Mutations of predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

BACKGROUND AND AIM

Neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive urothelial bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response after NAC. Herein, we used whole-exome sequencing (WES) to identify genetic mutations in MIBC that can predict NAC response.

METHODS

Forty MIBC patients were enrolled in this study, in which 33 were successfully examined by WES and Sanger sequencing in the discovery cohort (=13) and the validation cohort (=20), respectively. ANNOVAR software was used to identify the potential mutations based on the data of WES. In addition, tumor-specific somatic mutations including single nucleotide variants and indels were called with the muTECT and Strelka software. The mutational analysis of specific genes was carried out based on the data from cBioPortal for Cancer Genomics.

RESULTS

In the discovery cohort, the mutation frequencies of , , , , , , and were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of , , , , , , , , and in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of , , , , , , and were exclusively identified in NAC nonresponders, suggesting that these mutations may participate in the process of NAC resistance. In the validation cohort, the somatic mutations of , , and were significantly enriched in NAC responders while the somatic mutation of was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type .

CONCLUSION

The somatic mutation of can be a potential predictive biomarker of NAC response in MIBC patients.

RELEVANCE FOR PATIENTS

MIBC patients bearing mutated display a pathological response to NAC and have a significantly longer overall survival or disease/progression-free survival as compared to the patients bearing wild-type . Thus, the somatic mutation of is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.