Neutrophil extracellular trap as a predictive marker to cisplatin-based chemotherapy for patients with muscle-invasive bladder cancer.

person Bing-Qing Shang Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union, Beijing, China info_outline Bing-Qing Shang, Zhaoru Gu, Wang Qu, Rui-Yang Xie, Jie Wu, Ai-Ping Zhou, Jianzhong Shou

Authors person Bing-Qing Shang Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union, Beijing, China info_outline Bing-Qing Shang, Zhaoru Gu, Wang Qu, Rui-Yang Xie, Jie Wu, Ai-Ping Zhou, Jianzhong Shou Organizations Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union, Beijing, China, State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Abstract Disclosures Research Funding No funding received None. Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in both the neoadjuvant and first-line settings. However, the efficacy of MIBC for chemotherapy is only about 40%~60%. Patients without clear benefits from cisplatin-based chemotherapy still suffer from the potential toxicity, possibly missing the timing for other effective treatments. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. In bladder cancer, NETs were involved in radio-resistance, but the predictive role of chemotherapy is unclear. This study constructed a NET-related signature that predicted chemotherapy efficacy for MIBC patients. Methods: Transcriptome datasets were obtained from the transurethral resection of bladder tumor (TURBT) and metastatic lesion specimens. A dataset (GSE169455) of 149 MIBC patients who received preoperative cisplatin-based chemotherapy (neoadjuvant or induction) was enrolled for the training cohort. We used the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model to select candidate molecules based on the 250 NETs-initial biomarkers collected from the literature, and further developed a NETs-associated signature score (NETs-score) for therapeutic response prediction. The dataset reported by Taber A et al. of 96 MIBC patients who received cisplatin-based chemotherapy (neoadjuvant or first-line) was used as a validation cohort. Immunohistochemistry (IHC) was conducted to evaluate the potential role of NET-related genes in 51 patients who received neoadjuvant chemotherapy at our center from 2012 to 2019. Results: We constructed the NETs-score with 11 NETs-related genes by the LASSO Cox model. A higher NET score was observed in non-responders compared to responders in the training cohort (P<0.001). These results were confirmed in the validation cohort (P=0.006). Moreover, high NETs-score indicated reduced recurrence-free survival (RFS) [HR=2.07, 95% CI (1.26-3.40), P=0.003], cancer-specific survival (CSS) [HR=1.87, 95% CI (1.12-3.12), P=0.014], and overall survival (OS) [HR=1.83, 95% CI (1.13-2.94), P=0.012] among MIBC patients. Furthermore, in the IHC cohort, citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analysis [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Conclusions: In conclusion, our study suggested that NET was a predictive and prognostic biomarker for MIBC patients with cisplatin-based chemotherapy. Cohort Sample number Chosen markers of NETs p-value Training cohort 149 NETs-score <0.001 Validation cohort 96 NETs-score 0.006 IHC cohort 51 H3Cit 0.045