Medical Technology

ctDNA May Predict Worse Metastatic Biliary Tract Cancer Prognosis

Key Takeaway

  • This retrospective analysis of patients suggests that assessing circulating tumor DNA (ctDNA) in patients with metastatic cancers of the biliary tract (BTC) may help to determine patients with lower survival rates when they are treated with platinum-based chemotherapy. The preprint was posted on medRxiv November 2, but has not been peer reviewed.

Why It is Important

  • BTC is typically diagnosed in advanced stages, and only 20% of tumors can be easily resectable. The 5-year survival rate is around 4% in unresectable patients and the gains in first-line chemotherapy are minuscule. The majority of patients improve within a year.

  • There is a growing interest in the application of next-generation tumor genomic profiling and liquid biopsy to identify targeted genetic changes. Recent results suggest that ctDNA could be used to stratify patients in prospective randomized trials.

Study Design

  • Sixty-seven patients suffering from metastatic BTC who had ctDNA tests prior to first-line platinum-based chemotherapy between June 2016 to June 2020 were included. The following was added to the patient’s charts: We reviewed them to determine the rate of disease control and response to treatment.

  • The frequency of variant alleles (VAF), or the number of mutant molecules that exceed the total number of wild-type molecules in a particular genome location, was calculated from the ctDNA samples. The relationship between the dominant allele frequency of clones (DCAF) and overall and progression-free survival was analyzed.

Key Results

  • The median age of patients was 67 yearsold, and 80.6 percent were diagnosed with intrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma was diagnosed in 10.4 percent of patients, and 9 percent had gallbladder cancer. The majority (68.6 percent) of patients received Cisplatin plus gemcitabine and gemcitabine, while cisplatin was paired with another platinum-based therapy in a further 16.4%. The rate of disease control was 64.4%.

  • DCAF analysis revealed that TP53 and KRAS were the most common genes. The median DCAF was 3%.

  • DCAF >3 was associated with lower progression-free survival (PFS) at a median of 4.7 months against 7.7 months for DCAF <=3% ( P = .087) and significantly worse overall survival with a median of 10.8 months against 18.8 months ( P = .032).

  • The stratification of DCAF into quartiles showed a significantly lower PFS ( P =.014) and significantly worse overall survival ( P=..002).

  • After adjusting for patient age and gender metastatic sites, the size of the largest lesion primary tumor size, and CA19-9, every 1% increase in ctDNA was associated with a hazard ratio of death of 13.07 ( P = .034).


  • The study was limited by the small sample size and was a single center, retrospective analysis. In addition, the use of an targeted gene panel. In addition there were a small number of patients with diagnoses other that were not intrahepatic duct cancers.

Study Disclosures

  • The Mayo Clinic Hepatobiliary SPORE funded the statistical analysis used in this project. This research was supported by the National Institutes of Health; National Cancer Institute, SPORE Project Award, SPORE Supplement Award, Mayo Clinic Center for Individualized Medicine (CIM) Precision Cancer Therapeutics Program and Mayo Clinic Cancer Center.

  • No relevant financial relationships declared.

This is a summary of a preprint research study published on medRxiv on the 2nd of November. Pedro Luiz Serrano Uson Junior from Mayo Clinic, Scottsdale (Arizona) was the study’s primary author. Preprints are a draft version of a manuscript that has not yet been peer reviewed at an academic journal. The publication of an article on this server should not be interpreted as an endorsement of its authenticity or the suitability to be published as a standard of information or for guiding clinical practice.

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