E197: Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics and Survival

The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined. This study investigated the clinicopathologic and genomic factors associated with site of first recurrence and the impact on outcome after complete resection.

Methods:

Patients who underwent resection for IHC at two medical centers (MSKCC and EMC) with complete follow up and tumor genomic data were included. Sites of first 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. Clinical, histopathologic and genomic factors associated with site(s) of recurrence, RFS and OS were assessed.

Results:

318 patients (n=296 MSK, n=22 EMC) treated between 1993 and 2021 met inclusion criteria; 232 (73%) recurred. Median TTR was 11 (9.8, 12) months; OS and RFS was 26 (20, 33) and 14 (13, 18) months, respectively, among those 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 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, TP53mut (HR 2.01, 1.4-2.9; p < 0.001), CDKN2Adel (HR 1.96, 1.29-2.98; p = 0.003), CDKN2Bdel (HR 3.2, 2.03-5.05; p < 0.001) and KRASmut (HR 2.49, 1.56-3.96; p < 0.001) were associated with worse OS. 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 (17, 39) months in the 74 patients treated with systemic therapy alone.

Conclusions:

Recurrence after resection of IHC was common, and the liver was the most common site (66%). Clinicopathologic and genomic factors 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.