Clinical determinants of survival and a predictive immune biomarker for immunotherapy in fibrolamellar carcinoma: A comprehensive institutional analysis.

Abstract

552 Background: Fibrolamellar carcinoma (FLC) is a rare liver malignancy primarily in adolescents / young adults with limited therapeutic options. We analyzed clinical outcomes and genomic data and investigated tumor microenvironment (TME) to identify immunotherapy response markers. Methods: This is a retrospective review of 165 patients (pts) treated between 1992 and 2024. mRNA-seq was performed in 8 patients treated with immunotherapy. 15 immune gene signatures, through unsupervised clustering, revealed 2 dominant phenotypes: T-cell/Myeloid-Infiltrated (TMI) or Immune-Desert (ID). PFS/OS was correlated with TME via Kaplan-Meier and Log-rank test. Results: Out of 165 pts (median age 23, 48% F), 75% presented with stage III-IV. Adverse prognosticators included advanced stage, macrovascular invasion, and nodal metastasis. Surgery (liver resection and/or metastasectomy) is associated with improved survival (mOS 65.2 vs 19.7 m, p<0.001). Our institutional genomic analysis revealed low TMB (median 1.2 mut/Mb) and MSS. A separate genomic cohort (n=68) from FMI (no survival outcome data) showed mutations beyond DNAJB1-PRKACA fusion as Table1. In the immunotherapy cohort with available mRNA data, TMI phenotype (n=5) was associated with significantly longer PFS than ID phenotype (n=3), with mPFS of not reached vs. 4.3 m (p=0.008). Disease control rate was 100% for TMI group (2 PR, 3 SD) versus 0% for ID group on immunotherapy. Analysis of TME evolution in paired pre- and post-treatment biopsies from 2 exceptional responders revealed a marked on-treatment increase in key effector and helper immune cell signatures including T-cells (+34%), cytotoxic cells (+33%), Th1 cells (+37%), and B-cells (+44%). Compared to a pan-cancer cohort (TCGA), FLC tumors showed elevated expression of angiogenesis genes (VEGFA/B/C, KDR, FLT1/4) and ADC targets with GPC3 and CEACAM5 expression being over 3-fold higher than the pan-cancer average; no pts met criteria for high ERBB2 expression (log2(TPM+1) > 8.5). Conclusions: While surgical management including metastasectomy remains the cornerstone of FLC treatment, TME is a predictive biomarker for immunotherapy. The unique molecular landscape with high expression of angiogenesis factors and ADC targets suggests that rational combination therapies are needed to overcome resistance in Immune-Desert tumors. Immune gene signatures B-cells, CD45, CD8 T cells, Cytotoxic cells, DC (Dendritic Cells), Exhausted CD8, Macrophages, Mast cells, NK cells, Neutrophils, T-cells, TFH (T follicular helper cells), Th1 cells, Th2 cells, Treg (Regulatory T cells) Genomic alterations (n=68) TERT 17.7% (MD Anderson 11%), CDKN2A/B 11.8%, MYC 5.9%, LYN 4.4%, CTNNB1 4.4%, TP53 4.4% Immunotherapy Atezolizumab + bevacizumab (n=1); 5-fluorouracil + Interferon-a2 + nivolumab (n=7) ADC, antibody-drug conjugate.