Universität zu Köln

Ecke, Thorsten H., Voss, Paula Carolin, Schlomm, Thorsten, Rabien, Anja ORCID: 0000-0003-0124-4878, Friedersdorff, Frank, Barski, Dimitri, Otto, Thomas, Waldner, Michael, Veltrup, Elke, Linden, Friederike, Hake, Roland, Eidt, Sebastian, Roggisch, Jenny, Heidenreich, Axel, Rieger, Constantin, Kastner, Lucas, Hallmann, Steffen, Koch, Stefan and Wirtz, Ralph M. (2022). Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment. Int. J. Mol. Sci., 23 (14). BASEL: MDPI. ISSN 1422-0067

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Abstract

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome-rate of ypT0 status-to justify subsequent prospective validation within the BladderBRIDGister. Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal-Wallis, Mann-Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (similar to 6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy r = -0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ecke, Thorsten H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Voss, Paula Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlomm, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Rabien, Anja UNSPECIFIED orcid.org/0000-0003-0124-4878 UNSPECIFIED Friedersdorff, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Barski, Dimitri UNSPECIFIED UNSPECIFIED UNSPECIFIED Otto, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldner, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Veltrup, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Linden, Friederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Hake, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Eidt, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Roggisch, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Heidenreich, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Rieger, Constantin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kastner, Lucas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallmann, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirtz, Ralph M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-690938
DOI:	10.3390/ijrns23147898
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	23
Number:	14
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BREAST-CANCER; CLASSIFICATION; GUIDELINES; ER Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69093