Abstract Background: Fibrolamellar carcinoma (FLC) is a rare and aggressive primary liver cancer that primarily affects adolescents and young adults. It is biologically distinct from other forms of primary liver cancer, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). There are no standard or approved systemic therapies for advanced FLC, and most patients present with unresectable disease or experience recurrence after surgery. These factors underscore the need for new therapeutic approaches. Antibody-drug conjugates (ADCs) have shown efficacy in several solid tumors by delivering cytotoxic payloads to tumor-associated surface antigens with improved specificity, but their utility in FLC is not known. To evaluate the relevance of ADC-based therapies in FLC, we assessed the expression of five clinically actionable ADC targets (NECTIN4, TROP2, CLDN18.2, HER2, and B7-H3) in an expanded cohort of FLC specimens. Methods: Archival FFPE samples were obtained from consented patients through the Johns Hopkins Liver Cancer Tissue Bank and the Fibrolamellar Cancer Foundation, including FLC tumors (n=58; 38 primary and 20 metastatic lesions). Immunohistochemistry (IHC) was performed for all five markers. Expression patterns of interest in FLC were compared with control cohorts of HCC (n=10) and CCA (n=10). Three pathologists, blinded to clinical data, independently scored staining using both a 0 to 3 plus ordinal IHC scale and a semi-quantitative H-score. Results: Among the five ADC targets evaluated, only B7-H3 and HER2 showed detectable staining in FLC. NECTIN4, TROP2, and CLDN18.2 were uniformly negative, scored as 0+ in all tumors, and had H-scores of 0. B7-H3 demonstrated the strongest expression. 3+ staining was observed in 20 of 58 tumors (34.5%). Tumor-cell H-scores ranged from 10 to 240, with a mean of 132. B7-H3 was also expressed in the tumor microenvironment, with prominent staining in cancer-associated stroma and fibroblasts. Stromal H-scores ranged from 40 to 300, with a mean of 199, often exceeding tumor-cell expression. HER2 showed detectable 3+ staining in 12 of 58 tumors (21.7%), with H-scores ranging from 2 to 270 and a mean of 70. One patient in this cohort with 3+ HER2 expression received fam-trastuzumab deruxtecan-nxki, and experienced a durable partial response lasting approximately one year. Conclusions: B7-H3 and HER2 are promising ADC targets in FLC. While a subset of patients may already be eligible for fam-trastuzumab deruxtecan-nxki under its tumor-agnostic indication, B7-H3 shows particularly strong and widespread expression across both tumor and stromal compartments. These findings support further preclinical and clinical evaluation of B7-H3- and HER2-directed ADCs as targeted treatment strategies for advanced FLC. Citation Format: Waqar Arif, Elsa Hallab, Franshisca Hayek, Howard Liu Li, Mari Nakazawa, Mark E. Furth, Andrew S. Liss, Patricia Cogswell, Ezra G. Baraban, Jacqueline Birkness-Gartman, Marina Baretti, Robert A. Anders, Mark Yarchoan. Profiling the expression of antibody-drug conjugates in fibrolamellar hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2456.
Arif et al. (Fri,) studied this question.