Gottfrid Sjödahl1, Johan Abrahamsson2, Karin Holmsten3, Carina Bernardo4, Gunilla Chebil4, Pontus Eriksson4, Iva Johansson4, Petter Kollberg2, Claes Lindh5, Kristina Lövgren4, Nour-Al-Dain Marzouka4, Hans Olsson6, Mattias Höglund4, Anders Ullén7, Fredrik Liedberg2. 1. Department of Translational Medicine, Lund University, Malmö, Sweden; Department of Urology, Skåne University Hospital, Malmö, Sweden. Electronic address: gottfrid.sjodahl@med.lu.se. 2. Department of Translational Medicine, Lund University, Malmö, Sweden; Department of Urology, Skåne University Hospital, Malmö, Sweden. 3. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, Capio S:t Göran Hospital, Stockholm, Sweden. 4. Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden. 5. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. 6. Department of Pathology, Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden. 7. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Genitourinary Oncology and Urology unit, Karolinska University Hospital, Stockholm, Sweden.
Abstract
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.
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.
Authors: Florestan J Koll; Alina Schwarz; Jens Köllermann; Severine Banek; Luis Kluth; Clarissa Wittler; Katrin Bankov; Claudia Döring; Nina Becker; Felix K H Chun; Peter J Wild; Henning Reis Journal: Front Med (Lausanne) Date: 2022-06-16
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