Mismatch repair-deficient (dMMR) prostate cancer is rare and has not been well studied. We aimed to evaluate the clinical characterization of dMMR metastatic castrationresistant prostate cancer (mCRPC) patients. The MMR genes include MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, and EPCAM, and were analyzed by targeted sequencing of plasma cell-free DNA samples. A total of 109 mCRPC patients were identified, including 50 patients with MMR alterations (pathogenic alterations, n = 7; alterations of unknown significance, n = 43) and 59 patients with wild-type MMR. For the seven patients with pathogenic MMR alterations, the median age at diagnosis was 63.5 years, and 42.9% had a Gleason score ≥8. The median time from androgen deprivation therapy (ADT) initiation to CRPC was 24 months. Compared with the wild-type MMR subgroup, patients with MMR alterations, pathogenic MMR alterations, or MMR alterations of unknown significance showed higher rates of hotspot missense mutations or copy number amplifications in the AR gene (24/50 vs. 10/59, P = 7.8 × 10 −4 ; 7/7 vs. 10/59, P = 2.5 × 10 −5 ; 17/43 vs. 10/59, P = 0.013). The presence of any MMR alterations was associated with an inferior response to abiraterone [median progression-free survival (PFS): 5.0 vs. 10.9 months, P = 0.022]. Shorter PFS times were observed in both the pathogenic MMR alteration subgroup (median PFS: 5 months) and the MMR alterations of unknown significance subgroup (median PFS: 5.3 months), compared with the PFS of those with wild-type MMR genes (median PFS: 10.9 months, P = 0.052). There was no statistically significant difference in response to docetaxel chemotherapy between the MMR alterations of unknown significance and the wild-type MMR subgroups (median PFS: 8.2 vs. 8.1 months, P = 0.23). Our results demonstrate that dMMR mCRPC patients have an equivalent response to standard ADT and taxanebased chemotherapy treatments compared with wild-type MMR patients. Patients with both pathogenic and unknown significance alterations of MMR genes had poorer responses to abiraterone therapy.

The first-line treatment options for high-risk prostate cancer (PCa) are definitive external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT) and radical prostatectomy (RP) with or without adjuvant therapies. However, few randomized trials have compared the survival outcomes of these two treatments. To systematically evaluate the survival outcomes of high-risk PCa patients treated with EBRT- or RP-based therapy, a comprehensive and up-to-date meta-analysis was performed. A systematic online search was conducted for randomized or observational studies that investigated biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), and/or overall survival (OS), in relation to the use of RP or EBRT in patients with high-risk PCa. The summary hazard ratios (HRs) were estimated under the random effects models. We identified heterogeneity between studies using Q tests and measured it using I 2 statistics. We evaluated publication bias using funnel plots and Egger's regression asymmetry tests. Seventeen studies (including one randomized controlled trial [RCT]) of low risk of bias were selected and up to 9504 patients were pooled. When comparing EBRT-based treatment with RP-based treatment, the pooled HRs for bRFS, CSS, and OS were 0.40 (95% confidence interval [CI]: 0.24–0.67), 1.36 (95% CI: 0.94–1.97), and 1.39 (95% CI: 1.18–1.62), respectively. Better OS for RP-based treatment and better bRFS for EBRT-based treatment have been identified, and there was no significant difference in CSS between the two treatments. RP-based treatment is recommended for high-risk PCa patients who value long-term survival, and EBRT-based treatment might be a promising alternative for elderly patients.

Programmed cell death (PCD) refers to a molecularly regulated form of cell death that functions as an essential anticancer defense mechanism and serves as a target of anticancer therapies. Multiple types of PCD comprehensively regulate tumorigenesis and tumor progression and metastasis. However, a systemic exploration of the multiple types of PCD in cancers, especially bladder cancer, is lacking. In this study, we evaluated the expression pattern of genes associated with multiple types of PCD in bladder cancer using the “ssGSEA” method and conceptualized the multiple types of PCD as being collectively involved in “Pan-PCD”. Based on the differentially expressed genes related to Pan-PCD, we developed a Pan-PCD-related prognostic signature (PPRPS) to predict patient prognosis via univariate and multivariate Cox regression analysis. The PPRPS is an independent prognostic factor, and the AUC (Area Under Curve) for 3-year overall survival was 0.748. Combined with age and stage, PPRPS displayed excellent predictive ability. Based on the PPRPS, higher levels of immune cell infiltration, tumor microenvironment, and immune checkpoint molecules were observed in the high-PPRPS group. Furthermore, PPRPS enabled accurate risk prediction for metastatic urothelial carcinoma after anti-PD-L1 monoclonal antibody treatment. Patients in the high-PPRPS group had poor prognoses. Docetaxel, staurosporine, and luminespib were identified as potentially effective drugs for high-PPRPS bladder cancer patients. In summary, we developed the Pan-PCD signature to improve the accuracy of bladder cancer prognostic predictions and to provide a novel classification method to guide treatment selection.