Predictive value of molecular subtypes and APOBEC3G for adjuvant chemotherapy in urothelial bladder cancer.

Although targeted approaches have become available in second- and third-line settings, platinum-based chemotherapy remains the standard first-line treatment for advanced muscle-invasive bladder cancer (MIBC). Therefore, the prediction of platinum resistance is of utmost clinical importance.

In this study, we established a routine compatible method for the molecular classification of MIBC samples according to various classification systems and applied this method to evaluate the impact of subtypes on survival after adjuvant chemotherapy. This retrospective study included 191 patients with advanced MIBC (pT≥3 or pN+) who underwent radical cystectomy, with or without adjuvant chemotherapy. A 48-gene panel and classifier rule set were established to determine molecular subtypes according to TCGA, MDA, LundTax, and Consensus classifications. Additionally, 12 single platinum-predictive candidate genes were assessed. The results were correlated with patients' clinicopathological and follow-up data and were validated using independent data sets.

Our final evaluation of 159 patients demonstrated better survival in the luminal groups for those who received chemotherapy compared with those who did not. In contrast, no such differences were observed in basal subtypes. The use of chemotherapy was associated with better survival in patients with high APOBEC3G expression (p < 0.002). This association was confirmed using an independent data set of patients who received neoadjuvant platinum therapy.

The proposed method robustly replicates the most commonly used transcriptome-based subtype classifications from paraffin-embedded tissue samples. The luminal, but not basal, molecular subtypes had the greatest benefit from adjuvant platinum therapy. We identified and validated APOBEC3G as a novel predictive marker for platinum-treated patients.

Cancer medicine. 2022 Oct 07 [Epub ahead of print]

Csilla Olah, Henning Reis, Michèle J Hoffmann, Fabian Mairinger, Saskia Ting, Boris Hadaschik, Ulrich Krafft, Viktor Grünwald, Peter Nyirady, Melinda Varadi, Balázs Győrffy, Andras Kiss, Eszter Szekely, Gottfrid Sjödahl, Tibor Szarvas

Department of Urology, University of Duisburg-Essen, Essen, Germany., Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany., Department of Urology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Institute of Pathology, University Medicine Essen, University of Duisburg-Essen, Essen, Germany., Department of Medical Oncology, University of Duisburg-Essen, Essen, Germany., Department of Urology, Semmelweis University, Budapest, Hungary., Research Centre for Natural Sciences, Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary., 2nd Department of Pathology, Semmelweis University, Budapest, Hungary., Department of Translational Medicine, Lund University, Lund, Sweden.

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