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INTRODUCTION
Biliary tract cancer (BTC) includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), categorized based on anatomical location.1,2 Each subtype of BTC is characterized by distinct risk factors, genetic alterations, and treatment strategies, reflecting its heterogeneous nature.2 Although BTC is a rare malignancy with a low overall incidence, its complexity and heterogeneity pose significant therapeutic challenges. It is often diagnosed at an advanced stage, and even when resectable at an earlier stage, its high recurrence rate leads to a poor prognosis.3,4 With BTC’s low incidence but rising prevalence, there is an urgent need for comprehensive research. Given the high rates of late-stage diagnosis and recurrence even after curative resection, research efforts must focus on improving early diagnostic techniques and developing personalized therapeutic strategies based on patient-specific genomic profiling to improve patient outcomes.
BTC is of particular concern in certain regions. Korea has the second-highest incidence of BTC globally and the highest mortality rate worldwide, emphasizing the need for a deeper understanding of this disease.5 Additionally, Korea presents unique risk factors, such as liver fluke infections and hepatitis B virus (HBV) infection, which differentiate it from other countries and warrant further discussion.6,7
To address these issues, this review provides an in-depth analysis of BTC by examining its epidemiology, risk factors, and molecular features, along with corresponding targeted therapies. Special emphasis is placed on the unique characteristics of BTC in Korea, including region-specific risk factors and trends, to draw comparisons with global data. By integrating these insights, we aim to identify knowledge gaps and inform future research directions, ultimately contributing to advancements in early diagnosis and personalized treatment strategies for patients with BTC.
GLOBAL EPIDEMIOLOGY OF BTC: FOCUS ON KOREA
Incidence rates
The incidence of BTC, including ICC, ECC, and GBC, varies widely across geographical regions (Fig. 1).5 Globally, while BTC is considered a relatively rare malignancy, its incidence exhibits marked regional differences. Among all regions, South America, particularly Chile, reports the highest incidence rate at 11.7 cases per 100,000 person-years, whereas North America (2.0) and Europe (1.6-3.2) report comparatively lower rates. High incidence rates are observed in Asia, especially in East Asian countries such as China (3.1), Japan (5.4), and Korea (8.1). Notably, Korea has the highest BTC incidence rate in Asia.
The incidence rates of ICC and ECC follow a consistent geographical pattern (Table 1). In Western countries such as the United States, Canada, Chile, and European nations like Germany and France, the reported incidence rates of ICC and ECC are relatively low, typically less than 1.0 and 0.9, respectively. In East Asia, Japan and China report comparable ICC incidence rates of 0.7 and 0.6 cases, respectively, and ECC incidence rates of 2.7 and 0.9, respectively. However, Korea stands out with significantly higher incidence rates of both ICC (2.2) and ECC (2.7), underscoring the substantial burden of cholangiocarcinoma in this region.
In contrast, GBC exhibits more pronounced regional disparities. South America, particularly Chile, has an exceptionally high GBC incidence of 9.7, far exceeding the rates in countries such as the United States, Canada, Germany, and France, where the incidence ranges from 0.6 to 0.7. In East Asia, GBC incidence is relatively higher, with Japan and China reporting 1.9 and 1.4 cases, respectively. Korea closely follows with an incidence of 2.9, slightly surpassing the rates in Japan and China. This elevated GBC incidence further contributes to the overall high BTC incidence observed in Korea, highlighting the regional significance of this disease.
Sex-based differences in BTC incidence rates are observed across various regions, with distinct patterns among BTC subtypes (Supplementary Table 1). In general, ICC and ECC tend to be more prevalent in males, whereas GBC has a higher incidence in females. This trend is particularly evident in East Asian countries such as Japan and Korea, where males exhibit higher incidence rates of ICC and ECC. In Korea, ICC incidence is 3.1 in males compared to 1.4 in females, while ECC incidence is 3.8 in males and 1.9 in females. Conversely, GBC incidence is slightly higher in males (3.0) than in females (2.8) in Korea, with a similar pattern observed in Japan (2.0 in males vs. 1.9 in females). Meanwhile, in Chile, which has the highest overall BTC incidence, GBC is the predominant subtype and shows a pronounced sex disparity, with females (13.8) being significantly more affected than males (5.1). These findings highlight the importance of considering sex-based epidemiological differences in BTC research and clinical management.
Mortality rates
Building on the observed regional differences in incidence, BTC mortality rates show significant geographical disparities. These variations reflect differences in diagnostic practices, access to healthcare, and the prevalence of underlying risk factors. Globally, BTC mortality rates remain relatively low, but several European countries, including Italy (4.2 deaths per 100,000 person-years), Germany (3.8), France (3.1), and the United Kingdom (3.2), report particularly low mortality rates.5 In contrast, in East Asia, Japan has significantly higher rates, with a reported mortality rate of 7.2, while Korea has the highest mortality rate in the world, at 11.0.
In most countries, BTC mortality rates by anatomical location -including ICC, ECC, and GBC- exhibit comparable proportions (Table 1). However, in European nations, ICC accounts for the largest share of BTC mortality. Specifically, ICC contributes to 42.1% (1.6 out of 3.8) of overall BTC mortality in Germany, 67.7% (2.1 out of 3.1) in France, and 75.0% (2.4 out of 3.2) in the United Kingdom. Similarly, in Korea, ICC represents the largest share of BTC mortality at 38.2% (4.2 out of 11.0). In contrast, ECC accounts for the highest proportion in Japan, at 47.2% (3.4 out of 7.2).
Mortality rates by sex and age show consistent trends across most countries: 1) males have higher mortality rates for cholangiocarcinoma, whereas females have higher mortality rates for GBC (Supplementary Table 2), and 2) across all BTC subtypes, patients aged 75 years and older have higher mortality rates compared to those aged 20-70 years (Supplementary Table 3).
Overall, BTC mortality rates closely align with incidence rates, with East Asia consistently reporting higher rates than other regions. Notably, Korea not only has the second-highest BTC incidence rate but also the highest mortality rate globally. This striking pattern highlights the urgent need to investigate the specific factors contributing to these trends, including region-specific risk factors and driver gene mutations. Understanding these elements is crucial for developing effective strategies to reduce BTC mortality and improve outcomes for patients in Korea and beyond.
Risk factors
Global data on BTC risk factors and their relationships with different ethnicities remain limited. However, studies focusing on specific risk factors, such as liver fluke infections, have provided valuable insights into regional variations, forming a foundation for understanding the unique characteristics of BTC. Established BTC risk factors include liver fluke infection, choledochal cysts, hepatolithiasis, and primary sclerosing cholangitis (PSC) (Fig. 2).6-18 These risk factors vary in prevalence across regions and exhibit different associations with BTC.
In Western countries, PSC -an autoimmune disease that causes bile duct strictures- is a prominent BTC risk factor.19 In contrast, in East Asia, including Korea, liver fluke infections (e.g., Opisthorchis viverrini in Thailand and Clonorchis sinensis in Korea) are significant contributors.6,7 Choledochal cysts and hepatolithiasis occur in both Asian and Western populations; however, their incidence tends to be higher in Asian countries.20,21 Additionally, liver diseases such as cirrhosis and viral hepatitis, metabolic conditions such as type 2 diabetes, obesity, and metabolic dysfunction-associated steatotic liver disease, as well as lifestyle factors like alcohol consumption and smoking, are known BTC risk factors. Ongoing research is further exploring these associations.8,9 This review focuses on liver fluke infections and viral hepatitis, two risk factors with distinct regional patterns, particularly in Korea, where their prevalence and impact differ significantly from other countries.
Liver fluke infections are known to cause chronic inflammation and bile stasis in the biliary tract, increasing the risk of BTC. In Korea, Clonorchis sinensis infection is endemic, particularly in areas along major rivers, where the incidence of BTC is reported to be higher.22,23 According to a 2023 report from the Korea Disease Control and Prevention Agency (KDCA), the intestinal parasitic infection rate in Korea is 3.7%, with approximately 52.2% of these infections caused by Clonorchis sinensis, indicating a high prevalence of clonorchiasis.24 Several studies in Korea have demonstrated a significant correlation between Clonorchis sinensis infection and BTC development.6,7 Another liver fluke Opisthorchis viverrini, is endemic in Thailand, with one study reporting an odds ratio (OR) of 1.7 (95% confidence interval [CI], 0.4-7.0) for BTC associated with Opisthorchis viverrini.10 A meta-analysis examining liver fluke infections (Clonorchis sinensis and Opisthorchis viverrini) using methods such as stool ova detection, enzyme-linked immunosorbent assay, and radiological approaches demonstrated an OR of 4.8 (95% CI, 2.8-8.4), reinforcing that liver fluke infection is a strong BTC risk factor.17 In contrast, liver fluke infections are extremely rare in Western countries, limiting their significance as a BTC risk factor in those regions.
Recent studies have also focused on the impact of viral hepatitis, a major risk factor for hepatocellular carcinoma, in BTC development. A meta-analysis of 48 studies by Wang et al.18 demonstrated that both HBV (OR, 2.2; 95% CI, 1.7-2.7) and hepatitis C virus (HCV) (OR, 2.1; 95% CI, 1.6-2.8) are significant BTC risk factors. HBV increases BTC risk in both Asian and Caucasian populations, whereas HCV poses a higher risk in Caucasians. When analyzed by anatomical location, both HBV and HCV were more strongly associated with ICC, with ORs of 4.0 (95% CI, 3.1-5.2) and 2.9 (95% CI, 2.1-4.1), respectively.18
According to the World Health Organization (WHO), as of 2022, approximately 254 million people worldwide live with HBV, while 50 million are affected by HCV.25 In Korea, where HBV is endemic, prevalence is approximately 2.3%, with 52.3% of affected individuals receiving antiviral treatment.26,27 Given the high prevalence of chronic hepatitis in the Korean population, further research into early screening and diagnostic tools for high-risk groups is imperative.
Although several risk factors for BTC have been identified, most patients with BTC do not exhibit any specific, identifiable risk factors apart from age. This underscores the importance of vigilant monitoring in at-risk populations and highlights the need for further research to uncover additional contributing factors to BTC development.
GEOGRAPHICAL VARIATIONS IN MOLECULAR CHARACTERISTICS OF BTC
Several studies using next-generation sequencing (NGS) technologies, such as whole-exome or targeted sequencing, have demonstrated the substantial molecular complexities and drivers of BTC across different anatomical subtypes: intrahepatic, extrahepatic, and gallbladder.28-32 To determine the frequencies of notable genetic alterations in patients with BTC, we conducted a PubMed search using combinations of the following keywords: biliary tract cancer, cholangiocarcinoma, gallbladder cancer, genomic profiling, molecular profiling, alteration, and mutation.
Globally, BTC, including ICC, ECC, and GBC, has been associated with several key genetic mutations: TP53 (18.3-54.0%), KRAS (15.0-28.1%), ARID1A (11.8-20.2%), and PIK3CA (7.2-21.0%).33-37 Studies focusing specifically on Korean patients with BTC reported comparable mutation frequencies: TP53 (42.7-55.5%), KRAS (22.8-30.9%), ARID1A (10.1-15.1%), and PIK3CA (4.6-6.2%) (Fig. 3).38-42 Notably, the frequency of PIK3CA mutations in Korean patients was slightly lower compared to global averages. When considering the anatomical subtypes of BTC, genomic alterations in tumor suppressor genes and oncogenes exhibit geographic al variability. This section further examines significant molecular alterations according to BTC subtypes and their frequencies across major regions, with a focus on Korea (Fig. 3).
ICC
The tumorigenesis of ICC is frequently associated with IDH1 mutations (13.0-20.0%)43-45 and FGFR2 fusions (20.0%).46 These known genetic features are predominantly observed in small duct type ICC, whereas KRAS (15.0-30.0%) and TP53 (10.0-40.0%) mutations are commonly found in large-duct type ICC.45 IDH1 mutations, which result in gain-of-function activity in the protein-coding region, exhibit regional variations in frequency. Specifically, in the United States and the Netherlands, the frequency of IDH1 mutations is approximately 15.6-21.9%. In contrast, in Korea, it is slightly lower, ranging from 3.6-16.4% (Table 2). The prevalence of FGFR2 fusions in ICC is higher in Japan (5.5-12.2%)32,47 and the United States or the Netherlands (9.2-15.6%),30,48,49 whereas it is relatively low in Korea (3.3-3.6%).38,39
Recent advancements in circulating tumor DNA (ctDNA) NGS technology using blood samples have improved targeted therapy opportunities for Korean patients with BTC who have limited tissue samples.38 While the detection rate of FGFR2 fusions was lower in ctDNA compared to tumor tissue,50-52 this study improved FGFR2 fusion detection to a sensitivity of 66.7% and identified TNS1 as a novel FGFR2 fusion partner. These findings highlight that ctDNA profiling can expand targeted therapy options for Korean patients with ICC and FGFR2 fusions, despite their lower frequency.
ECC
ECC is predominantly characterized by a high frequency of KRAS mutations (12.0-47.0%)33,53,54 and ERBB2 amplification (1.3-11.0%),55 along with low frequencies of IDH1 mutations or FGFR2 fusions. In Korea, similar patterns have been observed, with KRAS mutations reported at frequencies of 19.6-40.0%38-41 and ERBB2 amplification at 2.0-11.4%38,40,41 IDH1 mutations (0.0-2.0%)56 and FGFR2 fusions (0.0%)38-41,56 remain rare in Korean patients with ECC, consistent with global trends (Fig. 3).
GBC
GBC is known to be associated with a high frequency of ERBB2 amplification (9.8-19.0%)57,58 and TP53 mutations (42.5-46.0%).34,54 The frequency of ERBB2 amplification varies geographically 8.4-10.3% in the United States,59,60 8.3% in Japan,47 and 14.8% in China.59 In Korea, a higher frequency of 14.3-22.0% has been reported,38-41 indicating some regional variability (Table 2). TP53 mutations are observed at similar frequencies in Korea (38.2-82.1%)38,42 compared to global reports (42.5-46.0%), reflecting consistency across populations.
TARGETED THERAPIES APPROVED IN KOREA FOR BTC
Recent advances in molecular profiling have transformed the treatment landscape for solid tumors, including ICC, ECC, and GBC. The United States Food and Drug Administration (FDA) has approved targeted therapies for genetic alterations, such as FGFR2 fusions,61,62 IDH1 mutations,43,63 NTRK fusions,64,65 BRAF V600E mutations,66,67 HER2-positive caused by ERBB2 amplification,68 and RET fusions,69 identified based on the anatomical location of BTC has expanded the treatment options for BTC (Table 3). Among these, the only drugs approved by the Ministry of Food and Drug Safety (MFDS) are ivosidenib for IDH1 mutations, pemigatinib for FGFR2 fusions, and both larotrectinib and entrectinib for NTRK fusions.
A recent study reported promising clinical outcomes of trastuzumab plus fluorouracil and oxaliplatin (FOLFOX) in Korean patients with BTC, leading to its pre-approval in Korea and highlighting ERBB2 amplification as a significant therapeutic target.70 Given the clinical significance of IDH1 mutations, FGFR2 fusions, and ERBB2 amplification in Korea, these targetable alterations play a crucial role in treatment decisions for Korean patients with BTC.
First, in 2020, ivosidenib, a targeted therapy for IDH1 mutations, demonstrated efficacy in cholangiocarcinoma, achieving a median progression-free survival (PFS) of 2.7 months compared to 1.4 months with placebo (hazard ratio, 0.4; 95% CI, 0.3-0.5; P<0.001).43 Based on these results, ivosidenib received FDA approval as the targeted therapy for patients with cholangiocarcinoma harboring IDH1 mutations, and was subsequently approved in Korea in 2024.
Second, FGFR2 fusions represent another important therapeutic target. The FIGHT-202 trial demonstrated the efficacy of pemigatinib, leading to FDA approval in 2020 for patients with advanced BTC harboring FGFR2 fusions or rearrangements.61 Pemigatinib was later approved in Korea in 2023. Although futibatinib, another FGFR2-targeting agent, has been approved by the FDA, it is not yet approved in Korea. These developments underscore the potential to benefit more BTC patients with FGFR2 fusions.
Lastly, trastuzumab combined with FOLFOX (KCSG HB19-14), targeting ERBB2 amplification, has shown promising clinical outcomes in Korean patients with BTC, leading to its approval through a pre-approval access program.70 HER2-positive patients who had previously received gemcitabine and cisplatin as first-line therapy demonstrated excellent outcomes when treated with trastuzumab plus FOLFOX as a second- or third-line therapy. The median PFS was 5.1 months (95% CI, 3.6-6.7), and the median overall survival was 10.7 months (95% CI, 7.9 to not reached). In addition, the regimen of pertuzumab and trastuzumab, evaluated in the MyPathway study -a multicenter, open-label, phase 2a, multiple basket trial- has also been made available in Korea through a pre-approval access program for patients with HER2-positive, metastatic BTC.71 This combination therapy demonstrated promising efficacy, achieving an objective response rate of 23% and a disease control rate of 76% in patients with HER2-positive BTC. These findings highlight the potential of dual HER2-targeting therapies to improve outcomes in this patient population. These studies emphasize the growing opportunities to personalize treatment and improve outcomes for patients with HER2-positive BTC.
In clinical practice, the detection of genomic alterations in BTC, such as IDH1 mutations, FGFR2 fusions, and ERBB2 amplifications, is primarily performed using NGS-based gene panel tests. However, while gene mutations are primarily identified through NGS-based testing, gene fusions and copy number variations can also be detected using protein-level diagnostic approaches, such as fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).72-74 For patients with BTC and ERBB2 amplification, determining HER2-positive status at the protein level is crucial because the FDA has approved protein-based diagnostic approaches for therapies that target ERBB2 amplification. Therefore, FISH or IHC test results are critical in guiding treatment decisions by providing direct evidence of HER2-positive status,74 which is essential for selecting appropriate targeted therapies. As a result, choosing diagnostic approaches tailored to the patient’s specific clinical context ensures that patients with BTC receive the most appropriate and effective targeted treatments.
CONCLUSION
BTC is a rare malignancy. While most countries report relatively low incidence and mortality rates, Korea exhibits notably higher rates for both. The unique risk factors and molecular features of BTC in Korea highlight significant geographical differences. Endemic liver fluke infections and HBV infections are strongly associated with the higher BTC incidence observed in the region.
At the molecular level, patients in Korea have lower frequencies of IDH1 mutations (3.6-16.4%) and FGFR2 fusions (3.3-3.6%) in ICC compared to other countries. However, ERBB2 amplification (14.3-22.0%) is more prevalent in GBC in Korea. Ivosidenib and pemigatinib have been approved in Korea, providing new treatment options for patients with IDH1 mutations or FGFR2 fusions.
Despite these advances, a significant proportion of BTC cases lack identifiable risk factors or actionable genomic alterations, posing ongoing challenges for early diagnosis and effective treatment. These findings emphasize the need for region-specific studies and tailored therapeutic strategies to address the unique challenges of BTC in Korea. By addressing these knowledge gaps, a better understanding of BTC in Korea can be achieved, ultimately leading to improved patient outcomes and serving as a model for tackling region-specific variations in cancer worldwide.
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