The NCCN has updated its Clinical Practice Guidelines in Oncology for Bladder Cancer to include recommendations for a tumor-informed multiplex PCR circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) test (Signatera) for patients with muscle invasive bladder cancer (MIBC), according to a news release from the developer, Natera.1
According to the updated guidelines, the panel “recommends the consideration of ctDNA-MRD testing as a tool for risk stratification and to determine the use of adjuvant immunotherapy after cystectomy in patients who have not received previous immune checkpoint inhibitor treatment using [the] multiplex PCR-NGS assay for ctDNA.”2
The guideline specifically recommended treatment with atezolizumab (Tecentriq) if testing with the assay is positive within 1 year following cystectomy. This recommendation is given regardless of receipt of prior cisplatin in the neoadjuvant setting.
“This guideline update marks an important turning point for patients with muscle-invasive bladder cancer,” Matthew D. Galsky, MD, deputy director of the Mount Sinai Tisch Cancer Center, director of Genitourinary Medical Oncology, and co-director of the Center of Excellence for Bladder Cancer at the Mount Sinai Tisch Cancer Center, stated in the news release.1 “For the first time, NCCN has incorporated ctDNA-MRD testing into clinical decision-making following cystectomy. These recommendations are supported by prospective phase 3 evidence showing that a ctDNA-guided approach, using Signatera, can help guide post-surgical treatment decisions.”
The Signatera test was validated in the phase 3 IMvigor011 trial (NCT04660344), which evaluated atezolizumab vs placebo among patients with no evidence of radiographic disease following cystectomy; an exploratory analysis of ctDNA dynamics in IMvigor011 presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium showed that serial ctDNA could differentiate patients with high vs low recurrence risk, potentially avoiding unnecessary treatment and correctly identifying those who would benefit with atezolizumab.3 Specifically, they noted that “[patients] with any detectable ctDNA had a poor prognosis” and that “atezolizumab efficacy was similar regardless of timing of positivity or concentration.”
Among all patients, regardless of the timing or concentration of ctDNA positivity, atezolizumab elicited similar efficacy. The HR for disease-free survival (DFS) was 0.62 (95% CI, 0.42-0.91) vs 0.67 (95% CI, 0.40-1.10) among those with ctDNA positivity at initial test vs subsequent test. For those with ctDNA concentrations of 0.1 MTM/mL or less, between 0.1 and 3 MTM/mL, and more than 3 MTM/mL, the HR for DFS was 0.81 (95% CI, 0.46-1.42), 0.59 (95% CI, 0.38-0.91), and 0.47 (95% CI, 0.24-0.94).
For overall survival (OS), the HR was 0.71 (95% CI, 0.42-1.17) vs 0.52 (95% CI, 0.24-1.12) for those with positive ctDNA at initial testing vs subsequent tests. For those with ctDNA concentrations of 0.1 MTM/mL or less, between 0.1 and 3 MTM/mL, and more than 3 MTM/mL, the HR for OS was 0.83 (95% CI, 0.38-1.85), 0.54 (95% CI, 0.29-1.01), and 0.64 (95% CI, 0.29-1.40).
Additionally, the investigators noted that pathology alone was insufficient to predict ctDNA timing or concentration for these patients, with high-risk pathology being associated with earlier time to positivity and high concentration, but higher variability observed within risk groups vs between them. They found that earlier ctDNA positivity and higher concentration of ctDNA were associated with inferior clinical outcomes.
“These recommendations reflect years of work to generate the clinical evidence establishing MRD as a clinically actionable and predictive tool,” Kevin Masukawa, PhD, vice president of Oncology Lifecycle Management at Natera, stated in the release.1 “The IMvigor011 study is an important example of how Signatera-generated evidence can help change clinical practice, and we believe this guideline update is just the beginning of a broader shift toward MRD-guided cancer care.”
In addition to approving atezolizumab for patients with ctDNA-positive MIBC post-cystectomy in May 2026, the FDA approved the Signatera CDx as a companion diagnostic for the identification of patients eligible for atezolizumab alone or with hyaluronidase-tqjs (Tecentriq Hybreza).4
References
- NCCN recommends ctDNA-MRD testing using Signatera™ technology in landmark bladder cancer guideline update. News release. Natera. June 23, 2026. Accessed June 23, 2026. https://tinyurl.com/3u8vcr65
- NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. Version 2.2026. National Comprehensive Cancer Network. Published June 22, 2026. Accessed June 23, 2026. https://tinyurl.com/3j78syzt
- Powles T, Grindheim J, Yilmaz M, et al. Circulating tumor (ct)DNA-guided adjuvant atezolizumab (atezo) in muscle-invasive bladder cancer (MIBC): exploratory analysis of ctDNA dynamics in the IMvigor011 trial. J Clin Oncol. 2026;44(suppl 7):633. doi:10.1200/JCO.2026.44.7_suppl.633
- FDA approves atezolizumab for adjuvant treatment of muscle invasive bladder cancer in patients with molecular residual disease. News release. FDA. May 15, 2026. Accessed June 23, 2026. https://tinyurl.com/msrrrt9u
