Homologous recombination deficiency (HRD) score in aggressive prostatic adenocarcinoma with or without intraductal carcinoma of the prostate (IDC-P).

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort. METHODS: This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients' prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method. RESULTS: The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4-5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort. CONCLUSIONS: M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort.

The heterogeneity of intraductal carcinoma of the prostate is associated with different efficacy of standard first-line therapy for patients with metastatic castration-resistant prostate cancer.

BACKGROUND: To explore whether metastatic castration-resistant prostate cancer (mCRPC) patients with distinct intraductal carcinoma of the prostate (IDC-P) subtypes respond differently to abiraterone and docetaxel treatment. METHODS: We retrospectively analyzed data of 170 mCRPC patients receiving abiraterone or docetaxel as first-line therapy. PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed based on the presence of IDC-P and its subpatterns. RESULTS: IDC-P was confirmed in 91/170 (53.5%) patients. Among them 36/91 (39.6%) and 55/91 (60.4%) harbored IDC-P patterns 1 and 2, respectively. Patients with IDC-P pattern 1 shared similar clinical outcomes to those without IDC-P in both abiraterone and docetaxel treatment. However, against cases without IDC-P or with IDC-P pattern 1, patients with IDC-P pattern 2 had markedly poorer prognosis in either abiraterone (mPSA-PFS: 11.9 vs. 11.1 vs. 6.1 months, p < 0.001; mrPFS: 18.9 vs. 19.4 vs. 9.6 months, p < 0.001) or docetaxel (mPSA-PFS: 6.2 vs. 6.6 vs. 3.0 months, p < 0.001; mrPFS: 15.1 vs. 12.6 vs. 5.5 months, p < 0.001) treatment. For patients without IDC-P, docetaxel had comparable therapeutic efficacy with abiraterone. However, the efficacy of docetaxel was significantly inferior to abiraterone in patients with either IDC-P pattern 1 (mPSA-PFS: 6.6 vs. 11.1 months, p = 0.021; mrPFS: 12.6 vs. 19.4 months, p = 0.027) or pattern 2 (mPSA-PFS: 3.0 vs. 6.1 months, p = 0.003; mrPFS: 5.5 vs. 9.6 months, p = 0.007). CONCLUSION: Compared to docetaxel, abiraterone exhibited better efficacy in patients with IDC-P of either pattern. However, IDC-P pattern 2 responded unsatisfactorily to either abiraterone or docetaxel therapy. Novel therapeutic strategies for IDC-P pattern 2 need further investigations.

MicroRNA-106a suppresses prostate cancer proliferation, migration and invasion by targeting tumor-derived IL-8.

BACKGROUND: Tumor-derived interleukin-8 (IL-8) promotes tumorigenesis and progression of prostate cancer (PCa). MicroRNAs (miRNAs) are noncoding regulatory RNAs and their dysregulation is known to be implicated in carcinogenesis. However, the post-transcriptional mechanism of IL-8 via miRNAs is not fully understood. This study was intended to investigate whether miR-106a could affect the progression of PCa via targeting IL-8 or not. METHODS: Using bioinformatics analysis, we postulated that IL-8 might be post-transcriptionally regulated by miR-106a. This was validated by dual reporter gene assays that miR-106a could bind to the predicted site of IL-8 mRNA. To determine the biological effects of miR-106a on PCa cells (PC-3 and DU145), MTT, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), migration and invasion assays were performed. RESULTS: We found that miR-106a was barely expressed in PCa cells, whereas IL-8 was aberrantly upregulated. Elevated miR-106a could reduce IL-8 expression by directly binding the 3'-UTR of IL-8. Overexpression of miR-106a in PCa cells triggered cell apoptosis and suppressed cell proliferation, migration, and invasion. CONCLUSIONS: This research showed that miR-106a could function as a tumor-suppressor by decreasing IL-8 levels in PCa.

The prognosis benefits of adjuvant versus salvage radiotherapy for patients after radical prostatectomy with adverse pathological features: a systematic review and meta-analysis.

BACKGROUND: The appropriate timing of radiotherapy (RT) for patients after radical prostatectomy (RP) with adverse pathological features (APFs) remains controversial. This systematic review was conducted to compare the efficacy of adjuvant radiotherapy (ART) and salvage radiotherapy (SRT). METHODS: PubMed, EMBASE, Web of Science and the Cochrane Library electronic databases were searched to retrieve the required. The hazard ratio (HR) and corresponding 95% confidence interval (CI) of overall survival (OS), biochemical recurrence-free survival (BRFS) and distant metastases-free survival (DMFS) were extracted. The survival benefits of ART with SRT (including early salvage radiotherapy (ESRT)) were analyzed. The process of the meta-analysis was performed with RevMan version 5.3. RESULTS: A total of fifteen retrospective studies were finally included in the final analysis including 5586 patients. The pooled analysis indicated that ART could achieve better control of prostate cancer and improve OS (p = 0.0006), BRFS (p < 0.0001) and DMFS (p < 0.0001), when compared to SRT. The subgroup analysis of the 5-year OS rate demonstrated that the ART group still had survival advantages compared to the SRT group (p = 0.0006). However, ART and SRT were comparable in 10-year OS rate (p = 0.07). ART had advantages over SRT in both 5-year (p = 0.0003) and 10-year BRFS (p = 0.0003). The subgroup analysis with different follow-up starting points from RP or RT was essentially consistent with the above results. The pooled analysis also showed that ART was superior to ESRT on OS (p = 0.008) and DMFS (p = 0.03), and comparable to ESRT on BRFS (p = 0.1). CONCLUSIONS: According to this meta-analysis, ART could be served as a preferential treatment for patients with APFs after RP to improve prognosis. Certainly, high-quality, multicenter randomized controlled trials (RCTs) are expecting to confirm the outcomes of our meta-analysis in the future.

The value of transperineal apical prostate biopsy in predicting urethral/apical margin status after radical prostatectomy.

PURPOSE: To investigate potential preoperative predictors of urethral or apical positive surgical margin (PSM) and the value of apical prostate biopsy in predicting urethral/apical margin status after radical prostatectomy (RP). METHODS: A total of 531 patients who underwent RP during 2010 to 2017 at West China Hospital were enrolled in this retrospective study. Preoperative and postoperative factors including age, BMI, PSA, clinical T stage and biopsy Gleason score were analyzed. Univariate analysis and logistic regression were used to find out the potential predictive factors for PSM. Two logistic regression models were built to evaluate the role of apical prostate biopsy in predicting urethral/apical margin status. RESULTS: The overall PSM rate was about 30.1% (160/531) and 97 of them were reported urethral/apical PSM. The incidence of urethral or apical PSM in patients with positive cores in the apical prostate was higher than those without (23.0% vs 9.9%, P < .001). We further found that the multivariable model with positive apical prostate biopsy could significantly increase the predictive value of urethral or apical PSM status (AUC: 0.744 vs 0.783, P = .016). Our analysis also showed that neo-adjuvant hormone therapy was an independent protective factor for urethral or apical PSM in patients with positive apical prostate biopsy, but not all patients. CONCLUSION: This study revealed the necessity of apical prostate biopsy to predict the risk of apical or urethral PSM. In clinical practice, neo-adjuvant hormone therapy should be given when patients with positive apical prostate biopsy to reduce the presence of PSM, especially patients with high/very high risk prostate cancer.