Background:High tumor mutational burden (TMB) has been associated with poor response to cisplatin-based chemotherapy in lung cancer, but the impact of TMB in muscle-invasive bladder cancer (MIBC) patients treated with neoadjuvant chemotherapy (NAC) is unknown. In this study, we sought to test the hypothesis that MIBC patients with high TMB would be less likely to achieve a pathologic complete response (pCR) to cisplatin-based NAC.

Methods:93 patients with MIBC who received cisplatin-based NAC followed by radical cystectomy were identified from institutional databases across two campuses. Sample size was prespecified by statistical design. Diagnostic transurethral resection of bladder tumor specimens were available in 91 patients and used for genomic analysis. Genomic analysis was performed using the Tempus xT platform. Clinically significant TMB thresholds are unknown in MIBC, so high TMB was defined as the upper TMB quintile within the cohort. Correlation of TMB values with clinical outcomes were performed using logistic regression, Cox proportional hazards models, and Kaplan-Meier techniques.

Results:Among the 91 patients who underwent genomic analysis, median follow time was 63.6 months. Only 4.4% (4/91) received adjuvant immune checkpoint inhibition (ICI). pCR was achieved in 31.9% (29/91). Mean and median TMB (Mut/Mb) for the entire cohort were 10.6 and 8.9, respectively. TMB threshold for the upper quintile was 14.7. Median TMB for patients who achieved ypT0 vs ypT1+ was 11.1 and 8.9. A statistically significant difference in pCR rates between the TMB upper quintile and lower four quintiles was not observed; however, a trend towards higher pCR rate was detected in the upper quintile (OR 0.43, p = 0.165). The median TMB in patients who relapsed (42%) was 7.7 compared to 10.5 for those who did not. A strong trend for lower relapse rate in the upper TMB quintile was observed (OR 0.30, p = 0.065). The median relapse-free survival (RFS) was not reached and 54.2 months in the upper and lower four quintiles, respectively (HR = 0.46, p = 0.080).

Conclusions:We designed this study to test the hypothesis that MIBC patients with high TMB would fare worse clinically; however, we found the contrary association. High TMB was unexpectedly associated with improved pCR and relapse rates as well as longer RFS in this cohort collected before widespread use of peri-operative ICI. These findings suggest that high TMB in MIBC patients improves sensitivity to cisplatin-based NAC. Our results require validation in a contemporary cohort and suggest that TMB may be an important potential biomarker in patients with MIBC.

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