Early-onset biliary tract cancers: clinical and molecular insights

The incidence of early-onset biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder adenocarcinoma, is rising, but factors underlying this trend remain unclear.

We conducted a retrospective study of BTC patients across three Mayo Clinic sites (2008-2024). Patients were categorized as early-onset (aged <50 years) or older-onset (aged ≥50 years). Clinical characteristics, comorbidities, molecular alterations, treatment patterns, and survival outcomes were compared between groups.

A total of 549 patients were included; 170 were enriched for early-onset cases, compared with a cohort of older-onset patients (n = 379) identified through the TEMPUS registry. Compared with older-onset patients [median age 68.0 years, interquartile range (IQR) 60.4, 73.0], early-onset patients (median age 40.5 years, IQR 34.5, 45.1) had significantly fewer metabolic comorbidities, higher frequency of FGFR2 alteration (18.8% versus 6.3%, P < 0.001) and lower frequency of KRAS alteration (15.3% versus 23.0%, P = 0.040). Tumor mutational burden was modestly lower in early-onset disease (3.0 versus 3.7 mutations/megabase, P = 0.003). Early-onset patients were more likely to enroll in clinical trials (25.9% versus 14.0%, P < 0.001) and received more lines of therapy (P = 0.005). Overall survival did not differ significantly between age groups. Among patients receiving first-line gemcitabine-cisplatin with immune checkpoint inhibition, progression-free survival was similar between early-onset and older-onset disease (7.6 versus 6.6 months; hazard ratio, 1.12; P = 0.59).

Early-onset BTC demonstrated distinct clinical and molecular profiles, but survival outcomes remained comparable to older-onset BTC. These findings highlight the need for further research into specific oncogenic drivers and tailored therapeutic strategies.