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Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes
Gottfrid Sjödahl1, Johan Abrahamsson1, Karin Holmsten2
1Department of Translational Medicine, Lund University, Malmö, Sweden; Department of Urology, Skåne University Hospital, Malmö, Sweden.
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.
