What's known on the subject? and What does the study add?
Even after a negative set of prostate biopsies, the risk of undetected prostate cancer remains clinically significant. Predictive markers of ...such a risk are undefined.
In addition to PSA and PSAD, low prostate volume and %fPSA are interesting time‐varying risk factors and are relevant in biopsy decision‐making.
Objective
To assess prospectively the time‐varying risk of rebiopsy and of prostate cancer (PCa) detection after an initial negative biopsy protocol.
Patients and Methods
Over a period of 10 years, 1995 consecutive patients with initially negative biopsies were followed.
Rebiopsies were performed in patients who had a persistent suspicion of PCa.
Predictive factors for rebiopsy and for PCa detection were tested using univariate, multivariate and time‐dependent models.
Results
A total of 617 men (31%) underwent at least one rebiopsy after a mean follow‐up of 19 months.
PCa detection rates during second, third, and fourth sets of biopsies were 16.7, 16.9 and 12.5%, respectively. The overall rate of detected PCa was 7.0%.
The 5‐year rebiopsy‐free and PCa‐free survival rates were 65.9 and 92.5%, respectively.
Indications for rebiopsy were more frequently reported in patients having a high prostate‐specific antigen (PSA) level (P = 0.006) or a high PSA density (PSAD; P < 0.001) and in younger patients (P = 0.008). The risk of PCa on rebiopsies was not correlated with age, but significantly increased more than twofold in cases of PSA >6 ng/mL, PSAD >0.15 ng/mL/g, free‐to‐total PSA ratio (%fPSA) <15, and/or prostate volume <50 mL. Time‐dependent analyses were in line with these findings.
The main study limitation was the lack of control of the absence of PCa and PSA kinetics in men not rebiopsied.
Conclusions
The overall risk of detected PCa after an initial negative biopsy was low.
In addition to PSA and PSAD, which are well‐used in rebiopsy indications, low prostate volume and %fPSA are interesting time‐varying risk factors for PCa on rebiopsy and could be relevant in biopsy decision‐making.
Abstract Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While ...mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo , with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance.
The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated.
The study ...investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers.
The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio OR = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients.
This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways.
Abstract Background Although the first laparoscopic radical prostatectomy was performed in 1997, few midterm oncologic data have been published for the extraperitoneal procedure. Objective To ...determine the oncologic outcome of extraperitoneal laparoscopic radical prostatectomy (ELRP). Design, setting, and participants From 2000 to 2007, 1115 consecutive patients underwent ELRP for a localized prostate cancer at our department. Follow-up was scheduled and standardized for all patients and recorded into a prospective database. Median postoperative follow-up was 35.6 mo. Intervention All ELRP were performed by three surgeons at the Department of Urology, Hospital Henri Mondor, Créteil, France. Measurements Biochemical recurrence was defined by prostate-specific antigen level ≥0.2 ng/ml. Results and limitations In pN0/pNx cancers, postoperative stage was pT2 in 664 patients (59.5%), pT3 in 350 patients (31.4%), and pT4 in 77 patients (6.9%). Positive lymph nodes were reported in 24 patients (2.2%). Margins were positive in 16.1% and 34.6% of pT2 and pT3 cancers, respectively. Final Gleason score was <7 in 288 men (25.8%), =7 in 701 men (62.9%), and >7 in 126 men (11.3%). Overall prostate-specific antigen (PSA) recurrence-free survival was 83% at 5 yr. The 5-yr progression-free survival rates were 93.4% for pT2, 74.5% for pT3a, and 55.0% for pT3b tumors, respectively. Multivariate Cox model showed that PSA, Gleason score, pT category, nodal status, and surgical margins were significant independent predictors of biochemical recurrence-free survival. Conclusions This assessment of oncologic results demonstrates that ELRP is a safe and effective procedure. On the basis of midterm follow-up data, the prognostic factors of PSA after ELRP failure are the same as those described previously in transperitoneal or open retropubic approaches. The oncologic results of ELRP also are in line with those reported with the use of the retropubic or the transperitoneal laparoscopic approaches.
Prostate cancer (PC) is one of the principal causes of death among men. Steroid hormones are involved in normal prostate growth and carcinogenesis. The purpose of our study was to investigate the ...effects on PC risk of polymorphisms from three steroid hormone receptor genes: the androgen (AR), and the alpha (ESR1) and beta (ESR2) estrogen receptors.
The study was performed on a Caucasian population of 1045 PC patients and 814 controls. Using a logistic regression model, the different alleles and genotypes from those polymorphisms were analyzed according to case/control status, the tumor aggressiveness, and the age at onset.
A significant association between PC risk and the pooled 4/5, 5/6, and 6/6 genotypes of the GGGA repeat located in the first intron of ESR1 (odds ratio (OR)=3.00, 95% CI=1.32-6.82, P=0.008) was observed. When we stratified the cases, this association was confined to patients with a Gleason score of 2-4 (OR=8.34, 95% CI=2.91-23.91, P<0.0001) or late onset PC (OR=2.91, 95% CI=1.22-6.93, P=0.016). An association between a short AR CAG repeat (less than 17 repeats) was also observed among patients with late onset PC (OR=2.34, 95% CI=1.15-4.76, P=0.019).
These findings suggest that the GGGA repeat from ESR1 and the CAG repeat from AR may be associated with risk of late onset PC.
Neuroendocrine prostate cancer (NEPC) is a multi-resistant variant of prostate cancer (PCa) that has become a major challenge in clinics. Understanding the neuroendocrine differentiation (NED) ...process at the molecular level is therefore critical to define therapeutic strategies that can prevent multi-drug resistance.
Using RNA expression profiling and immunohistochemistry, we have identified and characterised a gene expression signature associated with the emergence of NED in a large PCa cohort, including 169 hormone-naïve PCa (HNPC) and 48 castration-resistance PCa (CRPC) patients. In vitro and preclinical in vivo NED models were used to explore the cellular mechanism and to characterise the effects of castration on PCa progression.
We show for the first time that Neuropilin-1 (NRP1) is a key component of NED in PCa cells. NRP1 is upregulated in response to androgen deprivation therapies (ADT) and elicits cell survival through induction of the PKC pathway. Downmodulation of either NRP1 protein expression or PKC activation suppresses NED, prevents tumour evolution toward castration resistance and increases the efficacy of docetaxel-based chemotherapy in preclinical models in vivo.
This study reveals the NRP1/PKC axis as a promising therapeutic target for the prevention of neuroendocrine castration-resistant variants of PCa and indicates NRP1 as an early transitional biomarker.
Expression of class III β-tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies, but its use as a biomarker of tumor ...behavior in prostate cancer (PCa) remains largely unexplored. Here, we describe βIII-tubulin immunohistochemical staining patterns of prostate tumors obtained from a broad spectrum of PCa patients, some of whom subsequently received docetaxel therapy for castration-resistant PCa (CRPC). Elevated βIII-tubulin expression was significantly associated with tumor aggressiveness in PCa patients with presumed localized disease, as it was found to be an independent marker of biochemical recurrence after treatment. Additionally, βIII-tubulin expression in tumor cells was an independent predictor of lower overall survival for patients receiving docetaxel-based chemotherapy for CRPC. Manipulation of βIII-tubulin expression in human PCa cell lines using a human βIII-tubulin expression vector or βIII-tubulin small interfering RNA altered cell survival in response to docetaxel treatment in a manner that supports a role for βIII-tubulin expression as a mediator of PCa cell resistance to docetaxel therapy. Our findings suggest a role for βIII-tubulin as candidate theranostic biomarker to predict the response to docetaxel-based chemotherapy as well as to target for treatment of docetaxel-resistant CRPC.
Abstract Background The optimal selection of prostate cancer (PCa) patients for active surveillance (AS) is currently being debated. Objective To assess the impact of urinary prostate cancer antigen ...3 (PCA3) score as an AS criterion instead of and in addition to the current criteria. Design, setting, and participants We prospectively studied 106 consecutive low-risk PCa patients (prostate-specific antigen PSA ≤10 ng/ml, clinical stage T1c–T2a, and biopsy Gleason score 6) who underwent a PCA3 urine test before radical prostatectomy (RP). Measurements Performance of AS criteria (biopsy criteria, PCA3 score, PSA density, and magnetic resonance imaging MRI findings) was tested in predicting four prognostic pathologic findings in RP specimens: (1) pT3–4 disease; (2) overall unfavourable disease (OUD) defined by pT3–4 disease and/or pathologic primary Gleason pattern 4; (3) tumour volume <0.5 cm3 ; and (4) insignificant PCa. Results and limitations The PCA3 score was strongly correlated with the tumour volume in a linear regression analysis ( p < 0.001, r = 0.409). The risk of having a cancer ≥0.5 cm3 and a significant PCa was increased three-fold in men with a PCA3 score of ≥25 compared with men with a PCA3 score of <25 with most AS biopsy criteria used. There was a trend towards higher PCA3 scores in patients with unfavourable and non–organ-confined disease and Gleason >6 cancers. In a multivariate analysis taking into account each AS criterion, a high PCA3 score (≥25) was an important predictive factor for tumour volume ≥0.5 cm3 (odds ratio OR: 5.4; p = 0.010) and significant PCa (OR: 12.7; p = 0.003). Biopsy criteria and MRI findings were significantly associated with OUD (OR: 3.9 and 5.0, respectively; p = 0.030 and p = 0.025, respectively). Conclusions PCA3 score may be a useful marker to improve the selection for AS in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCa.
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