SSAT - CLINICAL AND MOLECULAR FEATURES OF YOUNG-ONSET INTRAHEPATIC CHOLANGIOCARCINOMA: A MULTI-INSTITUTIONAL ANALYSIS

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CLINICAL AND MOLECULAR FEATURES OF YOUNG-ONSET INTRAHEPATIC CHOLANGIOCARCINOMA: A MULTI-INSTITUTIONAL ANALYSIS
Adriana C. Gamboa^*¹, Elena Panettieri¹, Yun Shin Chun¹, Ashton A. Connor³, Milind Javle², Timothy E. Newhook¹, Shubham Pant², Hop S. Tran Cao¹, Ching-Wei D. Tzeng¹, Jean-Nicolas Vauthey¹
¹The University of Texas MD Anderson Cancer Center Division of Surgery, Houston, TX; ²The University of Texas MD Anderson Cancer Center Gastrointestinal Cancer Center, Houston, TX; ³Houston Methodist, Houston, TX

Background
Similar to other gastrointestinal cancers, the incidence of young-onset intrahepatic cholangiocarcinoma(YO-iCCA) has been increasing over the past two decades. However, data regarding prognostic factors and clinical outcomes for this population remain scarce and inconsistent.
Methods
Patients undergoing curative-intent hepatectomy for iCCA were retrospectively identified using a multi-institutional database(2000-2023). Patients were categorized by age at disease onset as YO-iCCA(?50 yrs) or AO (average-onset)-iCCA(>50 yrs). Clinicopathologic and molecular characteristics were compared between cohorts. Primary outcomes were recurrence-free survival(RFS) and overall survival(OS).
Results
Among 781 patients, 10.7% were categorized as YO-iCCA(n=84). Incidence of obesity and metabolic syndrome were similar between YO-iCCA and AO-iCCA(21.4 vs 20.8%, p=1.0; 8.3 vs 16.5%, p=0.07, respectively). Despite comparable median CA19-9 level at presentation(26.9 vs 44.6 U/mL, p=0.23), young patients were more likely to undergo systemic therapy, both as neoadjuvant(36.9 vs 18.8%, p<0.01) and adjuvant treatment(59.2 vs 43.5%, p=0.01). Pathologic analysis revealed similar incidence of node-positive disease(38.2 vs 29.4%, p=0.18), lymphovascular invasion (59 vs 51%, p=0.23), and R0 margin status(67.9 vs 67.1%, p=0.19), but a trend towards more multifocal disease in the YO-iCCA cohort (31.7 vs 22.7%, p=0.09).
Molecular profiling was obtained in 27.1%(n=212; 35.7% YO-iCCA vs 26.1% AO-iCCA). Both cohorts exhibited similar frequencies of mutations in genes implicated as oncogenic drivers such as KRAS(22.6 vs 13.7%, p=0.27), IDH1(26.7 vs 25.1%, p=0.96), and ARID1A(14.3 vs 13.8%, p=1.0). However, younger patients had a higher frequency of FGFR mutations(27.6 vs 6.3%, p<0.01), whereas TP53 mutations were more common in the older cohort, though this difference was not statistically significant(3.4 vs 14.9%, p=0.14).
Patients with YO-iCCA had worse median RFS compared with patients with AO-iCCA(11.1 vs 17.2 mos; p<0.01; FIG1A). However, these findings did not translate to worse OS which was similar between the groups(39.4 vs 41.4 mos; p=0.79; FIG1B). Young onset remained independently associated with RFS(HR 1.99, 95%CI 1.15-3.48, p=0.01) after accounting for prognostic factors including receipt of neoadjuvant or adjuvant chemotherapy, FGFR mutation, tumor size, N-stage, and multifocality.
Conclusion
In this multi-institution study, patients with YO-iCCA had worse RFS compared to AO-iCCA, a difference not solely attributable to known clinicopathologic or molecular factors. However, higher recurrence rate did not translate to worse OS possibly due to their likelihood of being successfully treated with salvage therapies. Future studies utilizing modern molecular panels are needed to better identify a potentially targetable genomic signature in young patients.

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