Urine test enables non-invasive bladder cancer detection

One of the first signs of bladder cancer can be blood in the urine (haematuria), but less than one in five patients presenting with haematuria who are referred for invasive cystoscopy are actually diagnosed with bladder cancer.

With this in mind, US and Korean researchers have developed a streamlined and simplified DNA-based urine test to improve early detection of bladder cancer in patients with haematuria, potentially reducing the need to refer patients for cystoscopy. Their work has been published in The Journal of Molecular Diagnostics.

“Despite recommendations for cystoscopy examination in patients presenting with microscopic and gross haematuria, the diagnostic yield of bladder cancer in this group ranges from 2% to 20%, leading to numerous unnecessary procedures,” said lead investigator Dr Sungwhan An, from Genomictree in South Korea and Promis Diagnostics in the USA.

“Moreover, due to the invasive nature of cystoscopy and low patient compliance, many haematuria patients, particularly microhaematuria patients, are not promptly referred for examination, resulting in missed opportunities for early bladder cancer detection and subsequent diagnosis at advanced stages, leading to both physical and economic burdens.”

Despite the US FDA’s approval of urine biomarker-based products, their efficacy in clinical practice for the initial diagnosis of primary bladder cancer has remained uncertain, as urine cytology has limited sensitivity — especially for primary bladder cancer detection. The good news is, aberrant DNA methylation has long been recognised as a promising diagnostic biomarker in various cancer types, including bladder cancer.

To improve bladder cancer detection accuracy using urine cytology, An and co-investigators had previously developed a novel molecular diagnostic tool to measure proenkephalin (PENK) methylation levels using two steps of real-time PCR in urine DNA to detect primary bladder cancer in patients with haematuria. They have now streamlined and optimised the entire process, integrating the previous two-step process into a one-step procedure incorporating two reactions of linear target enrichment (LTE) and quantitative methylation-specific PCR (qMSP) conducted via real-time PCR within a closed-single tube system: EarlyTect Bladder Cancer Detection (BCD).

In testing the sensitivity and specificity of EarlyTect BCD — a single-biomarker test — the results were comparable to or even better than the reported performance of multi-biomarker tests. In a retrospective training set (105 patients), an optimal cut-off value was determined to distinguish bladder cancer from non-bladder cancer, resulting in a sensitivity of 87.3% and a specificity of 95.2%. In a prospective validation set of 210 patients (122 Korean and 88 American), the overall sensitivity for detecting all stages of bladder cancer was 81%, with a high negative predictive value of 97.7% for distinguishing haematuria patients without bladder cancer. There was no significant difference between the two groups. EarlyTect BCD achieved a sensitivity of 100% in detecting high-grade non-invasive papillary carcinoma and higher stages of bladder cancer.

The team’s findings suggest that the test could significantly impact clinical practice, particularly during the initial diagnosis of haematuria patients. More accurate urine DNA results could mean that numerous cystoscopies could be avoided, while patients with a positive urine test can be actively referred for a cystoscopy examination, ultimately increasing the detection rate of early-stage bladder cancer.

“There is a rational imperative to accurately diagnose bladder cancer patients through non-invasive molecular diagnostic methods, particularly those with high-grade non-invasive papillary carcinoma and higher stages, who exhibit a heightened propensity for disease progression,” An said. “The non-invasive nature of using a urine sample and the simplified test procedure offer advantages such as facilitating access to early diagnostic opportunities, a shorter turnaround time for sample processing, and efficient, accurate and consistent analysis of results with minimised cross-contamination.

“With the urgent requirement for early bladder cancer detection during initial diagnosis, EarlyTect BCD emerges as a promising solution with minimal complexity, heightened robustness and, most importantly, user-friendliness, making it easy to implement in clinical laboratory practice,” An said. “These novel diagnostic approaches may revolutionise the field of bladder cancer diagnosis, reducing bladder cancer mortality rates and treatment-associated healthcare expenses.”

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