Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes.

For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.

To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.

Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.

Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.

Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.

Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

European urology. 2021 Nov 12 [Epub ahead of print]

Gottfrid Sjödahl, Johan Abrahamsson, Karin Holmsten, Carina Bernardo, Gunilla Chebil, Pontus Eriksson, Iva Johansson, Petter Kollberg, Claes Lindh, Kristina Lövgren, Nour-Al-Dain Marzouka, Hans Olsson, Mattias Höglund, Anders Ullén, Fredrik Liedberg

Department of Translational Medicine, Lund University, Malmö, Sweden; Department of Urology, Skåne University Hospital, Malmö, Sweden. Electronic address: ., Department of Translational Medicine, Lund University, Malmö, Sweden; Department of Urology, Skåne University Hospital, Malmö, Sweden., Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, Capio S:t Göran Hospital, Stockholm, Sweden., Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Department of Pathology, Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden., Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Genitourinary Oncology and Urology unit, Karolinska University Hospital, Stockholm, Sweden.

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