Intrahepatic cholangiocarcinoma: Recurrence patterns, genomics and survival.
Authors: Chandra Pratik , Song Yi , Drill Esther N. , Wei Alice Chia-Chi , Kemeny Nancy E. , Cercek Andrea , Connell Louise Catherine , Harding James J. , Abou-Alfa Ghassan K. , Park Wungki , Kingham T. Peter , Soares Kevin , Balachandran Vinod P. , Drebin Jeffrey A. , D'Angelica Michael Ian , O'Reilly Eileen Mary , Groot Koerkamp Bas , Jarnagin William R. 
Published: January 2024

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Background: Recurrence is common after resection of intrahepatic cholangiocarcinoma (IHC) but how recurrence patterns impact survival remains unclear. This study investigated the clinicopathologic and genomic factors associated with site of first recurrence and their impact on outcome after curative intent resection. Methods: Patients who underwent curative intent hepatectomy for IHC at two medical centers (MSKCC and EMC) with complete follow up and tumor genomic data were included. Documented sites of first disease recurrence were classified as liver only (LO), extrahepatic (EH) only or simultaneous liver and extrahepatic (SIM). Time to recurrence (TTR) and recurrence-free (RFS) were calculated from time of resection while OS was calculated from time of recurrence. Primary tumors underwent targeted next generation sequencing. Clinical, histopathologic and genomic factors associated with site(s) of recurrence, RFS and OS were assessed. Results: A total of 318 patients (n=296 MSK, n=22 EMC) treated between 1993 and 2021 met inclusion criteria and were analyzed; 232 patients (73%) developed recurrence. TTR was 11 (9.8, 12) months; OS and RFS was 26 (20, 33) and 14 (13, 18) months, respectively, among patients that recurred. Sites of first recurrence were LO 93 (40%), EH 80 (34%) and SIM 59 (26%). Median OS was similar in the LO (33 [26,42] months) and EH groups (33 [23,46] months) but much lower in SIM (12 [9.8,18] months) (p < 0.001). Moderate/poor tumor differentiation (p = 0.004), LVI (p = 0.004), N1 disease (p = 0.003), and PNI (p = 0.012) were associated with SIM; only positive resection margin predicted LO (p = 0.007). No individual genomic or pathway alterations predicted site of initial recurrence; however, for all patients, TP53 mut (HR 2.01, 1.4-2.9; p < 0.001), CDKN2A del (HR 1.96, 1.29-2.98; p = 0.003), CDKN2B del (HR 3.2, 2.03-5.05; p < 0.001) and KRAS mut (HR 2.49, 1.56-3.96; p < 0.001) were associated with worse survival. On multivariable analysis, SIM (HR 2.23, 1.49-3.34; p < 0.001), clinical stage III (HR 1.94, 1.26-2.99; p = 0.011), and alterations in TP53 (HR 2.07, 1.4-3.07; p < 0.001), CDKN2B (HR 4.1, 2.53-6.63; p < 0.001) and KRAS (HR 2.72, 1.68-4.43; p < 0.001) were independent predictors of worse OS. Of note, 13 LO patients were treated with regional chemotherapy after recurrence, with an associated median OS of 49 (33, NR) months compared to 28 (20, 39) months in the 80 patients treated with systemic therapy alone. Conclusions: Recurrence after resection of IHC was common, and the liver was the single most common site (66%). Clinicopathologic and genomic variables had limited ability to predict site of first recurrence. While LO and EH were associated with similar OS, simultaneous recurrences were dramatically worse. The data support adjuvant strategies targeting liver recurrence to improve outcome after resection of IHC.