Extrahepatic cholangiocarcinoma: Genomic variables associated with anatomical location and outcome.

Abstract

554 Background: Genomic determinants of outcome in intrahepatic cholangiocarcinoma have become clear but remain ill-defined in extrahepatic cholangiocarcinoma (ECA). We aimed to clarify the genomic alterations that define ECA, analyze differences between perihilar (PCA) and distal (DCA) disease, and determine clinicopathologic and genomic factors associated with survival. Methods: Patients with EHC with tissue available for targeted next-generation sequencing at Memorial Sloan Kettering Cancer Center were identified. Differences between PCA and DCA were compared, stratified by disease extent and treatment. Associations between genomic alterations and clinicopathologic features and outcomes were analyzed. Univariable and then multivariable cox proportional hazards regression were used to compare survival, which was reported from operation in resected patients and from diagnosis in non-resected patients. Results: Two-hundred-twenty-four patients (n=127 PCA, n=97 DCA, 2006-2022) met inclusion criteria. Median survival was 29 months (IQR [25, 35]; 43 months [35, 48] resection, 17 months [13, 19] without). Compared to PCA, DCA was enriched in TP53mut (67 [69%] vs. 42 [33%]), Q<0.01) and epigenetic pathway alterations (44 [45%] vs. 37 [29%], Q=0.041) and had more altered pathways (3 vs. 2, Q<0.01). KRASmut was similar between PCA (46 [36%]) and DCA (36 [37%]); however, PCA was enriched in KRAS G12V (16 [13%] vs. 4 [4%]) and Q61H (11 [9%] vs. 3 [3%], P=0.002). No other clinicopathologic or genomic variables distinguished PCA from DCA (Table). MDM2mut occurred in 19/141 (13%) patients with nodal/metastatic disease compared to 1/83 (1%) patients with local disease ( Q=0.03), but conferred no survival disadvantage. In resected patients, survival was similar between PCA and DCA and no genomic alterations were associated with outcome. By contrast, in patients without surgery, CDKN2Adel (HR 2.59, 95% CI [1.48, 4.52]) and APCmut (HR 5.11, 95% CI [1.96, 13.3]) were associated with survival disadvantages. Lack of resection (HR 3.13, 95% CI [2.25, 4.36]), CDKN2Amut (HR 1.80 [95% CI 1.80, 2.68), and APCmut (HR 2.00 [95% CI 1.04, 3.87]) were associated with poor survival in the entire cohort. Conclusions: In this study, aside from a higher incidence of TP53mut in DCA and some differences in KRAS subtype alteration patterns, genomic alterations were comparable between PCA and DCA. CDKN2Amut and APCmut were associated with poor survival in all patients but no biomarkers provided significant prognostic information when tumors were resected. [Table: see text]