ErbB Receptor Feedback Inhibitor 1 Mutation in Biliary Tract Cancers: Turning Resistance Into Response.

Abstract

<i>EGFR</i> alterations occur in a subset of biliary tract cancers (BTCs) and are often linked to disease progression and poor prognosis, yet targeted approaches remain underexplored. <i>ERRFI1</i>, encoding the epidermal growth factor receptor (EGFR) inhibitor MIG6, is mutated in various cancers, including BTC, representing a potential predictive biomarker. We investigated whether loss of <i>ERRFI1</i> function may enhance sensitivity to EGFR-targeted tyrosine kinase inhibitors (TKIs), presenting a potential therapeutic opportunity. This is a retrospective multicenter study of patients with BTC harboring <i>ERRFI1</i> alterations. Data were extracted from electronic health records following institutional approval. <i>ERRFI1</i> alterations were classified based on the alteration type, variant allele frequencies were documented, and coalterations were analyzed. Treatment outcomes including response, time to progression (TTP), overall survival (OS), safety profiles, and tumor marker kinetics were noted. Fourteen BTC patients with <i>ERRFI1</i> mutations were identified in our database; the median age was 50 years, 64% were males; all cases were intrahepatic cholangiocarcinomas. Common coalterations included <i>IDH1</i> (36%), <i>TP53</i> (29%), and <i>ARID1A</i> (29%). All patients received gemcitabine-cisplatin as first-line treatment, and 79% received immune checkpoint inhibitors. Eight patients (57%) received EGFR TKIs. Best responses to EGFR therapy included three partial responses (2 responses lasting >20 months), four stable diseases, and one progressive disease. The median TTP was 7 months (95% CI, 6 to 21 months). Treatment was well-tolerated: toxicities included rash (n = 2), transaminitis (n = 1), and diarrhea (n = 1). The median OS was 20 months (95% CI: 8-36 months); 50% remained alive at last follow-up. <i>ERRFI1</i> mutations represent actionable biomarkers in BTC, with EGFR-targeted therapy demonstrating meaningful clinical benefit in this heavily pretreated population. These findings support integration of <i>ERRFI1</i> testing into routine molecular profiling of BTC and other EGFR-driven malignancies.