Biliary tract cancers remain difficult to treat after progression on first-line therapy. Although molecular profiling has expanded treatment options for selected patients, many cases still lack clear actionable targets, highlighting the need for additional biomarkers.
A new retrospective multicenter study evaluated whether alterations in ERRFI1, a gene involved in EGFR pathway regulation, may help identify patients with biliary tract cancer who could benefit from EGFR-targeted therapy.
The original article, titled “ErbB Receptor Feedback Inhibitor 1 Mutation in Biliary Tract Cancers: Turning Resistance Into Response,” was published in JCO Precision Oncology on June 3, 2026.
Authors: Supriya Peshin, Fen Saj, Pashtoon M. Kasi, Felicity David, Janio Szklaruk, Quentin Kimana, Shubham Pant, Sunyoung S. Lee, Jennifer J. Knox, Mitesh J. Borad, and Milind Javle.
Read more about Bile Duct Cancer Cure Rate on OncoDaily.
Why ERRFI1 Matters
ERRFI1 encodes MIG6, a negative regulator of EGFR signaling. Loss of ERRFI1 function may reduce this feedback inhibition and lead to sustained EGFR pathway activity. In biliary tract cancers, EGFR-targeted therapy has not shown clear benefit in unselected populations. However, ERRFI1-mutant tumors may represent a biologically distinct group in which EGFR inhibition could be more relevant.
Study Design
This retrospective case series included patients with histologically confirmed biliary tract cancer harboring ERRFI1 alterations. Patients were treated at MD Anderson Cancer Center, City of Hope, and Mayo Clinic between January 2015 and February 2025.
The study collected clinical characteristics, ERRFI1 alteration type, variant allele frequencies, co-alterations, systemic treatments, response to EGFR tyrosine kinase inhibitors, time to progression, overall survival, safety, and available tumor marker or ctDNA dynamics.
A total of 14 patients were included. The median age was 50 years, 64% were male, and all patients had intrahepatic cholangiocarcinoma. Eight patients presented with localized disease, while six had metastatic disease at diagnosis. ERRFI1 mutations were rare. In the MD Anderson Cancer Center institutional database, the reported prevalence was 0.59%, with 12 cases among 2,049 patients with biliary tract cancer.
Molecular Findings
All 14 patients had ERRFI1 alterations. Ten patients had loss-of-function variants, two had missense mutations, and two had insufficient data to classify the variant type. Common co-alterations included IDH1 in 36%, TP53 in 29%, ARID1A in 29%, and PBRM1 in 21% of patients.
Treatment and Outcomes
All patients received gemcitabine and cisplatin as first-line therapy for metastatic disease, and 11 patients, or 79%, received immune checkpoint inhibitors. Eight patients received EGFR tyrosine kinase inhibitors. All eight patients treated with EGFR-targeted therapy received erlotinib 150 mg once daily. Two patients also received afatinib 40 mg once daily. Among the eight patients treated with EGFR tyrosine kinase inhibitors, the best responses were three partial responses, four stable diseases, and one progressive disease.
This means seven of eight patients achieved disease control with EGFR-directed therapy. Among the seven patients who achieved disease stability or response with EGFR TKI therapy, the median time to progression was 7 months, with a 95% confidence interval of 6 to 21 months. The median overall survival for the full ERRFI1-mutated cohort was 20 months, with a 95% confidence interval of 8 to 36 months. Among patients who received erlotinib, median overall survival was 34 months, with a 95% confidence interval of 17 to 47 months, compared with 18 months, with a 95% confidence interval of 9 to 30 months, among those who did not receive erlotinib.
Nine patients, or 64%, underwent surgery, and eight patients, or 57%, received radiotherapy. In addition to EGFR-targeted therapy, three patients received ivosidenib for IDH1 mutations, and one patient received pemigatinib for an FGFR2 fusion.
Some patients had notably prolonged benefit. One patient achieved a 21-month partial response to erlotinib. Another maintained stable disease for 29 months across sequential EGFR inhibitors, erlotinib followed by afatinib. A heavily pretreated patient with chemorefractory disease achieved a partial response lasting 7 months, with ctDNA showing a decline in ERRFI1 variant allele frequency from 21.0% to 3.3% during response. At progression, acquired resistance mechanisms included MET amplification and DTD1-BRAF fusion in one patient, and an EGFR M766I resistance mutation in another patient.
Safety
EGFR-targeted treatment was generally well tolerated. Reported toxicities included rash in two patients, liver enzyme elevation in one patient, and diarrhea in one patient. Only one patient discontinued treatment because of intolerable diarrhea.
Takeaway
This retrospective case series suggests that ERRFI1 mutations may define a rare but actionable molecular subset of biliary tract cancers. In heavily pretreated patients with ERRFI1-mutant intrahepatic cholangiocarcinoma, EGFR-targeted therapy showed clinically meaningful activity, including partial responses and prolonged stable disease.
The findings support the inclusion of ERRFI1 in routine molecular profiling for biliary tract cancers and highlight the need for broader collaborative efforts, molecular tumor boards, and basket-style approaches to better define treatment strategies for this rare subgroup.