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Patients with bladder cancer treated with radical cystectomy and adjuvant therapy need continuing surveillance. Regular cystoscopic monitoring, however, is highly invasive and places a substantial burden on quality of life. It also makes bladder cancer on a per-patient basis.

Liquid biopsies have emerged as a minimally invasive tool for the analysis of tumor-derived markers in bodily fluids, with cell-free DNA (cfDNA) methylation analysis improving early diagnosis, disease monitoring, and risk assessment in colorectal, hepatocellular, renal cell, and .

A study in the indicates that MIR145 core promoter methylation in pretreatment cfDNA could provide minimally invasive, personalized risk stratification after radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). The results, in 120 bladder cancer patients age-matched with 20 healthy controls, showed that reduced pretreatment cfDNA methylation of MIR145 core promoter was associated with short-term disease progression (HR 2.027, P=0.010) and poor overall survival (HR 2.098, P=0.009) after radical cystectomy.

"Remarkably, multivariate Cox regression models adjusted for tumor stage, patients' age, and sex demonstrated MIR145 core promoter methylation in cfDNA as a minimally invasive and independent predictor of MIBC progression that resulted in superior risk stratification of treatment outcomes and MIBC prognosis," Margaritis Avgeris, PhD, of the National and Kapodistrian University of Athens in Greece, and colleagues wrote. "Methylation profiling of MIR145 core promoter in pretreatment cfDNA could emerge as a promising marker for blood-based surveillance in bladder cancer."

In a of MIR-143/145 gene cluster epigenetics, the team found that lower levels of MIR145 core promoter methylation were associated with aggressive disease phenotypes and independently predicted progression of superficial tumors and inferior survival outcomes in MIBC.

None of the authors responded to requests for comment, and the following Q&A is based on excerpts from the new study.

What was the rationale for the study?

Bladder cancer ranks as the most frequently diagnosed urinary malignancy among men globally. MIBC accounts for about 25% of primary tumors that are associated with high mortality rates. Consequently, there is an urgent need for novel molecular diagnostics that can contribute to clinical decision-making and individualized treatment approaches, alleviating the need for expensive, high-morbidity interventions.

In light of our earlier findings, we wanted to analyze the methylation imprinting of MIR145 core promoter in pretreatment cfDNA to evaluate its clinical utility for improving risk stratification and personalized prognosis.

Did your cohort consist primarily of men?

Yes. Of the 120 participants in our screening cohort, the median age was 70.1 years and 80.8% were male; 20 participants had a diagnosis of non-muscle invasive bladder cancer (NMIBC), and 80 had a diagnosis of MIBC.

Did you conduct separate survival analyses in these groups?

Owing to the marked molecular/cellular heterogeneity of bladder tumors, the disease course is significantly diversified among patients with similar clinicopathologic traits. We used tumor relapse and progression as clinical endpoints in patients with NMIBC, and disease progression and death in those with MIBC.

What is your main take-home message for practicing oncologists?

Our findings clearly highlight the clinical benefit and compelling diagnostic potential of MIR145 core promoter methylation analysis in pre-treatment cfDNA as a minimally invasive and independent predictor of treatment outcome in MIBC. We think it could emerge as a promising blood-based marker that guides modern decision-making in MIBC.

In addition, our study has unveiled an intriguing correlation between the reduced methylation of MIR145 core promoter in pretreatment cfDNA and treatment outcomes in MIBC. This specific clinical impact for the patients with MIBC is aligned with the reduced MIR145 promoter methylation and increased leakage of cfDNA compared with superficial tumors.

What's next for this research?

We have assessed pretreatment cfDNA samples, but post-treatment cfDNA methylation analysis has yet to be included. To address this gap, future studies should incorporate evaluation of both pre- and post-neoadjuvant therapy and/or post-cystectomy as well as post-systemic therapy cfDNA methylation levels of the MIR145 core promoter.

Read the study here.