NCCN Guidelines Recommend ctDNA-MRD Testing in MIBC Care

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for Bladder Cancer to incorporate tumor-informed, multiplex PCR-based circulating tumor DNA (ctDNA) molecular residual disease (MRD) testing into the treatment algorithm for patients with muscle-invasive bladder cancer (MIBC).¹

The revised guidelines state that the NCCN panel recommends considering ctDNA-MRD testing as a tool for risk stratification and to help determine the use of adjuvant immunotherapy after cystectomy in patients who have not previously received immune checkpoint inhibitor treatment, using an FDA-approved, personalized, tumor-informed, multiplex PCR–next-generation sequencing (NGS) assay for ctDNA. This marks the first time NCCN guidelines have recognized personalized, tumor-informed ctDNA-MRD testing as a prognostic and predictive biomarker in MIBC, which the guideline developers characterized as a significant advance over previous recommendations.

Signatera: A Tumor-Informed ctDNA Assay

Signatera is a personalized, tumor-informed, multiplex PCR-NGS ctDNA assay that served as the MRD testing platform in the phase 3 IMvigor011 trial (NCT04660344), which generated the evidence supporting the recommendation. The trial data now underpins a category 1 recommendation—NCCN's highest level of designation—for Signatera-guided adjuvant atezolizumab (Tecentriq), initiated upon MRD positivity within 1 year following cystectomy.

In May 2026, the FDA approved Signatera CDx concurrently with adjuvant atezolizumab as a companion diagnostic to identify patients with MIBC who are ctDNA-MRD positive and who may benefit from treatment with adjuvant immunotherapy.²

“This guideline update marks an important turning point for patients with [MIBC],” Matthew D. Galsky, MD, of Mount Sinai Tisch Cancer Center, stated in a 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 postsurgical treatment decisions.”

Clinical Context

For those managing patients with MIBC after cystectomy, the guideline update provides a more structured, biomarker-based framework for selecting candidates for adjuvant immunotherapy. Postoperative decision-making in this setting has relied primarily on pathologic risk features; the category 1 designation for Signatera-guided adjuvant atezolizumab signals a high level of supporting evidence and panel consensus for using ctDNA-MRD status—rather than clinicopathologic criteria alone—to guide adjuvant treatment decisions in checkpoint inhibitor–naive patients who test MRD-positive within the first year after surgery.

The update ultimately reflects a broader trend toward integrating MRD-based testing into standard treatment pathways across malignancies, with bladder cancer joining Merkel cell carcinoma and diffuse large B-cell lymphoma as tumor types where ctDNA-MRD assessment is now incorporated into NCCN-recommended care.

REFERENCES

1. NCCN Recommends ctDNA-MRD Testing Using Signatera™ Technology in Landmark Bladder Cancer Guideline Update. News release. Natera. June 23, 2026. Accessed June 24, 2026. https://tinyurl.com/3am9d4j5

2. FDA approves atezolizumab for adjuvant treatment of muscle invasive bladder cancer in patients with molecular residual disease. News release. US Food and Drug Administration. May 15, 2026. Accessed June 25, 2026. https://tinyurl.com/ynejujam