Gefitinib-based therapy in refractory hepatocellular carcinoma with EGFR overexpression: a spatial profiling-guided...

Current systemic treatments for advanced hepatocellular carcinoma (HCC) such as antiangiogenic targeted therapies, immune checkpoint inhibitors (ICIs), and their combinations have shown benefit, but widespread drug resistance severely limits patient outcomes and underscores an urgent need for effective post-progression strategies. We herein present a case of a patient with advanced HCC who developed cutaneous, pulmonary, and lymphatic metastases following failure of multiple lines of tyrosine kinase inhibitors (TKIs) including donafenib and regorafenib, and lenvatinib plus anti-programmed death-1 (PD-1) monoclonal antibody (tislelizumab) alongside radiotherapy. Next-generation sequencing (NGS) of the primary liver surgical sample confirmed wild-type EGFR status without canonical driver mutations, whereas retrospective immunohistochemistry (IHC) and cyclic multiplexed tyramide signal amplification (CmTSA) of the cutaneous metastatic sample demonstrated EGFR protein overexpression. Subsequent spatial analysis demonstrated that EGFR-high tumor regions strongly correlated with hyper-proliferative Ki67+ tumor cells. Furthermore, this EGFR-high niche was spatially associated with an immunosuppressive microenvironment characterized by the infiltration of PD-L1+ myeloid cells, CD14+ monocytes, regulatory T cells (Tregs), and PD-L1+/IDO1+ tumor cells. Therefore, we formulated a spatial profiling-guided therapeutic hypothesis and added gefitinib to the prior regimen of lenvatinib plus tislelizumab concurrent with radiotherapy, achieving significant tumor regression despite subsequent intracranial progression. In conclusion, these findings suggest that spatial profiling offers valuable therapeutic insights, highlighting the potential benefit of an EGFR-targeted triplet strategy in refractory HCC with EGFR protein overexpression. While confounding effects from concurrent therapies cannot be excluded, this profiling-guided hypothesis warrants further prospective clinical and mechanistic validation.