Biomarker Exploration for neoadjuvant chemotherapy with gemcitabine combined with cisplatin in muscle-invasive bladder cancer.

e16556 Background: Neoadjuvant chemotherapy (NCT) is a standard treatment for muscle-invasive bladder cancer (MIBC). However, there is still a considerable proportion of patients who respond suboptimally to available treatments or experience adverse effects. Thus, identifying novel biomarkers to predict response to NCT of MIBC is urgently needed. Methods: A total of 23 patients were enrolled in this study, all of whom were cT2-T4aNxM0 MIBC and received 2̃4 cycles CG (gemcitabine and cisplatin) NCT. Radiographic assessment was performed at the end of each cycle or at the time of progression. Tumor tissue were collected from all patients before NCT. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed for tissue samples. In addition, peripheral blood was collected as a control for WES. Treatment responses were assessed by comparing the imaging data before and after treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with CR and PR were regarded as the responder group, and those with SD and PD were regarded as the non-responder group. Results: Number of patients received 2̃4 cycles NCT were 16 for the responder group and 7 for the non-responder group. Of 19 patients completed WES, 13 patients achieved response and 6 patients did not respond. In the responder group, 6 patients (46%) had variant in any of RB1, ERCC2 and ATM, which were previously reported to predict better response to NCT. Only a patient (16.7%) in the non-responder group had any of those variants. Additionally, our results showed that 3 patients in the non-responder group had MAST4 gene mutations, but not in the responder group, and there was a significant difference between the two groups (p < 0.05). There were no differences in Tumor Mutational Burden (TMB) and Microsatellite instability (MSI) between the two groups. RNA-seq was also completed in 18 patients, of which 14 patients achieved response and 4 patients did not respond. Significant differences in gene expression (eg. UPK3A, CD8B2, TUBB2B) between the two groups were found. The KEGG pathway enrichment analysis revealed that down-regulated DEGs were enriched in the Cytokine-cytokine receptor interaction pathway and up-regulated DEGs were enriched in the Steroid hormone biosynthesis. The infiltration of immune cells in the non-responder group was higher, and the CD4 cells, B cells, Th17 cells, and NK cells in the non-response group were significantly higher than those in the responder group (p < 0.05). Conclusions: Patients with MAST4 mutations may be insensitive to GC NCT. The non-response group had higher levels of immune cell infiltration and may be more sensitive to immunotherapy. These results require further validation in additional sample sets.