When patients develop a narrowing or blockage in the bile ducts – the tubes connecting the liver, gallbladder and intestines – physicians must determine whether the cause is cancer or a benign condition. The location of these blockages adds challenges to the diagnosis, and this uncertainty can delay treatment decisions for patients in the event they have this rare type of cancer.
Scientists at UPMC Hillman Cancer Center and the University of Pittsburgh School of Medicine developed BiliSeq, a molecular test that detected bile duct cancer with twice the sensitivity of the standard test, giving physicians a more accurate picture of the patient's diagnosis.
Published today in Gastroenterology, the flagship journal of the American Gastroenterological Association, the study evaluated BiliSeq's real-world performance over six years in more than 2,000 patients across the United States, analyzing nearly 3,000 bile duct specimens. BiliSeq detected approximately 82% of bile duct cancers, compared to 44% with pathology alone. More importantly, when combined with pathology, BiliSeq increased cancer detection to nearly 90% while rarely misclassifying benign disease as malignant.
Because bile duct tumors are often small, difficult to reach and surrounded by inflammation or scar tissue, standard biopsy and cytology methods often fail to give doctors a clear diagnosis.
"For decades, in bile duct cancer we've known that a negative biopsy doesn't always rule out cancer," said Adam Slivka, M.D., Ph.D., professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at Pitt. "That uncertainty drives repeat testing and sometimes surgery without clear answers."
BiliSeq addresses this limitation by detecting genetic mutations associated with cancer in bile duct tissue. The test functions even when tumor cells are sparse, damaged or indistinguishable from inflammation under the microscope — a key limitation of traditional pathology, which can miss cancers and produce false-negative results.
BiliSeq is not a screening test for the general population. Instead, it is used for patients with bile duct narrowing or obstructions that need a clearer diagnosis.
One of the most important advantages of BiliSeq is that it provided more than a simple yes-or-no answer to patients waiting for a diagnosis. In the study, BiliSeq identified treatment-relevant genetic information in about one out of every five patients. In nearly one-third of those cases, that information led doctors to change how care was managed. "That's where this really becomes personalized medicine," said Slivka, who directs the gastroenterology service line at UPMC. In addition, BiliSeq results are already being used alongside standard clinical evaluation to help inform liver transplant decision-making in select patients at UPMC.
The study also reported on BiliSeq's detection performance across high-risk patient groups, including patients with primary sclerosing cholangitis (PSC) and Hispanic patients. In these populations, pathology alone could miss up to half of cancers. However, when combined with BiliSeq, clinicians were able to identify up to 86% of cancer cases.
This work extends a broader effort by Pitt and UPMC researchers to develop molecular tools that improve cancer diagnosis and treatment decisions, including prior work in pancreatic cancer and pre-cancerous cysts, developed by Aatur Singhi, M.D., Ph.D, associate professor of pathology at Pitt, Director of the UPMC Developmental Laboratory, who is a co-author of the study.
The large, prospective, multi-institutional design makes the findings representative of real-world clinical practice. "We receive and analyze samples from patients at medical centers across the country," Slivka said, "For these patients, BiliSeq means less testing, less waiting and more options."
Additional authors on the study include Rohit Das, M.D., Harkirat Singh, M.D., Jennifer Chennat, M.D., Mordechai Rabinovitz, M.D., Savreet Sarkaria, M.D., Charles Gabbert, M.D., Sultan Mahmood, M.D., Randall E. Brand, M.D., Kevin McGrath, M.D., Kenneth Fasanella, M.D., Anne Marie Lennon, M.D., Dennis Hsu, M.D., Anwaar Saeed, M.D., Janie Zhang, M.D., Vikram Gorantla, M.D., John Rhee, M.D., Robert Bubar, M.D., Abigail I. Wald, Ph.D., Sara A. Singhi, Katelyn Smith, B.A., Nuha Shaker, M.D., Marina N. Nikiforova, M.D., Liron Pantanowitz, M.D., Ph.D., N. Paul Ohori, M.D., and Sara E. Monaco, M.D., all of Pitt, UPMC or both. Additional corresponding authors of the study are Aatur Singhi, M.D., Ph.D. from Pitt and UPMC, and Nisa Kubiliun, M.D., from the University of Southwestern Texas.
This study was supported in part by the National Institutes of Health (P30DK120531, U01CA200466 and P30CA047904), Western PA Chapter- National Pancreas Foundation , the Sky Foundation and the Pancreatic Cancer Action Network.
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About UPMC Hillman Cancer Center
UPMC Hillman Cancer Center connects patients to the integrated expertise of leading clinicians, academic researchers, specialty programs and treatment centers. By partnering with the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, the only National Cancer Institute-designated Comprehensive Cancer Center in the region, is accelerating the breakthroughs from the lab to clinical practice around the world. UPMC - nationally ranked by U.S. News & World Report for excellence in cancer care - has 80 cancer treatment locations throughout Pennsylvania, Ohio, New York and Maryland as well as centers in Ireland, Italy and Croatia. Backed by the collective strength of UPMC, UPMC Hillman Cancer Center provides leading-edge treatments and the latest in clinical investigations to transform cancer research, care and prevention—one patient at a time.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top recipients of funding from the National Institutes of Health since 1998. In rankings released by the National Science Foundation, Pitt is in the upper echelon of all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC
