URINE TEST TO PREDICT BLADDER CANCER RECURRENCE

A new noninvasive test may be able to detect bladder cancer recurrence earlier than standard cytology and cystoscopy, according to new findings published online July 7 in the British Journal of Cancer.

French researchers found that a urinary test that measures telomerase reverse transcriptase (TERT) promoter mutations accurately identified recurrent urothelial bladder cancer (UBC), especially in patients whose disease had not yet invaded the muscle wall.

They compared the TERT urine test with cytology results in 348 patients with UBC and found that the TERT test was more accurate. The TERT test had an overall sensitivity of 80.5% and specificity of 89.8% for detecting bladder cancer.

Conversely, the overall sensitivity of cytology was just 33.6%, and the sensitivity for low-grade pTa nonmuscle invasive disease was especially low, at 5.5%.

Of importance, note the authors, sensitivity in the TERT test was not affected by disease stage or grade, and the presence of the TERT promoter mutation in urine was strongly associated with recurrence in patients with nonmuscle invasive bladder cancer (NMIBC) (P < .0001).

"The standard cytology test needs a doctor to look down a microscope to read the results, but the TERT test is read by a machine, which is simpler, more accurate, and available to use straightaway," said study coauthor Alain Ruffion, MD, PhD, from the University Hospital of Lyon in France, in statement.

"While the TERT test costs slightly more than standard cytology, it is likely to become cheaper over time," Dr Ruffion noted. "The fact that the test doesn't react to urinary tract infections is very interesting because it shows that it is robust and unlikely to give misleading results."

Approached by Medscape Medical News for an independent comment, an expert pointed out that "poor specificity and sensitivity have been the Achilles heel of traditional biomarkers for bladder cancer.

"The use of somatic TERT promoter mutations utilizing a genomic approach may hold the key to this problem and open new ways to streamline surveillance of bladder cancer," said Khurshid A. Guru, MD, chair of the Department of Urology and director of robotic surgery at the Roswell Park Cancer Institute in Buffalo, New York.

High Sensitivity and Specificity

The authors note that UBC is associated with a high risk for recurrence, and although cystoscopy and urine cytology are the current gold standards for monitoring patients, they have low sensitivity in NMIBC.

In this study, Dr Ruffion and colleagues assessed the use of TERT promoter mutations in urine as a method of detecting UBC lesions, including low-grade lesions for which standard cytology lacks sensitivity.

The cohort included 275 patients with NMIBC (pTa or pT1), 61 with muscle invasive disease (>pT1), and 12 with carcinoma in situ. The overall TERT mutation rate was 80.5% (280/348).

The sensitivity of the TERT test (280/348, 80.5%) was significantly higher than urine cytology (117/348, 33.6%) (chi-squared test, P < .0001), regardless of tumor stage.

When stratified by tumor grade (low-grade pTa, high-grade pTa/pTis, and pT1), cytology showed a sensitivity of 5.5%, 43.3%, and 50%, respectively, whereas sensitivity of the TERT test remained high in all groups (74.3%, 92.5%, and 77.6%, respectively).

However, the authors point out that the sensitivity of the TERT test in muscle invasive disease (>pT1) did not significantly differ from that of cytology (P = .0515).

For specificity, 167 patients who did not have UBC were assessed for comparison (125 patients had either benign bladder lesions or were healthy individuals, and 42 patients had other cancers).

Specificity was 92.0% (115/125) for patients with benign bladder lesions and for healthy individuals; it was 83.3% for patients with other cancer types (35/42).

Among those with infectious or inflammatory conditions, only one patient presented with a TERT mutation (specificity 96.3%, 26/27). Among patients with prostate cancer who did not have UBC, specificity of the TERT test was 87.9% (29/33).

Detects Recurrence in NMIBC

The authors also assessed the use of the TERT test for detecting cancer recurrence.

In a cohort of 100 patients with recurrence-free survival who were followed for a minimum of 6 months and who initially presented with NMIBC without pTis, they found that the presence of the TERT promoter mutation was strongly associated with recurrence (P < .0001).

On univariate analysis, the presence of a TERT mutation was associated with a risk for recurrence that was increased 5.34-fold in the NMIBC subset (P = .0004), although this association was diminished in multivariate analysis (hazard ratio, 1.72; P = .3015).

When stratified by cystoscopy status, the TERT mutation was still significantly associated with recurrence (P = .034) in patients whose cystoscopy results were negative (46 of 100 patients).

Conversely, the presence of a TERT mutation did not provide additional information for relapse-free survival among patients who had positive cystoscopy results (n = 54; P = .9728).

Clinical Utility Needs Study

Commenting on the study, Matthew Galsky, MD, director of the Novel Therapeutics Program, the Clinical Trials Program, and genitourinary medical oncology at the Tisch Cancer Institute at Mount Sinai Medical Center in New York City, emphasized that there is a clear clinical need for noninvasive approaches to detect recurrence in this disease.

"Several urine-based biomarkers have been explored," he told Medscape Medical News, "but these are associated with limitations."

The current prospective study explored the presence of TERT mutations in the urine as a potential biomarker, Dr Galsky noted, and "this strategy is rational, as TERT mutations are common in bladder cancer, and such mutations would be anticipated to be quite specific for cancer vs normal cells.

"Indeed, this prospective study demonstrates that TERT mutations are both specific and sensitive for bladder cancer and are associated with overall more favorable performance characteristics than conventional cytology," he said.

A limitation of the study is that it was performed at a single center. "But more importantly, while this study does establish the clinical validity of this biomarker, clinical utility must still be established ― that is, does the TERT mutation assay inform clinical decisions such that patients benefit in some way?" commented Dr Galsky. "Further studies are needed to establish clinical utility."

The authors have disclosed no relevant financial relationships.

Br J Cancer. Published online July 7, 2017. Abstract