Biliary tract cancer (BTC) encompasses a rare and diverse group of tumors characterized by varying anatomical locations-including extrahepatic, intrahepatic, and gallbladder lesions. Therapeutic innovations in advanced BTC are hindered by the rarity and heterogeneity of its subtypes, with particularly high incidence and mortality rates observed in Korea.
Recent advances in molecular profiling have enabled the identification of potential therapeutic targets for BTC. These findings have led to the approval of several therapies for BTC, including those targeting IDH1 mutations, FGFR2 fusions, ERBB2 amplifications, as well as immunotherapies for DNA mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) subtypes. Genomic profiling is essential to detect these targetable alterations, helping to guide appropriate, targeted therapies for patients with BTC. Traditional genomic profiling is typically conducted using formalin-fixed paraffin-embedded (FFPE) tumor tissues; therefore, the challenge of obtaining adequate tumor tissue samples in BTC can impede molecular evaluations. Circulating tumor DNA (ctDNA) from blood may offer an alternative to tissue-based analysis.
In a previous study, the investigators assessed the concordance between ctDNA and tissue genomic profiling in a large cohort of Asian patients with advanced BTC and evaluated the feasibility of liquid biopsy in the treatment of BTC. As a result, ctDNA-based genotyping exhibited acceptable concordance with tissue genomic profiling for clinically significant mutations classified as tier 1 or 2, with a sensitivity of 84.8% and a positive predictive value (PPV) of 79.4%. Notably, high concordance of actionable alterations between ctDNA and tissue for IDH1 mutations was observed, with 100% sensitivity (5/5) and 71.4% PPV (5/7), and for FGFR2 fusions with 66.7% sensitivity (2/3) and 100% PPV (2/2). Additionally, using ctDNA, five IDH1 mutations were identified in tissue samples and two additional IDH1 mutations were detected only in ctDNA.
The IDH1 mutations have significant clinical implications for patients with BTC due to their considerable frequency (approximately 13% in intrahepatic cholangiocarcinoma; range, 9-20%) and the availability of targeted therapy; ivosidenib was approved by both the U.S. Food and Drug Administration (FDA) and the Ministry of Food and Drug Safety (MFDS) in Korea. Although relatively high concordance between ctDNA and tumor tissue for IDH1 mutations was found, the occurrence of these alterations was low, and a more comprehensive comparative analysis is warranted. Therefore, the validation of ctDNA genomic profiling in a larger cohort of patients with BTC is not just a suggestion, but a pressing need to establish its potential as a promising approach for guiding personalized treatment strategies.
Justification for ctDNA in BTC:
The Korean Cancer Study Group (KCSG) Biliary Tract Cancer Subcommittee includes nearly 100 specialists from hospitals across the country. However, not all hospitals in Korea have in-house capabilities for NGS (Next-Generation Sequencing), making it challenging to implement NGS as recommended in biliary tract cancer treatment guidelines. In contrast, ctDNA allows for the detection of a patient's genetic alterations through a simple, non-invasive blood sampling process. This method can identify targetable alterations, facilitating appropriate treatments. Additionally, ctDNA offers a shorter turnaround time, which can help shorten diagnostic timelines and streamline patient access to treatments like ivosidenib.
Long-Term Benefits:
As demonstrated in a recently published study by Immune \& Biotech Diagnostics (IMBDx, Seoul, South Korea), IMBDx's ctDNA test, Alpha Liquid 100, not only identified all five cases of IDH1 mutation detected by conventional tissue NGS but also identified two additional IDH1 mutations that tissue NGS failed to detect. This capability could enable more patients to access treatment with ivosidenib. Moreover, if ctDNA-based NGS testing becomes routine within the KCSG Biliary Tract Cancer Subcommittee, which includes a substantial number of specialists dedicated to treating biliary tract cancer in Korea, it is likely that the use of ctDNA for IDH1 mutation detection will continue beyond this study.
