Detection of Malignancy in Biliary Brushings Using Genomic Markers: A Phase 1 Study

Lay summary

Developmental Research Program Overview

Bile ducts are tubes that drain bile from the liver to the intestine for digestion of fat and absorption of vitamins. Cancer of the bile duct (cholangiocarcinoma) is difficult to detect early because the symptoms usually are vague. In addition, these tumors are difficult to see with CT or MRI. Biopsies often are negative even if there is cancer in the bile ducts. The current standard of care is brush cytology. Another test, fluorescence in situ hybridization (FISH), improves the ability to detect cholangiocarcinoma (CCA). However, FISH testing is limited to a few large medical centers because it requires laboratory expertise and significant time to process and interpret the samples. Therefore, FISH testing is not widely performed. Genomic testing is a new way to test tumors and has been used for diagnosing many different cancers.

In this work in the Developmental Research Program in the Mayo Clinic Hepatobiliary SPORE, we are studying if using genomic testing would improve the accuracy of diagnosing cholangiocarcinoma.

Testing of stored samples has demonstrated that genomic testing has improved sensitivity for diagnosing cholangiocarcinoma. For this study, we propose to use fresh samples from patients with and without cholangiocarcinoma to determine if genomic testing has better test characteristics for diagnosing cholangiocarcinoma compared with the current standard of care. In addition, this test would have a faster processing time, would be cheaper and would allow for more widespread use because it doesn't require special laboratory expertise.

Head and shoulders photograph of Vinay Chandrasekhara, M.D.
  • Vinay Chandrasekhara, M.D.
  • 2020-2022 Awardee


Biliary malignancies, in particular cholangiocarcinoma, are associated with poor prognosis and limited treatment options. Therefore, early diagnosis is critical for maximizing treatment outcomes. Identification of these malignancies is complicated by diagnostic challenges, including differentiation of benign from malignant biliary strictures by imaging, sample failure of conventional cytologic brushings, and well-differentiated tumor cells that mimic reactive inflammatory nonmalignant processes. The sensitivity of conventional brush cytology during endoscopic retrograde cholangiopancreatography (ERCP) is as low as 8% for the detection of CCA.

Members of our investigational team first described the use of fluorescence in situ hybridization (FISH) to improve the sensitivity for the detection of malignancy in bile duct brushing specimens compared with standard cytology. We then demonstrated that a refined optimized set of FISH probes further increased diagnostic sensitivity. While FISH improves the diagnostic sensitivity for cholangiocarcinoma, it's a time-intensive test requiring expertise and manual review that results in increased cost, longer turn-around time and lack of widespread adoption. Thus, brush cytology remains the diagnostic standard at most medical centers around the world despite its suboptimal performance characteristics.

Genomic testing is now playing a large role in the diagnosis, risk-stratification and choice of therapy for a variety of malignancies. Genomic testing is easier to perform compared with FISH and widely available, therefore making it an attractive option for the diagnosis of biliary malignancy. In addition, genomic testing can be performed as a standard assay, which doesn't require manual review or skilled trained laboratory staff for analysis, thereby allowing for easier test interpretation and dissemination.

The purpose of this phase 1 study is to identify a set of genomic markers with the potential to improve the detection of malignancy in a prospectively collected biliary brush sample discovery cohort. A future prospective validation cohort would require expansion of this effort into a potential program in the Hepatobiliary SPORE.