Bringing Precision Medicine
to Biliary Cancers
Biliary tract cancers — including intra- and extrahepatic
cholangiocarcinomas, and gallbladder cancer — are aggressive malignancies with poor clinical outcomes.
By Alok Khorana, MD, and Davendra Sohal, MD, MPH
Most patients present with advanced disease, and current management options are limited to chemotherapy agents such as gemcitabine and cisplatin, with modest benefit.
In many other cancers, physician-scientists have been able to improve clinical outcomes by identifying molecular aberrations in tumors and by conducting clinical trials of novel therapies aimed at those molecular targets.
There are several obstacles, however, to studying biliary tract malignancies:
They are a group of relatively uncommon cancers.
Tissue biorepositories are rare or nonexistent.
Federal funding for scientific research is limited.
Patients present late in the course of the disease, making enrollment in clinical trials difficult.
Surmounting the Obstacles to Binary Cancer Research
At Cleveland Clinic’s Taussig Cancer Institute, we are building a research program to overcome these hurdles. With the Frank and Nancy Porter family’s creation of the Porter Family Genomics Fund, we are able to initiate a comprehensive research program in biliary malignancies that will be quickly translatable into innovative clinical trials.
Our initial focus is the creation of a robust biorepository of tumor tissue specimens collected both retrospectively and prospectively from patients seen at Cleveland Clinic. We will utilize these biospecimens to develop an easily reproducible platform to study molecular alterations in biliary tract cancers.
Dealing with the Scarcity of Tumor Tissue Samples
In the past, we have been limited because traditional clinical specimens contain only small amounts of tumor tissue. Most diagnoses of biliary tract cancers are made using fine-needle aspiration samples or bile duct brushings collected during procedures such as endoscopic ultrasound or endoscopic retrograde cholangiopancreatography.
Partnering with Case Comprehensive Cancer Center scientists who have extensive experience in clinical genomics, we have identified tumor sequencing platforms that can allow us to identify DNA and RNA changes in archived biliary tract cancer specimens obtained during routine clinical care. Our collaborators will use leading-edge high-throughput next-generation sequencing techniques and bioinformatics methods that can surmount the usual problems of quantity and quality of tumor tissue.
Next, we envision being able to correlate these molecular findings with clinical data to understand the impact of various molecular alterations on clinical outcomes. We are therefore also building a robust clinical data set to complement potential molecular findings.
In addition, comparisons between biliary tract cancer specimens and non-neoplastic biliary tissues, such as specimens obtained during cholecystectomies, will allow us to further home in on alterations that play a critical role in cancer development and progression. Thus, we will be able to create a catalog of clinically relevant molecular alterations in biliary tract cancers.
Employing Clinical Trials to Targeted Therapies
Finally, we plan to apply this knowledge to clinical trials of novel targeted therapies. We already have a unique clinical genomics program at the Cancer Institute. As part of this program, we perform extended genomic sequencing of clinical specimens from patients with advanced solid tumors. Results are reviewed at a dedicated Genomics Tumor Board — a weekly meeting of clinical and translational oncologists.
Participants review each result in detail and make recommendations for targeted therapy — on-label drugs, off-label use or clinical trials — which are communicated to treating physicians.
We have a portfolio of clinical trials of targeted therapies encompassing many genomic alterations of known clinical value and many solid tumor histologies. We will build on our experience with this initial broad program, with a focus on obtaining novel agents and innovative trials specifically for our patients with biliary malignancies.
We are privileged to have the support of patient survivors and advocates such as Lisa Craine and her foundation, “Craine’s Cholangiocarcinoma Crew.”
Soon we hope to utilize modern tumor sequencing methods and novel targeted therapies in conjunction with a well-established program of patient identification, tumor sequencing, and coordinated patient access and enrollment into clinical trials of targeted therapies based on their individual tumor genome. This effort will bring individualized therapies and precision oncology to each of our patients with biliary malignancies.
Dr. Khorana is a staff member of Cleveland Clinic’s Department of Hematology and Medical Oncology and Director of the Taussig Cancer Institute’s Gastrointestinal Malignancies Program.
He can be reached at firstname.lastname@example.org or 216.636.2690. On Twitter: @aakonc
Dr. Sohal is a staff physician in the Department of Hematology and Medical Oncology and Director of the Taussig Cancer Institute’s Clinical Genomics Program.
He can be reached at email@example.com or
K E Y P O I N T S
Biliary tract cancers are aggressive and difficult to treat successfully.
Attempts to improve outcomes have been hampered by the cancers’ relative rarity, the advanced stage of most tumors upon presentation, and the scarcity of tissue biorepositories and research funding.
Cleveland Clinic is building a comprehensive biliary cancer research and targeted treatment program to overcome these obstacles.