{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:39:24Z","timestamp":1792201164988,"version":"4.4.0"},"reference-count":94,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"697","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,5,24]]},"abstract":"<jats:p>The recommended treatment for patients with high-risk non\u2013muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Gu\u00e9rin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1\/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.<\/jats:p>","DOI":"10.1126\/scitranslmed.abn4118","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T13:58:51Z","timestamp":1684936731000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":98,"title":["Non\u2013muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Gu\u00e9rin"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-5982","authenticated-orcid":true,"given":"Florus C.","family":"de Jong","sequence":"first","affiliation":[{"name":"Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7016-7354","authenticated-orcid":true,"given":"Teemu D.","family":"Laajala","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."},{"name":"Department of Mathematics and Statistics, University of Turku, FI-20014 Turku, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Hoedemaeker","sequence":"additional","affiliation":[{"name":"Pathan, Pathological Laboratory, 3045 PM Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8380-7157","authenticated-orcid":true,"given":"Kimberley R.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique C.\u00a0J.","family":"van der Made","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egbert R.","family":"Boev\u00e9","sequence":"additional","affiliation":[{"name":"Department of Urology, Franciscus Gasthuis &amp; Vlietland, 3045 PM Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6113-5150","authenticated-orcid":true,"given":"Deric K.\u00a0E.","family":"van der Schoot","sequence":"additional","affiliation":[{"name":"Department of Urology, Amphia, 4818 CK, Breda, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3417-8344","authenticated-orcid":true,"given":"Bart","family":"Nieuwkamer","sequence":"additional","affiliation":[{"name":"Department of Urology, Reinier de Graaf Gasthuis, 2625 AD Delft, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-5396","authenticated-orcid":true,"given":"Emiel A.\u00a0M.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2060-9353","authenticated-orcid":true,"given":"Tokameh","family":"Mahmoudi","sequence":"additional","affiliation":[{"name":"Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, Netherlands."},{"name":"Department of Pathology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-0436","authenticated-orcid":true,"given":"Joost L.","family":"Boormans","sequence":"additional","affiliation":[{"name":"Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8708-8206","authenticated-orcid":true,"given":"Dan","family":"Theodorescu","sequence":"additional","affiliation":[{"name":"Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CA 90048, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3158-9682","authenticated-orcid":true,"given":"James C.","family":"Costello","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0991-0812","authenticated-orcid":true,"given":"Tahlita C.\u00a0M.","family":"Zuiverloon","sequence":"additional","affiliation":[{"name":"Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2021.08.010"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2012.10.039"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/JU.0000000000001422"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-26002-6"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2018.09.002"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2017.10.003"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2011.09.026"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2018.06.024"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2014.11.031"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00386-6"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3121"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.08.005"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22465-w"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22126-x"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2017.05.040"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-3323"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2020.06.048"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.007"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.euf.2016.12.011"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-1920"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3593"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag1166"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64396-9"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3612"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0638-6"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7493-1_12"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.26476"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)35678-1"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003586"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0267"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2018.06.045"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.4070"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.598118"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncoscience.335"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.08.002"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072468"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aav2437"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61392"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2019.07.002"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0109-13"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9537"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-016-1945-z"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-018-0055-4"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1731"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1080\/1040841X.2016.1185603"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00147-9"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22062800"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25501"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1085-z"},{"key":"e_1_3_3_53_2","first-page":"EVIDoa2200167","article-title":"IL-15 superagonist NAI in BCG-unresponsive non\u2013muscle-invasive bladder cancer","volume":"2","author":"Chamie K.","year":"2022","unstructured":"K.\u00a0Chamie, S. S.\u00a0Chang, E.\u00a0Kramolowsky, M. L.\u00a0Gonzalgo, P. K.\u00a0Agarwal, J. C.\u00a0Bassett, M.\u00a0Bjurlin, M. L.\u00a0Cher, W.\u00a0Clark, B. E.\u00a0Cowan, R.\u00a0David, E.\u00a0Goldfischer, K.\u00a0Guru, M. W.\u00a0Jalkut, S. D.\u00a0Kaffenberger, J.\u00a0Kaminetsky, A. E.\u00a0Katz, A. S.\u00a0Koo, W. J.\u00a0Sexton, S. N.\u00a0Tikhonenkov, E. J.\u00a0Trabulsi, A. F.\u00a0Trainer, P.\u00a0Spilman, M.\u00a0Huang, P.\u00a0Bhar, S. A.\u00a0Taha, L.\u00a0Sender, S.\u00a0Reddy, P.\u00a0Soon-Shiong, IL-15 superagonist NAI in BCG-unresponsive non\u2013muscle-invasive bladder cancer. NEJM Evid. 2, EVIDoa2200167 (2022).","journal-title":"NEJM Evid."},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(06)92006-9"},{"key":"e_1_3_3_55_2","first-page":"109","article-title":"Getting across the cell envelope: Mycobacterial protein secretion","volume":"374","author":"van der Woude A. D.","year":"2013","unstructured":"A. D.\u00a0van der Woude, J.\u00a0Luirink, W.\u00a0Bitter, Getting across the cell envelope: Mycobacterial protein secretion. Curr. Top. Microbiol. Immunol. 374, 109\u2013134 (2013).","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.06.013"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e16-10-0722"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642358"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1928"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.038"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004485"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-019-0262-7"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201708163"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1817323"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1097\/JU.0000000000001633"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11291-0"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2018.09.003"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.018"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-020-0304-1"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.02.028"},{"key":"e_1_3_3_71_2","unstructured":"M. M\u00e4chler P.\u00a0Rousseeuw A.\u00a0Struyf M.\u00a0Hubert K.\u00a0Hornik Cluster: Cluster Analysis Basics and Extensions (2015); R package version 2.0.3."},{"key":"e_1_3_3_72_2","unstructured":"H. Pag\u00e8s M.\u00a0Carlson S.\u00a0Falcon N.\u00a0Li AnnotationDbi: Manipulation of SQLite-Based Annotations in Bioconductor (2020); R package version 1.50.3."},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq170"},{"key":"e_1_3_3_74_2","unstructured":"R.\u00a0T.\u00a0T. Hastie B.\u00a0Narasimhan and G.\u00a0Chu pamr: Pam: Prediction Analysis for Microarrays (2019); R package version 1.56.1."},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2019.09.006"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2940"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318376111"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.01.009"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz369"},{"key":"e_1_3_3_85_2","doi-asserted-by":"crossref","unstructured":"H. Wickham ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag 2016).","DOI":"10.1007\/978-3-319-24277-4"},{"key":"e_1_3_3_86_2","unstructured":"R.\u00a0S.\u00a0Blighe K Lewis M. EnhancedVolcano: Publication-Ready Volcano Plots With Enhanced Colouring and Labeling (2020); R package version 1.6.0."},{"key":"e_1_3_3_87_2","unstructured":"R. Kolde pheatmap: Pretty Heatmaps (2019); version 1.0.12."},{"key":"e_1_3_3_88_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz363"},{"key":"e_1_3_3_89_2","unstructured":"G. FM. aracne.networks: ARACNe-Inferred Gene Networks From TCGA Tumor Datasets (2020); R package version 1.14.0."},{"key":"e_1_3_3_90_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0669-z"},{"key":"e_1_3_3_91_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"e_1_3_3_92_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_3_3_93_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1842-9"},{"key":"e_1_3_3_94_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_3_95_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abn4118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T13:25:36Z","timestamp":1705411536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abn4118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,24]]},"references-count":94,"journal-issue":{"issue":"697","published-print":{"date-parts":[[2023,5,24]]}},"alternative-id":["10.1126\/scitranslmed.abn4118"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abn4118","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.11.30.21266988","asserted-by":"object"}]},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,24]]},"assertion":[{"value":"2021-12-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eabn4118"}}