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Multiomic Characterization of Early and Metastatic Biliary Tract Cancer (BTC)
ESMO GI 2025PRESENTATION
AuthorsNakul M. Shah, Jessica Symons, Brooke Rhead, Jacob Mercer, Quentin Kimana, Tejal Patel, Gentry King, Milind Javle
Background – Immunogenomic characterization between early and metastatic (met) BTC is limited, yet paramount for clinical trial strategies. We evaluated the immunogenome in BTC to inform trial designs in the perioperative and metastatic settings.
Methods – We selected de-identified BTC patients (pts) from the Tempus database sequenced by xT (DNA seq) and a subset with whole transcriptome analysis by xR (RNA-seq). Pts were stratified by stage: I-III (early) or IV (met) and subtype: intrahepatic (iCCA) n=1492, extrahepatic (eCCA), n=537 and gallbladder (GBC), n=912. Targetable driver alterations (dAlts) included SNVs/indels in IDH1 and KRAS; BRAF p.V600E variants; FGFR2, RET, and NTRK1-3 fusions (if present in ≥4% of pts); ERBB2 amps; or no dAlt. Immune cell (IC) proportions (%) were estimated by quanTIseq; TMB (mt/Mb) was analyzed. Significance (p<0.05) was assessed using ꭓ2 or Wilcoxon/Kruskal-Wallis rank sum.
Results – dAlt prevalences were similar between early and met within each subtype, except KRAS in GBC, 5.9 vs 11%, p=0.024. Significant differences in dAlt rates between iCCA, eCCA, and GBC included IDH1 (16%, 1.9%, 0.3%); KRAS (14%, 40%, 10%); FGFR2 fusions (12%, 1.3%, 1.6%); and ERBB2 (2.1%, 3.5%, 9.9%). In early and met iCCA, pts with FGFR2 fusions had the lowest % of CD8 T cells while pts without dAlt had the highest (early, pglobal=0.011, met, pglobal=0.003). Early eCCA and GBC had a higher % of adaptive and total IC vs early iCCA. Met GBC had the highest % of CD8 T cells and Tregs (Table). There was a higher % of adaptive and total IC in early vs met BTC (table, p<0.001, not including CD8 T cells and total IC in iCCA). Early and met GBC had the highest median TMB while iCCA had the lowest (Table).
Conclusions – The prevalence of dAlts was similar by BTC stages but differed by subtypes. The immunogenicity was unique between dAlt, BTC subtype and stage. Future trials should analyze how these immunogenomic findings impact the efficacy of targeted and immunotherapy across BTC stages.