Jason A Efstathiou1, Kent W Mouw2, Ewan A Gibb3, Yang Liu3, Chin-Lee Wu4, Michael R Drumm5, Jose Batista da Costa6, Marguerite du Plessis3, Natalie Q Wang3, Elai Davicioni3, Felix Y Feng7, Roland Seiler8, Peter C Black6, William U Shipley5, David T Miyamoto9. 1. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jefstathiou@partners.org. 2. Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA. 3. GenomeDx Biosciences Inc, Vancouver, Canada. 4. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 5. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 6. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 7. Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA. 8. Department of Urology, University of Bern, Bern, Switzerland. 9. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Abstract
BACKGROUND: Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. OBJECTIVE: To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. DESIGN, SETTING, AND PARTICIPANTS: We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5yr, and median follow-up time for patients without an event was 5.0yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. RESULTS AND LIMITATIONS: Gene expression profiling of TMT cases identified luminal (N=40), luminal-infiltrated (N=26), basal (N=54), and claudin-low (N=16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14-0.65], p=0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p=0.006), but not in the TMT cohort. This study is limited by its retrospective nature. CONCLUSIONS: Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. PATIENT SUMMARY: We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.
BACKGROUND: Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. OBJECTIVE: To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. DESIGN, SETTING, AND PARTICIPANTS: We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBCpatients treated with TMT at a single institution. We observed 60 overall survival events at 5yr, and median follow-up time for patients without an event was 5.0yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBCpatients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. RESULTS AND LIMITATIONS: Gene expression profiling of TMT cases identified luminal (N=40), luminal-infiltrated (N=26), basal (N=54), and claudin-low (N=16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14-0.65], p=0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p=0.006), but not in the TMT cohort. This study is limited by its retrospective nature. CONCLUSIONS: Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. PATIENT SUMMARY: We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.
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