Fibrolamellar Carcinoma in the Molecular Era: From DNAJB1::PRKACA Biology to Precision Therapeutic Strategies.

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.