Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics, and Survival

Pratik Chandra; Yi Song; Esther Drill; Alice C. Wei; Nancy Kemeny; Andrea Cercek; Louise Connell; James Harding; Ghassan Abou-Alfa; Wungki Park; T. Peter Kingham; Kevin Soares; Vinod Balachandran; Jeffrey Drebin; Michael D'Angelica; Eileen O'Reilly; Bas Groot Koerkamp; William R. Jarnagin

doi:10.1200/PO-25-00402

Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics, and Survival

Pratik Chandra
, Yi Song
, Esther Drill
, Alice C. Wei
, Nancy Kemeny
, Andrea Cercek
, Louise Connell
, James Harding
, Ghassan Abou-Alfa
, Wungki Park
, T. Peter Kingham
, Kevin Soares
, Vinod Balachandran
, Jeffrey Drebin
, Michael D'Angelica
, Eileen O'Reilly
, Bas Groot Koerkamp
, William R. Jarnagin^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE:

– The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes.

METHODS:

– Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence.

RESULTS:

– Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73%) recurred. SOFR were LO = 93 (40%), EH = 80 (34%), and SIM = 59 (26%). Median OS from recurrence 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 <.001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P <.05) were associated with SIM; only positive resection margin predicted LO (P =.007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P =.002), CDKN2Adel (n = 34, 15%; HR, 3.4 [95% CI, 2.2 to 5.3]; P <.001), CDKN2B (n = 25, 11%; HR, 3.2 [95% CI, 2.0 to 5.0]; P <.001), and KRASmut (n = 25, 11%; HR, 2.5 [95% CI, 1.6 to 4.0]; P =.002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95% CI, 1.7 to 3.5]; P <.001), N1 status (HR, 1.8 [95% CI, 1.2 to 2.6]; P =.004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36%; HR, 2.4 [95% CI, 1.7 to 3.3]; P <.001) were independent predictors of poor OS.

CONCLUSION:

– Recurrence after resection of IHC is common, and the liver was the most common site (66%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.

Original language	English
Journal	JCO Precision Oncology
Volume	9
DOIs	https://doi.org/10.1200/PO-25-00402
Publication status	Published - 23 Oct 2025

Bibliographical note

Publisher Copyright:
© 2025 American Society of Clinical Oncology

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10.1200/PO-25-00402

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Chandra, P., Song, Y., Drill, E., Wei, A. C., Kemeny, N., Cercek, A., Connell, L., Harding, J., Abou-Alfa, G., Park, W., Kingham, T. P., Soares, K., Balachandran, V., Drebin, J., D'Angelica, M., O'Reilly, E., Koerkamp, B. G., & Jarnagin, W. R. (2025). Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics, and Survival. JCO Precision Oncology, 9. https://doi.org/10.1200/PO-25-00402

@article{f27dc8a87b364b4a82004e8b9e9521c4,

title = "Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics, and Survival",

abstract = "PURPOSE:– The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes. METHODS:– Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence. RESULTS: – Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73\%) recurred. SOFR were LO = 93 (40\%), EH = 80 (34\%), and SIM = 59 (26\%). Median OS from recurrence 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 <.001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P <.05) were associated with SIM; only positive resection margin predicted LO (P =.007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22\%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P =.002), CDKN2Adel (n = 34, 15\%; HR, 3.4 [95\% CI, 2.2 to 5.3]; P <.001), CDKN2B (n = 25, 11\%; HR, 3.2 [95\% CI, 2.0 to 5.0]; P <.001), and KRASmut (n = 25, 11\%; HR, 2.5 [95\% CI, 1.6 to 4.0]; P =.002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95\% CI, 1.7 to 3.5]; P <.001), N1 status (HR, 1.8 [95\% CI, 1.2 to 2.6]; P =.004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36\%; HR, 2.4 [95\% CI, 1.7 to 3.3]; P <.001) were independent predictors of poor OS. CONCLUSION:– Recurrence after resection of IHC is common, and the liver was the most common site (66\%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.",

author = "Pratik Chandra and Yi Song and Esther Drill and Wei, \{Alice C.\} and Nancy Kemeny and Andrea Cercek and Louise Connell and James Harding and Ghassan Abou-Alfa and Wungki Park and Kingham, \{T. Peter\} and Kevin Soares and Vinod Balachandran and Jeffrey Drebin and Michael D'Angelica and Eileen O'Reilly and Koerkamp, \{Bas Groot\} and Jarnagin, \{William R.\}",

note = "Publisher Copyright: {\textcopyright} 2025 American Society of Clinical Oncology",

year = "2025",

month = oct,

day = "23",

doi = "10.1200/PO-25-00402",

language = "English",

volume = "9",

journal = "JCO Precision Oncology",

issn = "2473-4284",

publisher = "Lippincott Williams \& Wilkins",

}

Chandra, P, Song, Y, Drill, E, Wei, AC, Kemeny, N, Cercek, A, Connell, L, Harding, J, Abou-Alfa, G, Park, W, Kingham, TP, Soares, K, Balachandran, V, Drebin, J, D'Angelica, M, O'Reilly, E, Koerkamp, BG & Jarnagin, WR 2025, 'Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics, and Survival', JCO Precision Oncology, vol. 9. https://doi.org/10.1200/PO-25-00402

TY - JOUR

T1 - Intrahepatic Cholangiocarcinoma

T2 - Recurrence Patterns, Genomics, and Survival

AU - Chandra, Pratik

AU - Song, Yi

AU - Drill, Esther

AU - Wei, Alice C.

AU - Kemeny, Nancy

AU - Cercek, Andrea

AU - Connell, Louise

AU - Harding, James

AU - Abou-Alfa, Ghassan

AU - Park, Wungki

AU - Kingham, T. Peter

AU - Soares, Kevin

AU - Balachandran, Vinod

AU - Drebin, Jeffrey

AU - D'Angelica, Michael

AU - O'Reilly, Eileen

AU - Koerkamp, Bas Groot

AU - Jarnagin, William R.

PY - 2025/10/23

Y1 - 2025/10/23

N2 - PURPOSE:– The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes. METHODS:– Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence. RESULTS: – Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73%) recurred. SOFR were LO = 93 (40%), EH = 80 (34%), and SIM = 59 (26%). Median OS from recurrence 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 <.001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P <.05) were associated with SIM; only positive resection margin predicted LO (P =.007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P =.002), CDKN2Adel (n = 34, 15%; HR, 3.4 [95% CI, 2.2 to 5.3]; P <.001), CDKN2B (n = 25, 11%; HR, 3.2 [95% CI, 2.0 to 5.0]; P <.001), and KRASmut (n = 25, 11%; HR, 2.5 [95% CI, 1.6 to 4.0]; P =.002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95% CI, 1.7 to 3.5]; P <.001), N1 status (HR, 1.8 [95% CI, 1.2 to 2.6]; P =.004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36%; HR, 2.4 [95% CI, 1.7 to 3.3]; P <.001) were independent predictors of poor OS. CONCLUSION:– Recurrence after resection of IHC is common, and the liver was the most common site (66%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.

AB - PURPOSE:– The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes. METHODS:– Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence. RESULTS: – Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73%) recurred. SOFR were LO = 93 (40%), EH = 80 (34%), and SIM = 59 (26%). Median OS from recurrence 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 <.001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P <.05) were associated with SIM; only positive resection margin predicted LO (P =.007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P =.002), CDKN2Adel (n = 34, 15%; HR, 3.4 [95% CI, 2.2 to 5.3]; P <.001), CDKN2B (n = 25, 11%; HR, 3.2 [95% CI, 2.0 to 5.0]; P <.001), and KRASmut (n = 25, 11%; HR, 2.5 [95% CI, 1.6 to 4.0]; P =.002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95% CI, 1.7 to 3.5]; P <.001), N1 status (HR, 1.8 [95% CI, 1.2 to 2.6]; P =.004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36%; HR, 2.4 [95% CI, 1.7 to 3.3]; P <.001) were independent predictors of poor OS. CONCLUSION:– Recurrence after resection of IHC is common, and the liver was the most common site (66%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.

UR - https://www.scopus.com/pages/publications/105026638245

U2 - 10.1200/PO-25-00402

DO - 10.1200/PO-25-00402

M3 - Article

C2 - 41129766

AN - SCOPUS:105026638245

SN - 2473-4284

VL - 9

JO - JCO Precision Oncology

JF - JCO Precision Oncology

ER -

Intrahepatic Cholangiocarcinoma: Recurrence Patterns, Genomics, and Survival

Abstract

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