{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:53:31Z","timestamp":1779288811458,"version":"3.51.4"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum RWTH Aachen"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract\n<\/jats:title><jats:p>High-grade non-muscle-invasive bladder cancer (HG NMIBC) patients are at high risk (HR) of progression to muscle-invasion. Bladder-preserving therapies for this patient subgroup are limited, and additional treatments are desirable. Recently, enfortumab vedotin, targeting cancer-associated NECTIN4, has been approved for the treatment of advanced urothelial carcinoma. However, data on the expression of NECTIN4 and its therapeutic potential for HR NMIBC are scarce. Here, NECTIN4 was immunohistochemically analyzed in urothelial HG NMIBC by studying cohorts of carcinoma in situ (CIS)\/T1HG (N\u2009=\u2009182 samples), HG papillary tumors from mixed-grade lesions (mixed TaHG) (N\u2009=\u200987) and papillary HG tumors without a history of low-grade disease (pure TaHG\/T1HG) (N\u2009=\u200998) from overall 225 patients. Moreover, inter-lesional NECTIN4 heterogeneity in multifocal HG NMIBC tumors was determined. A high prevalence of NECTIN4 positivity was noted across HG NMIBC subgroups (91%, N\u2009=\u2009367 samples), with 77% of samples showing moderate\/strong expression. Heterogenous NECTIN4 levels were observed between HG NMIBC subgroups: non-invasive areas of CIS\/T1HG and pure TaHG\/T1HG samples showed NECTIN4 positivity in 96% and 99%, with 88% and 83% moderate\/strong expressing specimens, respectively, whereas significantly lower NECTIN4 levels were detected in mixed TaHG lesions (72% positivity, 48% of samples with moderate\/strong NECTIN4 expression). Moreover, higher NECTIN4 heterogeneity was observed in patients with multifocal mixed TaHG tumors (22% of patients) compared to patients with multifocal CIS\/T1HG and pure TaHG\/T1HG tumors (9% and 5%). Taken together, NECTIN4-directed antibody\u2013drug conjugates might be promising for the treatment of HR NMIBC patients, especially for those exhibiting CIS\/T1HG and pure TaHG\/T1HG tumors without a history of low-grade disease.<\/jats:p>","DOI":"10.1007\/s00428-022-03328-1","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T18:17:15Z","timestamp":1651169835000},"page":"83-92","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Heterogenous NECTIN4 expression in urothelial high-risk non-muscle-invasive bladder cancer"],"prefix":"10.1007","volume":"481","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5447-3207","authenticated-orcid":false,"given":"Stefan","family":"Garczyk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Degener","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Bischoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tician","family":"Schnitzler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Salz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhard","family":"Golz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Buchner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerald B.","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine T.","family":"Gaisa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Kn\u00fcchel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,4,28]]},"reference":[{"key":"3328_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394\u2013424. https:\/\/doi.org\/10.3322\/caac.21492","journal-title":"CA Cancer J Clin"},{"key":"3328_CR2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/nrc3817","volume":"15","author":"MA Knowles","year":"2015","unstructured":"Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15:25\u201341. https:\/\/doi.org\/10.1038\/nrc3817","journal-title":"Nat Rev Cancer"},{"key":"3328_CR3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.eururo.2021.08.010","volume":"81","author":"M Babjuk","year":"2022","unstructured":"Babjuk M, Burger M, Capoun O, Cohen D, Comp\u00e9rat EM, Dominguez Escrig JL, Gontero P, Liedberg F, Masson-Lecomte A, Mostafid AH, Palou J, van Rhijn BWG, Roupr\u00eat M, Shariat SF, Seisen T, Soukup V, Sylvester RJ (2022) European Association of Urology Guidelines on Non\u2013muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). Eur Urol 81:75\u201394. https:\/\/doi.org\/10.1016\/j.eururo.2021.08.010","journal-title":"Eur Urol"},{"key":"3328_CR4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/bju.14915","volume":"125","author":"J Taylor","year":"2020","unstructured":"Taylor J, Becher E, Steinberg GD (2020) Update on the guideline of guidelines: non-muscle-invasive bladder cancer. BJU Int 125:197\u2013205. https:\/\/doi.org\/10.1111\/bju.14915","journal-title":"BJU Int"},{"key":"3328_CR5","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.urology.2005.06.135","volume":"66","author":"RJ Sylvester","year":"2005","unstructured":"Sylvester RJ, van der Meijden A, Witjes JA, Jakse G, Nonomura N, Cheng C, Torres A, Watson R, Kurth KH (2005) High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 66:90\u2013107. https:\/\/doi.org\/10.1016\/j.urology.2005.06.135","journal-title":"Urology"},{"key":"3328_CR6","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1177\/1756287215599694","volume":"7","author":"DH Tang","year":"2015","unstructured":"Tang DH, Chang SS (2015) Management of carcinoma in situ of the bladder: best practice and recent developments. Ther Adv Urol 7:351\u2013364. https:\/\/doi.org\/10.1177\/1756287215599694","journal-title":"Ther Adv Urol"},{"key":"3328_CR7","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s11934-018-0852-6","volume":"19","author":"TK Nykopp","year":"2018","unstructured":"Nykopp TK, Batista da Costa J, Mannas M, Black PC (2018) Current Clinical Trials in Non-muscle Invasive Bladder Cancer. Curr Urol Rep 19:101. https:\/\/doi.org\/10.1007\/s11934-018-0852-6","journal-title":"Curr Urol Rep"},{"key":"3328_CR8","doi-asserted-by":"publisher","first-page":"5041","DOI":"10.1200\/jco.2020.38.15_suppl.5041","volume":"38","author":"AV Balar","year":"2020","unstructured":"Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Bajorin DF, Roumigui\u00e9 M, Singer EA, Krieger LEM, Grivas P, Seo HK, Nishiyama H, Konety BR, Nam K, Zambon JP, Kapadia E, De Wit R (2020) Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Gu\u00e9rin (BCG) unresponsive, high-risk (HR) non\u2013muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057. J Clin Oncol 38:5041\u20135041. https:\/\/doi.org\/10.1200\/jco.2020.38.15_suppl.5041","journal-title":"J Clin Oncol"},{"key":"3328_CR9","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.1158\/0008-5472.CAN-15-1313","volume":"76","author":"PM Challita-Eid","year":"2016","unstructured":"Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, Raitano A, Nadell R, Liu W, Lortie DR, Capo L, Verlinsky A, Leavitt M, Malik F, Avina H, Guevara CI, Dinh N, Karki S, Anand BS, Pereira DS, Joseph IBJ, Donate F, Morrison K, Stover DR (2016) Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 76:3003\u20133013. https:\/\/doi.org\/10.1158\/0008-5472.CAN-15-1313","journal-title":"Cancer Res"},{"key":"3328_CR10","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1200\/JCO.19.02044","volume":"38","author":"J Rosenberg","year":"2020","unstructured":"Rosenberg J, Sridhar SS, Zhang J, Smith D, Ruether D, Flaig TW, Baranda J, Lang J, Plimack ER, Sangha R, Heath EI, Merchan J, Quinn DI, Srinivas S, Milowsky M, Wu C, Gartner EM, Zuo P, Melhem-Bertrandt A, Petrylak DP (2020) EV-101: A phase I study of single-agent enfortumab vedotin in patients with nectin-4\u2013positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol 38:1041\u20131049. https:\/\/doi.org\/10.1200\/JCO.19.02044","journal-title":"J Clin Oncol"},{"key":"3328_CR11","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/s41585-020-00394-5","volume":"18","author":"EI Heath","year":"2021","unstructured":"Heath EI, Rosenberg JE (2021) The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nat Rev Urol 18:93\u2013103. https:\/\/doi.org\/10.1038\/s41585-020-00394-5","journal-title":"Nat Rev Urol"},{"key":"3328_CR12","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1007\/s00428-021-03054-0","volume":"479","author":"S Garczyk","year":"2021","unstructured":"Garczyk S, Bischoff F, Schneider U, Golz R, von Rundstedt FC, Kn\u00fcchel R, Degener S (2021) Intratumoral heterogeneity of surrogate molecular subtypes in urothelial carcinoma in situ of the urinary bladder: implications for prognostic stratification of high-risk non-muscle-invasive bladder cancer. Virchows Arch 479:325\u2013335. https:\/\/doi.org\/10.1007\/s00428-021-03054-0","journal-title":"Virchows Arch"},{"key":"3328_CR13","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s13402-020-00524-6","volume":"43","author":"T Schnitzler","year":"2020","unstructured":"Schnitzler T, Ortiz-Br\u00fcchle N, Schneider U, Lurje I, Guricova K, Buchner A, Schulz GB, Heidenreich A, Gaisa NT, Kn\u00fcchel R, Garczyk S (2020) Pure high-grade papillary urothelial bladder cancer: a luminal-like subgroup with potential for targeted therapy. Cell Oncol 43:807\u2013819. https:\/\/doi.org\/10.1007\/s13402-020-00524-6","journal-title":"Cell Oncol"},{"key":"3328_CR14","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1007\/s00428-018-2354-9","volume":"472","author":"I Barth","year":"2018","unstructured":"Barth I, Schneider U, Grimm T, Karl A, Horst D, Gaisa NT, Kn\u00fcchel R, Garczyk S (2018) Progression of urothelial carcinoma in situ of the urinary bladder: a switch from luminal to basal phenotype and related therapeutic implications. Virchows Arch 472:749\u2013758. https:\/\/doi.org\/10.1007\/s00428-018-2354-9","journal-title":"Virchows Arch"},{"key":"3328_CR15","doi-asserted-by":"publisher","first-page":"2710","DOI":"10.1158\/0008-5472.CAN-15-1795","volume":"76","author":"F Li","year":"2016","unstructured":"Li F, Emmerton KK, Jonas M, Zhang X, Miyamoto JB, Setter JR, Nicholas ND, Okeley NM, Lyon RP, Benjamin DR, Law CL (2016) Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res 76:2710\u20132719. https:\/\/doi.org\/10.1158\/0008-5472.CAN-15-1795","journal-title":"Cancer Res"},{"key":"3328_CR16","first-page":"138","volume":"8","author":"W Remmele","year":"1987","unstructured":"Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138\u2013140","journal-title":"Pathologe"},{"key":"3328_CR17","doi-asserted-by":"publisher","first-page":"3651","DOI":"10.1200\/JCO.2000.18.21.3651","volume":"18","author":"G Pauletti","year":"2000","unstructured":"Pauletti G, Dandekar S, Rong H, Ramos L, Peng H, Seshadri R, Slamon DJ (2000) Assessment of Methods for Tissue-Based Detection of the HER-2\/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry. J Clin Oncol 18:3651\u20133664. https:\/\/doi.org\/10.1200\/JCO.2000.18.21.3651","journal-title":"J Clin Oncol"},{"key":"3328_CR18","doi-asserted-by":"publisher","first-page":"5123","DOI":"10.1158\/1078-0432.CCR-20-4175","volume":"27","author":"CE Chu","year":"2021","unstructured":"Chu CE, Sjostrom M, Egusa EA, Gibb EA, Badura ML, Zhu J, Koshkin VS, Stohr BA, Meng MV, Pruthi RS, Friedlander TW, Lotan Y, Black PC, Porten SP, Feng FY, Chou J (2021) Heterogeneity in NECTIN4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin. Clin Cancer Res 27:5123\u20135130. https:\/\/doi.org\/10.1158\/1078-0432.CCR-20-4175","journal-title":"Clin Cancer Res"},{"key":"3328_CR19","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.1002\/1878-0261.12375","volume":"12","author":"IH Rye","year":"2018","unstructured":"Rye IH, Trinh A, S\u00e6tersdal AB, Nebdal D, Lingj\u00e6rde OC, Almendro V, Polyak K, B\u00f8rresen-Dale AL, Helland \u00c5, Markowetz F, Russnes HG (2018) Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. Mol Oncol 12:1838\u20131855. https:\/\/doi.org\/10.1002\/1878-0261.12375","journal-title":"Mol Oncol"},{"key":"3328_CR20","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1200\/jco.2019.37.15_suppl.502","volume":"37","author":"O Metzger Filho","year":"2019","unstructured":"Metzger Filho O, Viale G, Trippa L, Li T, Yardley DA, Mayer IA, Abramson VG, Arteaga CL, Spring L, Waks AG, Janiszewska M, Wrabel E, Demeo M, Bardia A, King TA, Polyak K, Winer EP, Krop IE (2019) HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. J Clin Oncol 37:502\u2013502. https:\/\/doi.org\/10.1200\/jco.2019.37.15_suppl.502","journal-title":"J Clin Oncol"},{"key":"3328_CR21","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1097\/PAI.0000000000000938","volume":"29","author":"JH Hoffman-Censits","year":"2021","unstructured":"Hoffman-Censits JH, Lombardo KA, Parimi V, Kamanda S, Choi W, Hahn NM, McConkey DJ, McGuire BM, Bivalacqua TJ, Kates M, Matoso A (2021) Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes. Appl Immunohistochem Mol Morphol 29:619\u2013625. https:\/\/doi.org\/10.1097\/PAI.0000000000000938","journal-title":"Appl Immunohistochem Mol Morphol"},{"key":"3328_CR22","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1200\/JCO.19.01140","volume":"37","author":"JE Rosenberg","year":"2019","unstructured":"Rosenberg JE, O\u2019Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP (2019) Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1\/programmed death ligand 1 therapy. J Clin Oncol 37:2592\u20132600. https:\/\/doi.org\/10.1200\/JCO.19.01140","journal-title":"J Clin Oncol"},{"key":"3328_CR23","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.eururo.2021.10.009","volume":"81","author":"W Choi","year":"2022","unstructured":"Choi W, Lombardo K, Patel S, Epstein G, Feng M, Gabrielson A, Hahn NM, Hoffman-Censits J, McConkey D, Bivalacqua TJ, Matoso A, Kates M (2022) A Molecular Inquiry into the Role of Antibody-Drug Conjugates in Bacillus Calmette-Gu\u00e9rin-exposed Non\u2013muscle-invasive Bladder Cancer. Eur Urol 81:138\u2013142. https:\/\/doi.org\/10.1016\/j.eururo.2021.10.009","journal-title":"Eur Urol"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-022-03328-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-022-03328-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-022-03328-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T01:05:08Z","timestamp":1656032708000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-022-03328-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,28]]},"references-count":23,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["3328"],"URL":"https:\/\/doi.org\/10.1007\/s00428-022-03328-1","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,28]]},"assertion":[{"value":"12 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This retrospective immunohistochemical study was performed on FFPE tissue samples from the archives of the Institute of Pathology, RWTH Aachen and the Institute of Pathology, Helios University Hospital Wuppertal, and was approved by the Ethics Committee of the University of Witten\/Herdecke (No. 55\/2019) and the Ethics Committee at the RWTH Aachen Faculty of Medicine (EK 011\/21).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors have no competing interests to declare that are relevant to the content of this article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}}]}}