Urine test may aid detection of high-grade invasive bladder cancer
Key takeaways:
- A urinary DNA methylation test outperformed the nuclear matrix protein 22 test or urine cytology test.
- Additional research is needed to evaluate the test in a more diverse cohort.
A urinary DNA methylation test showed potential for detecting high-grade or invasive bladder cancer, according to results of a prospective multicenter study.
The approach — which outperformed the nuclear matrix protein 22 (NMP22) test and urine cytology test — showed “excellent negative predictive value” but its positive predictive value proved “suboptimal,” researchers wrote.
An accurate noninvasive biomarker test is necessary to improve early diagnosis of bladder cancer, according to study background.
In Gab Jeong, MD, PhD, of the department of urology at Asan Medical Center in the Republic of Korea, and colleagues conducted a prospective study at 10 sites to evaluate the performance of the urinary DNA methylation test (PENK methylation).
Investigators compared diagnostic accuracy of this approach with that of the NMP22 test and a urine cytology test.
The analysis included 1,099 patients (55.9% men) aged older than 39 years enrolled between March 11, 2022, and May 30, 2024. All participants had hematuria and were scheduled to undergo cystoscopy within 3 months.
The sensitivity and specificity of the urinary DNA methylation test for high-grade or invasive bladder cancer served as the primary outcome. Accuracy of the test for overall bladder cancer detection, as well as a comparison of sensitivity and specificity between test types, served as secondary outcomes.
Researchers determined 219 (19.9%) study participants had bladder cancer, and 176 (16%) had high-grade or invasive cancer.
For detection of high-grade or invasive bladder cancer, the urinary DNA methylation test showed a sensitivity of 89.2% (95% CI, 84.6%-93.8%) and a specificity of 87.8% (95% CI, 85.6%-89.9%).
For detection of any stage or grade of bladder cancer, the test had a sensitivity of 78.1% (95% CI, 72.6%-83.6%) and a specificity of 88.8% (95% CI, 86.7%-90.8%).
Analyses revealed a positive predictive value for high-grade or invasive bladder cancer of 61.3% (95% CI, 55.4%-67.3%) and a negative predictive value of 97.6% (95% CI, 96.6%-98.7%).
The urinary DNA methylation test showed “significantly superior sensitivity” for the detection of high-grade of invasive bladder cancer and for overall bladder cancer compared with the NMP22 test or urine cytology test, Jeong and colleagues wrote.
Researchers acknowledged study limitations, including the relatively high proportion of individuals who provided informed consent with samples that could not be evaluated according to study protocol. In addition, the study included a small cohort that consisted only of individuals from within the Republic of Korea, highlighting the need for more research in a cohort with greater racial and ethnic diversity.
Perspective
Back to Top
Hematuria is a common complaint in primary care and urology clinics and has a wide differential diagnosis. Between 1% and 5% of patients will have bladder cancer diagnosed after workup of gross hematuria, whereas less than 1% of patients with microhematuria have bladder cancer. In addition to upper tract imaging and urinary cytology, part of the workup recommended by American Urological Association includes cystoscopy, where a small flexible camera is passed into the anesthetized urethra for visual inspection of the entire bladder and urothelial mucosa. Most bladder cancers are identified with this diagnostic modality. However, invasive tests on awake patients often cause anxiety, pain and, rarely, more significant complications such as urethral stricture, worsening hematuria and infections. For this reason, multiple groups have tried to develop urine tests which could be used as a way to avoid cystoscopy in patients without bladder tumors. This is, after all, the rationale for cytology — to detect urothelial cancer noninvasively.
What do these study findings mean? The operating characteristics are very impressive, but would they change practice? Would urologists or patients feel comfortable deferring cystoscopy in test-negative patients? It depends on the patient’s risk tolerance and understanding of the test result.
“There is an 11% chance that if you have bladder cancer — we are not detecting it with this negative test result,” “There is a 2.5% chance we are missing a significant cancer with this negative test” and “There is a 61% chance that this positive test means you have significant bladder cancer” all are ways that the performance metrics of the test can be conveyed to a patient. These statements mean different things to different people depending on their lived experiences. What is the significance of cystoscopy avoidance in a patient with high-grade bladder cancer? Delay in diagnosis might not materially affect the patient’s ultimate clinical destiny, but one could easily foresee a delay in diagnosis being a significant missed opportunity. Although invasive tests such as cystoscopy are uncomfortable and anxiety-provoking, it is often a 30- to 60-second test that can be tolerated well in the outpatient setting. However, this experience is lived differently by many patients, and the tradeoffs between missed diagnostic opportunities and plastic objects being placed into one’s urethra are interpreted differently by patients in all walks of life.
Ideally, the cost of an additional test — such as PENK methylation testing — would be offset by cost reduction through elimination of unnecessary tests, such as cystoscopy for patients without bladder cancer and any costs associated with cystoscopy complications. The decision to adopt novel bladder cancer diagnostic tests will, therefore, be a function of test performance, the tradeoffs between missed opportunities and consenting for invasive tests, and cost effectiveness.
Collapse
Read more about