Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

After cisplatin-based neoadjuvant chemotherapy (NAC) 60% of patients with muscle-invasive bladder cancer still have residual invasive disease at radical cystectomy (RC). The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied.

RC samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry on tissue microarrays were used to confirm tissue sampling and gene expression analysis.

Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised consensus clustering revealed four distinct consensus clusters (CC). The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pre-treatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar-like subtype expressed genes associated with wound-healing/ scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar-like tumors had the most favorable prognosis.

This study expands our knowledge on muscle-invasive bladder cancer not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Sep 17 [Epub ahead of print]

Roland Seiler, Ewan A Gibb, Natalie Q Wang, Htoo Zarni Oo, Hung-Ming Lam, Kim E Van Kessel, Charlotte S Voskuilen, Brian Winters, Nicholas G Erho, Mandeep M Takhar, James Douglas, Funda Vakar-Lopez, Simon J Crabb, Bas W G van Rhijn, Elisabeth E Fransen van de Putte, Ellen C Zwarthoff, George N Thalmann, Elai Davicioni, Joost L Boormans, Marc Dall'Era, Michiel S van der Heijden, Jonathan L Wright, Peter C Black

Department of Urology, University Hospital of Bern ., R&D, GenomeDx Biosciences., GenomeDx Biosciences., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Urology, University of Washington School of Medicine., Department of Pathology, Erasmus Medical Center., Urology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital., Urology, University of Washington., Research and Development, GenomeDx Biosciences., Clinical Laboratory, GenomeDx Biosciences Inc., Cancer Sciences Unit, University of Southampton., Pathology, University of Washington., Urology, The Netherlands Cancer Institute., Pathology, Erasmus MC., Department of Urology, Inselpital Bern., Urology, Erasmus MC., UC Davis Comprehensive Cancer Center., Surgical Oncology, The Netherlands Cancer Institute.