Extrahepatic Cholangiocarcinoma: Genomic Variables Associated With Anatomic Location and Outcome.

Abstract

This study aimed to define genomic differences between perihilar cholangiocarcinoma (PCA) and distal cholangiocarcinoma (DCA) and identify genomic determinants of survival. Consecutive patients with ECA with tissue for targeted next-generation sequencing were analyzed, stratified by anatomic site (PCA/DCA), disease extent, and treatment. Associations between genomic alterations, clinicopathologic features, and outcomes were analyzed using Cox proportional hazards regression to compare survival. In total, 224 patients diagnosed between 2004 and 2022 (n = 127 PCA; n = 97 DCA) met inclusion criteria. The median survival was 29 months (43 after resection and 17 from diagnosis for unresectable disease). Compared with PCA, DCA was enriched in <i>TP53alt</i> (alterations; 69% <i>v</i> 33%; <i>Q</i> < 0.01), epigenetic pathway alterations (45% <i>v</i> 29%; <i>Q</i> = 0.041), and had more total altered pathways (median 3 <i>v</i> 2; <i>Q</i> < 0.01). <i>KRASalt</i> frequency was similar between PCA (36%) and DCA (37%); however, DCA was enriched in <i>KRAS</i> G12D (19% <i>v</i> 9%; <i>P = .002</i>). No other clinicopathologic or genomic variables distinguished subtypes. In resected patients, no genomic alterations were associated with outcome. However, in unresectable patients, <i>CDKN2Aalt</i> (hazard ratio [HR], 2.59 [1.48 to 4.52]) and <i>APCalt</i> (HR, 5.11 [1.96 to 13.3]) were associated with reduced survival. For the entire cohort, irresectability (HR, 3.13 [2.25 to 4.36]), <i>CDKN2Aalt</i> (HR, 1.80 [1.80 to 2.68]), and <i>APCalt</i> (HR, 2.00 [1.04 to 3.87]) were associated with poor survival. <i>CDKN2Aalt</i> and <i>APCalt</i> were associated with poor survival in ECA, primarily in advanced disease. As PCA and DCA were genetically similar, coanalysis of PCA and DCA in future genomic studies is reasonable.