evidence on systemic and precision therapies for FLC. RESULTS: Molecular and functional studies establish DNAJB1::PRKACA as the defining oncogenic driver of FLC, while alternative PKA-activating lesions broaden its molecular spectrum. Surgery remains the cornerstone of curative-intent treatment, but frequent recurrence and the absence of effective adjuvant therapy underscore the need for systemic strategies. Available systemic treatments are supported predominantly by small, non-randomized studies, with no established comparative superiority. Fusion-directed immunotherapy has provided early clinical proof of concept: a phase 1 trial of a fusion peptide vaccine combined with nivolumab and ipilimumab reported an objective response rate of 19%, with fusion-specific T-cell responses in 9 of 12 patients completing the priming phase. These findings support further investigation, although the contribution of vaccination cannot be separated from that of checkpoint blockade. CONCLUSION: The molecular characterization of FLC has established a rationale for fusion-directed therapeutic development. Current care should integrate molecular confirmation, multidisciplinary management, and early clinical trial referral, consistent with the 2026 guideline.