Improving the management of prostate cancer using advanced biofluid diagnostics
John Lewis, University of Alberta
Lead Investigator Bio:
John Lewis holds the Frank and Carla Sojonky Chair in Prostate Cancer Research at the University of Alberta. He is an Associate Professor in the Department of Oncology and chairs the Alberta Prostate Cancer Research Initiative. As an entrepreneur, Dr. Lewis has also founded three Canadian biotechnology companies. Dr. John Lewis’s laboratory studies prostate cancer, the most commonly diagnosed cancer in Canadian men. Since no man dies of prostate cancer that stays in his prostate, the group uses real-time intravital imaging of the tumour microenvironment to learn about the mechanisms of cancer metastasis, including the invasion, intravasation and extravasation steps that lead to metastatic dissemination. The group has used this approach to identify key drivers of metastatic progression in prostate and other cancers, and is leveraging this information to develop non-invasive tests to detect aggressive prostate cancer and to develop novel nanoparticles to block the spread of prostate cancer.
While many prostate cancers are diagnosed at an early stage, our limited diagnostic tools prevent us from answering the simplest clinical questions: How dangerous is my cancer, and does it require aggressive treatment? Given that metastasis, or the spread of cancer, is responsible for more than 90% of prostate cancer deaths, it is critical that we develop new tests that can predict the risk of cancer metastasis. In this project, we will utilize a recently developed blood test called EV-FPS that seems to predict how cancer will progress. We will evaluate the use of this test in a clinical laboratory environment to see if it improves significantly on the current PSA test. This should provide more reliable information about how dangerous a patient’s cancer is so that an appropriate treatment decision can be made.
Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer deaths in men. The early diagnosis of prostate cancer (PCa) is critical because aggressive treatment can be curative when tumors are caught early. However, as not all men with PCa are destined to progress – even without treatment, the distinction between high risk and low risk disease is equally important because many patients with low grade disease can be monitored through active surveillance and avoid the morbidity of treatment. Current screening for PCa is done mainly by digital rectal examination (DRE) and serum prostate-specific antigen (PSA) measurement. More than 20 million men are screened this way each year in North America. If these tests are abnormal, the patient is then referred for a prostate biopsy, which is done via a transrectal biopsy under ultrasound guidance. While needle biopsies are the principal diagnostic tool in PCa, it is clear that most biopsies show no cancer and yet subject the patient to anxiety and risks of biopsy including sepsis requiring hospitalization. PSA can be a valuable clinical tool for monitoring outcomes after treatment, but in the intermediate range (2-10 ng/mL), PSA testing performs very poorly at predicting aggressive disease (AUC of 0.58). Gleason grade remains one of the best PCa prognostic indicators. Low grade Gleason PCa rarely progresses to aggressive disease and PCa with Gleason 3+3 and Gleason 3+4 are generally considered as clinically insignificant (indolent). In comparison, cancers with higher Gleason scores (Gleason ≥ 4+3) have a worse prognosis and are considered clinically significant (potentially lethal). Unfortunately, the Gleason Score must be ascertained from a biopsy. Consequently, hundreds of thousands of men without PCa or with clinically insignificant PCa are biopsied every year, resulting in substantial morbidity and considerable healthcare costs. Consequently, there is an immediate need for improved diagnostics to reduce unnecessary biopsies and over-diagnosis of indolent disease, and allow thousands of under-diagnosed men who have clinically significant PCa to receive appropriate early diagnosis. To address this, we have recently developed a robust blood-based assay called the extracellular vesicle fingerprint score (EV-FPS) to predict the outcome of a prostate biopsy. We have completed an initial clinical validation of EV-FPS in a prospective cohort of 377 Albertan men for whom a prostate biopsy was ordered. EV-FPS was significantly higher in aggressive vs. indolent prostate cancer. At a sensitivity of 95%, clinical features including PSA provided only 17% specificity for aggressive prostate cancer with an AUC of 0.72. Combining EV-FPS with clinical features at sensitivity 95% increased the specificity for aggressive prostate cancer to 56% with an AUC of 0.84. Using a score cut-off that achieves 95% sensitivity, our decision curve analysis suggest that up to 40% of men could use this information to potentially avoid a biopsy. In order to move this promising new test into the clinic, it is necessary to perform clinical validation in the AHS/DynaLIFE environment to properly validate the performance of the test in a real-world clinical environment. Once the technology translation into DynaLIFE is complete and the performance of EV-FPS is validated propectively in this environment, it can be incorporated into clinical care in the province.
Impact on prostate cancer patients:
The potential impact is considerable; successful implementation could eventually eliminate up to 600,000 unnecessary biopsies, 24,000 hospitalizations and up to 50% of unnecessary treatments for prostate cancer in North America alone. Beyond an estimated cost savings to the healthcare system of more than $1.4B per year, this will have a dramatic impact on the healthcare experience and quality of life for men.