A first-of-its kind rapid autopsy program is helping reveal the molecular characteristics of advanced bladder cancers — and point the way toward better treatment strategies for these deadly, understudied tumors.
In a new study, researchers described molecular differences in two different types of bladder cancer that had spread, or metastasized, through the body. The team’s analysis revealed potential therapeutic vulnerabilities in these metastatic tumors. They discovered that for 70% of potentially druggable targets, a biopsy of a single metastasis may be enough to help oncologists tailor a treatment regimen that targets all of a patient’s tumors. Their work also illuminated how bladder cancer can metastasize, showing that small areas of the original tumor can seed new tumors.
The study was published in final form on June 11 in JCI Insight by researchers from Fred Hutchinson Cancer Research Center and the University of Washington.
“The ultimate goal is to know the disease better so we can precisely treat it,” said Dr. Andrew Hsieh, a Fred Hutch physician-scientist who studies cancers of the genitourinary system and led the study.
Bladder cancer, also known as urothelial cancer, is the sixth-most common type of cancer in the U.S. This year, about 80,500 people are expected to be diagnosed with the disease. Surgery, chemotherapy and immunotherapy are longstanding standard treatment strategies. Checkpoint inhibitors, a newer type of immunotherapy, were approved for bladder cancer in 2017.
Patients diagnosed with localized bladder tumors are nearly as likely to survive the next five years as people who don’t have bladder cancer. But if a patient’s bladder tumor is diagnosed after it has metastasized, the stats get grimmer quickly. Only half of patients diagnosed with metastatic bladder cancer live nine to 15 months past diagnosis.
While there have been many informative studies mining the molecular characteristics of localized, early stage bladder cancer, Hsieh said, “localized disease is not what inevitably kills patients — it’s metastatic disease. In order to target metastatic disease, we need to understand it. In order to understand it, we need to be able to study it, and in order to study it, we need to have access to these precious and rare tissues.”
This need drove Hsieh and his UW colleagues Drs. Ming Lam, Jonathan Wright and Bruce Montgomery to create a joint Fred Hutch/UW metastatic bladder cancer rapid autopsy program. To Hsieh’s knowledge, the program is the first in the world to focus on advanced bladder cancer. Patients who participate in the program agree to donate samples of their tumor and normal tissues to research after their death. Taken within six hours after patients pass away, the donated, de-identified samples are giving scientists new insights into metastatic disease.
Hsieh and a team of investigators including co-first authors Drs. Brian Winters and Navonil De Sarkar examined tumors from seven patients with advanced bladder cancer who donated tissue through the rapid autopsy program. In four of the patients, the original tumors arose in the bladder. In the other three, the primary tumors began in the tubes, called ureters, that connect the bladder and kidneys. They also compared patients’ metastatic tumors to their original tumors.
The researchers found differences in the mutations that appeared to drive the formation of upper-tract tumors that arose in the ureters versus lower-tract tumors that arose in the bladder. Large chromosomal changes were more common in tumors from the upper bladder tract. Tumors that arose in the lower tract were more likely to share common mutations among different patients.
Many of the mutations they found created changes that theoretically could be targeted with drugs. This suggests that these kinds of analyses could help guide patient care by alerting oncologists to which drugs are most likely to be effective against an individual patient’s disease. And, the team found that for almost three quarters of these so-called druggable mutations, the same mutation was found in every one of a patient’s metastases.
“This is encouraging,” said Hsieh. “It suggests doing a biopsy on one metastasis could suggest what’s there — and druggable — in all of them.”
The grain of salt, he cautioned, was the fact that the other 30% of potentially druggable changes were not shared among all of an individual patient’s metastases.
The findings also deepened the researchers’ understanding of how metastatic bladder cancer develops, a first step toward finding new ways of combating it. Hsieh’s team found that metastases from patients with upper-tract tumors appeared to be seeded by cells from the original tumor that carried rare mutations.
Though this first study is small, the team has big plans for the future of the UW/Fred Hutch bladder cancer program. The team is now analyzing tumors from 19 more patients who have donated tissue. Researchers involved in the program are working to answer questions that have dogged the field, including determining which combinations of mutations drive the most aggressive forms of the disease, and develop better alternatives to standard biopsies.
“The ultimate goal is to develop this into a program that provides … researchers worldwide [the opportunity] to learn more about the most advanced stage of disease,” Hsieh said.
The work was supported by philanthropy at Fred Hutch from a few generous individuals and Seattle Translational Tumor Research.
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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