A global comparative study on real-world clinical and genomic differences in advanced biliary tract cancer.
Authors: Abidoye Oluseyi , Hoyek Celine , Zheng-Lin Binbin , Kosiorek Heidi E. , Eslinger Cody , Sonbol Mohamad Bassam , Wu Christina , Tran Nguyen H. , Babiker Hani M. , Yoshino Takayuki , Ikeda Masafumi , Morizane Chigusa , Bando Hideaki , Nakamura Yoshiaki , Fujisawa Takao , Shibuki Taro , Ahn Daniel H. , Roberts Lewis R. , Borad Mitesh J. , Bekaii-Saab Tanios S. 
Published: January 2025

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Background:
Biliary tract cancers (BTC) are aggressive malignancies with poor survival outcomes and limited treatment options. This study compared the epidemiological and molecular differences of advanced BTC patients through a global collaboration involving the Mayo Clinic and National Cancer Center Hospital East.
Methods:
We included patients with advanced BTC who underwent comprehensive tumor molecular profiling who received at least 30 days of systemic therapy. Patients were grouped based on specific alterations. Overall survival (OS) was calculated from the start of first-line therapy until death and compared among subgroups using Cox regression models.
Results:
332 (36%) out of 932 patients had at least one actionable mutation
: somatic BRCA1/2
mutations N=106,
FGFR2
fusions N=61,
HER2
amplifications N=65,
KRAS G12C/D
mutations N=46,
IDH1
mutations N=38, and TMB >10 mut/Mb N=16.
BRCA1/2
-mutated BTC were more commonly found in older Asian males with intrahepatic tumors and often presented with peritoneal and liver metastases upon initial diagnosis.
FGFR2
fusions were more prevalent in younger White females with intrahepatic tumors, while
HER2
amplifications were mainly seen in Asian females with gallbladder tumors.
KRAS
mutations were primarily observed in Asian males, and
IDH1
mutations were common in White males with intrahepatic tumors, frequently presenting with liver metastasis. Survival outcomes varied significantly based on the alteration type: patients with
FGFR2
fusions had the longest median OS (mOS) at 23.3 months (mo) (95%CI 18.4-34.9), followed by those with
IDH1
mutations (19.3 mo; 95% CI 17.4-NE) and TMB >10 mut/Mb (17.8 mo; 95% CI 13.6-NE).
BRCA
mutations had a mOS of 16 mo (95% CI 14.6-19.8), while
HER2
amplifications and
KRAS
mutations had mOS of 15.5 (95% CI 11.9-20.2) and 11.6 mo (95% CI 10.0-20.9), respectively.
Conclusions:
These findings underscore the heterogeneity in clinical and genomic characteristics among BTC patients, highlighting the importance of tailored therapeutic approaches.

Baseline patient characteristics stratified by mutation status.

KRAS G12C/D
(N=46)

BRCA 1/2
(N=106)

IDH1
(N=38)

HER2
amplification(N=65)

FGFR2
fusion(N=61)

TMB>10 mut/Mb(N=16)
P-value

Median Age, year
67
68
64
66
52
73
<0.001

Female, n (%)
19 (41)
34 (32)
18(47)
34 (52)
45(74)
6 (38)
<0.001

Race, n (%)

<0.001

Asian
31 (67)
97 (92)
13 (34)
51 (79)
10 (16)
6 (38)

White
14 (30)
8 (8)
24 (63)
13 (20)
48 (79)
10 (63)

Primary tumor location, n (%)

<0.001

Intrahepatic
28 (68)
45 (45)
33 (100)
19 (31)
54(95)
10 (67)

Extrahepatic
9 (22)
27(27)
0 (0)
10 (16)
2 (4)
4 (27)

Gallbladder
4 (10)
28 (28)
0 (0)
32 (53)
1 (2)
1 (7)

Sites of Metastasis at diagnosis, n (%)

Abdominal Wall / Peritoneal
9 (24)
15 (19)
4(13)
7 (12)
6 (10)
4 (27)
0.309

Bone
33 (92)
70 (90)
26 (87)
2 (3)
9(15)
0 (0)
0.212

Liver
20 (49)
52 (61)
28 (82)
45 (73)
45 (76)
6 (38)
0.001

Lung
26 (70)
65 (82)
22 (69)
36 (58)
27(45)
11 (69)
0.006