Journal
EUROPEAN UROLOGY
Volume 81, Issue 5, Pages 523-532Publisher
ELSEVIER
DOI: 10.1016/j.eururo.2021.10.035
Keywords
Bladder cancer; Urothelial carcinoma; Molecular subtypes; Luminal; Basal/squamous; Cisplatin; Chemotherapy; Neoadjuvant; Response; Survival; Osteopontin; SPP1; Signature
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This study investigates the impact of molecular subtypes on pathological response and survival in patients with muscle-invasive bladder cancer (MIBC) receiving preoperative cisplatin-based chemotherapy. The results suggest that patients with certain molecular subtypes, such as genomically unstable (GU) and urothelial-like (Uro) tumors, are more responsive to cisplatin-based neoadjuvant chemotherapy and have improved survival compared to those with the basal/squamous (Ba/Sq) subtype. The study highlights the potential of subtype-specific biomarkers, such as osteopontin (SPP1), for developing a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.
Background: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. Objective: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participants: 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. Outcome measurements and statistical analysis: 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. Results and limitations: 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. Conclusions: 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. Patient summary: 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. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.
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