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Multicenter Study
. 2019 Jun;123(6):959-967.
doi: 10.1111/bju.14673. Epub 2019 Feb 5.

Diagnostic accuracy, clinical utility and influence on decision-making of a methylation urine biomarker test in the surveillance of non-muscle-invasive bladder cancer

David D'Andrea  1 , Francesco Soria  1   2 , Sonja Zehetmayer  3 , Kilian M Gust  1 , Stephan Korn  1 , J Alfred Witjes  4 , Shahrokh F Shariat  1   5   6
Affiliations
Multicenter Study

Diagnostic accuracy, clinical utility and influence on decision-making of a methylation urine biomarker test in the surveillance of non-muscle-invasive bladder cancer

David D'Andrea et al. BJU Int. 2019 Jun.

Abstract

Objectives: To investigate prospectively the clinical utility and influence on decision-making of Bladder EpiCheck™, a non-invasive urine test, in the surveillance of non-muscle-invasive bladder cancer (NMIBC).

Materials and methods: Urine samples from 440 patients undergoing surveillance for NMIBC were prospectively collected at five centres and evaluated using the Bladder EpiCheck test (NCT02647112). A multivariable nomogram and decision-curve analysis (DCA) were used to evaluate the impact of Bladder EpiCheck on decision-making when used in routine clinical practice. The test was designed to exclude recurrent disease.

Results: Data from 357 patients were available for analysis. The test had a specificity of 88% (95% confidence interval [CI] 84-91), a negative predictive value (NPV) of 94.4% (95% CI 91-97) for the detection of any cancer and an NPV of 99.3% for the detection of high-grade cancer. In multivariable analysis, positive Bladder EpiCheck results were independently associated with any and high-grade disease recurrence (odds ratio [OR] 18.1, 95% CI 8.7-40.2; P < 0.001 and OR 78.3, 95% CI 19.2-547; P < 0.001). The addition of Bladder EpiCheck to standard variables improved its predictive ability for any and high-grade disease recurrence by a difference of 16% and 22%, respectively (area under the curve 85.9% and 96.1% for any and high-grade cancer, respectively). DCA showed an improvement in the net benefit relative to cystoscopy over a large threshold of probability, resulting in a significant reduction in unnecessary investigations. These results were similar in subgroups assessing the impact of specific clinical features.

Conclusions: Bladder EpiCheck is a robust high-performing diagnostic test in patients with NMIBC undergoing surveillance that can potentially reduce the number of unnecessary investigations.

Keywords: #BladderCancer; #blcsm; non-muscle-invasive; prediction; surveillance; urinary biomarker.

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Conflict of interest statement

Dr D'Andrea reports personal fees from Nucleix (Rehovot, Israel), during the conduct of the study. Drs Korn, Soria and Zehetmayer have nothing to disclose. Dr Witjes reports personal fees from Nucleix during the conduct of the study. Dr Gust reports personal fees and other fees from serving on the Advisory Boards for Cepheid, Roche, MSD and Ferring and as a Speaker for Astellas, Astra Zeneca, BMS, Ipsen, MSD and Roche, and meeting/travel expenses from Allergan, Astellas, Astra Zeneca, Bayer, BMS, Janssen, MSD, Novartis, Pfizer, Pierre Fabre and Roche outside the submitted work. Dr Shariat reports personal fees from Nucleix (Rehovot, Israel), during the conduct of the study, other from Method to determine prognosis after therapy for prostate cancer (granted 9 June 2002), other from Method to determine prognosis after therapy for bladder cancer (granted 19 June 2003), other from Prognostic methods for patients with prostatic disease (granted 5 August 2004), other from Soluble Fas urinary marker for the detection of bladder transitional cell carcinoma (granted 20 July 2010), and other from Astellas, Astra Zeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Roche, Sanochemia, Sanofi and Wolff, outside the submitted work.

Figures

Figure 1
Figure 1
Logistic regression nomogram for the prediction of bladder cancer (BCa) (A) and high‐risk BCa (B) in the follow‐up of patients with previous non‐muscle invasive bladder cancer. CIS, carcinoma in situ; LG, low grade; HG, high grade; PUNLMP, papillary urothelial neoplasm of low malignant potential.
Figure 2
Figure 2
Decision‐curve analysis assessing the clinical impact of the nomograms estimating the prediction of bladder cancer (BCa) (A) and high‐risk BCa (B) in the follow‐up of patients with previous non‐muscle‐invasive BCa. The inclusion of EpiScore is compared with current clinical prognostic models and the strategies of evaluating all or none of the patients with cystoscopy and cytology.
Figure 3
Figure 3
Interventions avoided by the use of Bladder EpiCheck in the decision‐making of evaluating a patient with cystoscopy and cytology during the follow‐up of non‐muscle‐invasive bladder cancer (BCa), based on the risk of having any BCa (A) or high‐risk BCa (B) recurrence.
See this image and copyright information in PMC

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