Clinical and genomic characterization of biliary tract tumors (BTT) with ARID1A mutations: A case-control study

Introduction: ARID1A is a tumor suppressor gene involved in chromatin remodeling and is commonly mutated across several cancer types. In biliary tract cancer (BTC), the clinical and genomic landscape of ARID1A mutations remains poorly defined. This study aims to characterize the demographic, clinical, and molecular features of patients (pts) with ARID1A-mutated (ARID1A-mut) BTC compared with a control cohort harboring wild-type (ARID1A-wt) ARID1A. Methods: From a consecutive retrospective cohort of 146 pts with molecularly profiled BTC, 14 (9.6%) exhibited pathogenic ARID1A mutations. Of these, 13 (8.9%) with available clinical data were compared to a randomly selected group of 13 ARID1A-wt controls. The study was approved by the local ethics committeee. Resuls Out of 146 patients screened, total of 27 were found eligible: 14 ARID1A-mut and 13 ARID1A-wt. ARID1A-mut pts (vs ARID1A-wt) were predominantly female (77% vs 46%; p=0.23). Median age was 64 years. Primary tumor distribution was intrahepatic (76.9%), hilar (15.4%), and gallbladder (7.7%) (p=1). Disease stage at diagnosis, performance status, and first-line (1L) treatment regimens were comparable across both cohorts. ARID1A-mut pts showed a trend toward higher partial response (PR) rates to 1L therapy (53.9% vs 30.1%; p=0.43). Median progression-free survival (PFS) on 1L treatment was similar (11.4 vs 9.3 months; HR 0.67, 95% CI 0.29-1.57; p=0.36), as was overall survival (OS) (21.4 vs 22.5 months; HR 1.47, 95% CI 0.51-4.28; p=0.48). Genomic profiling revealed a distinct co-alteration pattern: BAP1 (28.6% vs 0%; p=0.09), IDH1 (21.4% vs 0%; p=0.22), and PBRM1 (28.6% vs 7.7%; p=0.33) were more frequent in ARID1A-mut pts, whereas TP53 (38.5% vs 28.6%; p=0.69), KRAS (30.8% vs 16.7%; p=0.38), and DNMT3A (23.1% vs 0%; p=0.09) predominated in the ARID1A-WT cohort. Conclusion: BTC with ARID1A mutations represents a distinct molecular subgroup characterized by a trend toward improved partial response and enrichment in epigenetic co-alterations. Prospective validation is warranted to assess the prognostic and therapeutic implications. Targeted therapeutic strategies against ARID1A in BTC should be further explored in early-phase (I/II) clinical trials.