Circulating tumor DNA as a Predictive and Prognostic Biomarker in the Perioperative Treatment of Muscle-invasive Bladder Cancer: A Systematic Review

Predictive and prognostic biomarkers in the perioperative treatment of muscle-invasive bladder cancer (MIBC) are an unmet need. Circulating tumor DNA (ctDNA) holds promise as a biomarker in this setting. To review the evidence of ctDNA as a prognostic and predictive biomarker in the perioperative treatment of MIBC. We systematically reviewed the literature using PubMed, MEDLINE, and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We included prospective studies investigating neoadjuvant and/or adjuvant chemotherapy and/or immunotherapy for MIBC (T2-T4a, any N, and M0) treated with radical cystectomy. We reported ctDNA results to monitor and/or predict disease status, relapse, and progression. The research retrieved 223 records. Six papers were considered for this review based on prespecified inclusion criteria. Our review confirms the prognostic role of ctDNA after cystectomy and shows a potential predictive benefit in using neoadjuvant chemotherapy and preoperative immunotherapy. Circulating tumor DNA was used to monitor recurrence, and changes in ctDNA status anticipated radiological progression with a median difference of time from 101 to 932 d. A subgroup analysis of the phase 3 Imvigor010 trial showed that only ctDNA-positive patients treated with atezolizumab had an improvement in disease-free survival (DFS; hazard ratio [HR] = 3.36, 95% confidence interval [CI]: 2.44–4.62). Clearance of ctDNA after two cycles of adjuvant atezolizumab was associated with improved outcomes (DFS HR = 0.26, 95% CI: 0.12−0.56, p = 0.0014; overall survival HR = 0.14, 95% CI: 0.03–0.59). Circulating tumor DNA is a prognostic factor after cystectomy and may be used to monitor recurrence. In the adjuvant immunotherapy setting, ctDNA might select patients who benefit the most from this strategy. In the perioperative treatment of muscle-invasive bladder cancer, circulating tumor DNA (ctDNA) positivity correlates with the outcomes after cystectomy and might select patients who may benefit from neoadjuvant chemotherapy and/or immunotherapy. Changes in ctDNA status anticipated radiological progression.