Only some non-muscle-invasive bladder cancer (NMIBC) patients benefit from intravesical Bacillus Calmette-Guérin (BCG), and predictive biomarkers remain lacking. While urine tumor DNA (utDNA) analysis is promising, mutations in tumor-adjacent normal urothelium, namely the field effect, limit specificity. Here, we show that the prevalence of somatic mutations in the urine increases with age. We introduce an improved utDNA minimal residual disease (MRD) approach that increases specificity by removing field-effect mutations. Applying this field-effect-informed MRD approach to 261 samples from NMIBC patients undergoing surgery and adjuvant BCG, we identify three molecular response classes, including surgical responders, BCG responders, and non-responders. Molecular predictors of response to the two treatments differ, with pre-existing immune activation and higher mutation burden enriched in BCG but not surgery responders. These findings highlight the potential of field-effect-informed liquid biopsy methods for guiding personalized therapy and uncovering biomarkers for individual components of multimodal treatments.
Cell. 2026 Jan 27 [Epub ahead of print]
William Y Shi, Kevin J Liu, Mohammad S Esfahani, Kathleen E Mach, Nick A Phillips, Diego Almanza, Ravi K Bajpai, Joseph G Schroers-Martin, Ludimila Trabanino, Timothy J Lee, Vinh La, Gabriela Rodriguez, Grace Holton, Simon B Chen, Patrick Mullane, Douglas J Wu, Monica C Nesselbush, Takeshi Sugio, Jordan C Cheng, Isabel Jabara, Emily G Hamilton, Stefan K Alig, Chih-Long Liu, Dylan J Peterson, Kris Prado, Eugene Shkolyar, Alan Thong, Jay B Shah, Harcharan Gill, Christian A Kunder, Emily Chan, Ali Raza Khaki, Eila C Skinner, Ash A Alizadeh, Joseph C Liao, Maximilian Diehn
Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Program in Cancer Biology, Stanford University, Stanford, CA, USA., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Radiation Oncology, Stanford University, Stanford, CA, USA., Department of Urology, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Program in Cancer Biology, Stanford University, Stanford, CA, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA., Department of Radiation Oncology, Stanford University, Stanford, CA, USA., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA., Department of Pathology, Stanford University, Stanford, CA, USA., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA., Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA., Department of Urology, Stanford University, Stanford, CA, USA., Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address: ., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Urology, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. Electronic address: ., Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address: .