{"doi":"10.1371/journal.pmed.1003732","title":"Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study","abstract":"BACKGROUND: The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS AND FINDINGS: We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. CONCLUSIONS: utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.","journal":"PLoS Medicine","year":2021,"id":150270,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":95,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":638712,"name":"Kevin Chen","orcid":"0009-0003-4223-7938","position":1,"is_corresponding":false},{"id":638713,"name":"Ramandeep K. Babbra","orcid":"0000-0002-6244-5107","position":2,"is_corresponding":false},{"id":570222,"name":"Wenjia Feng","orcid":"0000-0002-6320-3927","position":3,"is_corresponding":false},{"id":311533,"name":"Nadja Pejovic","orcid":"0000-0002-1930-1319","position":4,"is_corresponding":false},{"id":638714,"name":"Armaan Nallicheri","orcid":"0000-0001-5993-5407","position":5,"is_corresponding":false},{"id":570221,"name":"Peter K. Harris","orcid":"0000-0003-1557-1722","position":6,"is_corresponding":false},{"id":639611,"name":"Katherine Dienstbach","orcid":null,"position":7,"is_corresponding":false},{"id":639612,"name":"Andrew Atkocius","orcid":null,"position":8,"is_corresponding":false},{"id":638715,"name":"Lenon Maguire","orcid":"0000-0002-6718-5439","position":9,"is_corresponding":false},{"id":570626,"name":"Faridi Qaium","orcid":null,"position":10,"is_corresponding":false},{"id":628389,"name":"Jeffrey J. Szymanski","orcid":"0000-0002-8005-701X","position":11,"is_corresponding":false},{"id":638716,"name":"Brian C. Baumann","orcid":"0000-0002-7482-1413","position":12,"is_corresponding":false},{"id":108228,"name":"Li Ding","orcid":"0000-0003-1517-2975","position":13,"is_corresponding":false},{"id":476703,"name":"Dengfeng Cao","orcid":"0000-0002-6551-2723","position":14,"is_corresponding":false},{"id":402677,"name":"Melissa A. Reimers","orcid":"0000-0002-5167-3630","position":15,"is_corresponding":false},{"id":277531,"name":"Eric H. Kim","orcid":"0000-0002-0284-8342","position":16,"is_corresponding":false},{"id":402679,"name":"Zachary L. Smith","orcid":"0000-0002-5945-3288","position":17,"is_corresponding":false},{"id":638717,"name":"Vivek Arora","orcid":"0000-0003-1694-9109","position":18,"is_corresponding":false},{"id":110534,"name":"Aadel A. Chaudhuri","orcid":"0000-0003-3115-3061","position":19,"is_corresponding":false},{"id":638711,"name":"Pradeep S. Chauhan","orcid":"0000-0003-4304-011X","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-18T23:43:01.325389Z","pmid":"34464379","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}