Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features

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• dc.contributor.author Font, Albert
• dc.contributor.author Doménech, Montserrat
• dc.contributor.author Ramirez, Jose Luis
• dc.contributor.author Marqués, Miriam
• dc.contributor.author Benítez, Raquel
• dc.contributor.author Ruiz de Porras, Vicenç
• dc.contributor.author Gago, José L.
• dc.contributor.author Carrato, Cristina
• dc.contributor.author Sant, Francesc
• dc.contributor.author López, Héctor
• dc.contributor.author Castellano, Daniel
• dc.contributor.author Malats i Riera, Núria
• dc.contributor.author Calle, M. Luz
• dc.contributor.author Real, Francisco X.
• dc.date.accessioned 2023-10-03T06:16:34Z
• dc.date.available 2023-10-03T06:16:34Z
• dc.date.issued 2023
• dc.description.abstract Background and objective: Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression. Material and methods: From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method. Results: LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02). Conclusions: We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.
• dc.format.mimetype application/pdf
• dc.identifier.citation Font A, Domenech M, Ramirez JL, Marqués M, Benítez R, Ruiz de Porras V, Gago JL, Carrato C, Sant F, Lopez H, Castellano D, Malats N, Calle ML, Real FX. Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features. Front Oncol. 2023 Aug 3;13:1155244. DOI: 10.3389/fonc.2023.1155244
• dc.identifier.doi http://dx.doi.org/10.3389/fonc.2023.1155244
• dc.identifier.issn 2234-943X
• dc.identifier.uri http://hdl.handle.net/10230/58020
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Oncol. 2023 Aug 3;13:1155244
• dc.rights © 2023 Font, Domenech, Ramirez, Marqués, Benítez, Ruiz de Porras, Gago, Carrato, Sant, Lopez, Castellano, Malats, Calle and Real. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Bladder cancer
• dc.subject.keyword Integrated signature
• dc.subject.keyword mRNA expression
• dc.subject.keyword Neoadjuvant chemotherapy
• dc.subject.keyword Pathological response
• dc.subject.keyword Taxonomical classification
• dc.title Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion