Prognostic Factor In Prostate Cancer Research Articles

Abstract 3554: miR-139 is associated with improved prognosis in patients with localized prostate cancer

Abstract Background: We previously identified a panel of five miRNAs associated with biochemical recurrence and metastasis following prostatectomy based on NGS-based whole miRNome discovery and qPCR-based validation analysis. In this analysis, we examine the effect of miR-139-5p, one of the down-regulated miRNAs identified in the panel, in greater detail. Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that over-expressed miR-139 or transiently transfected cells using miR-139 mimics for functional assays. Finally, we examined pathways through which miR-139 may function using prediction algorithms and confirmed targets by Western blotting and reporter assays. Results: MiR-139 down-regulation was significantly associated with a variety of accepted prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity and lymph node status. MiR-139 was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (p=0.0004 and 0.038, respectively). After adjusting for known prognostic factors, patients with high miR-139 expression had significantly lower risk of recurrence (HR 0.77, 95% 0.58-1.04). Validation in the TCGA dataset showed a significant association between dichotomized miR-139 expression and biochemical recurrence (OR 0.52, 95% CI 0.33-0.82). Over-expression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared to control cells, with cells arrested in G2 of cell cycle. IGF1R, RUNX1 and AXL were identified as potential gene targets of miR-139 based on their association with prostate cancer growth pathways and multiple miRNA binding site prediction tools. The reporter assays using luciferase gene constructs containing the predicted miRNA targeting sequence from IGFR1 and RUNX1 verified them as direct targets of miR-139. Furthermore, Western blotting of prostate cancer cells demonstrated RUNX1 and AXL expression were inhibited by miR-139 treatment, which was reversed by addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated Akt and cyclin D1, with upregulation of the CDK inhibitor p21. Conclusions: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through inhibition of IGF1R, RUNX1 and/or AXL and their associated growth signaling pathways. Citation Format: Tania Benatar, Robert K. Nam, Elizabeth Kobylecky, Yutaka Amemiya, Arun K. Seth. miR-139 is associated with improved prognosis in patients with localized prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3554.

Treatment outcomes of prostate cancer patients with Gleason score8-10 treated with definitive radiotherapy : TROD 09-001 multi-institutional study.

To validate the clinical outcomes and prognostic factors in prostate cancer (PCa) patients with Gleason score (GS)8-10 disease treated with external beam radiotherapy (EBRT) + androgen deprivation therapy (ADT) in the modern era. Institutional databases of biopsy proven 641 patients with GS8-10PCa treated between 2000 and 2015 were collected from 11institutions. In this multi-institutional Turkish Radiation Oncology Group study, astandard database sheet was sent to each institution for patient enrollment. The inclusion criteria were, T1-T3N0M0 disease according to AJCC (American Joint Committee on Cancer) 2010 Staging System, no prior diagnosis of malignancy, at least 70 Gy total irradiation dose to prostate ± seminal vesicles delivered with either three-dimensional conformal RT or intensity-modulated RT and patients receiving ADT. The median follow-up time was 5.9years (range 0.4-18.2years); 5‑year overall survival (OS), biochemical relapse-free survival (BRFS) and distant metastases-free survival (DMFS) rates were 88%, 78%, and 79%, respectively. Higher RT doses (≥78 Gy) and longer ADT duration (≥2years) were significant predictors for improved DMFS, whereas advanced stage was anegative prognosticator for DMFS in patients with GS9-10. Our results validated the fact that oncologic outcomes after radical EBRT significantly differ in men with GS8 versus those with GS9-10 prostate cancer. We found that EBRT dose was important predictive factor regardless of ADT period. Patients receiving 'non-optimal treatment' (RT doses <78 Gy and ADT period <2years) had the worst treatment outcomes.

MON-313 High Expression of Nucleobindin-2 Is Associated with Poor Prognosis in Gastric Cancer

Nucleobindin-2 (NUCB2) is a 396-amino acid protein, cleaved into the N-terminal nesfatin-11-82, nesfatin-285-163and the C-terminal nesfatin-3166-396. NUCB2 contains a signal peptide, a leucine zipper structure, two Ca2+binding EF-hand domains, and has a wide variety of basic cellular functions. NUCB2 is also a precursor protein of nesfatin-1, which was originally identified in hypothalamic nuclei, and which is a regulatory factor involved in the central control of food intake and energy balance. There are several reports indicating that NUCB2 is also expressed in various human peripheral tissues. Moreover, recent studies have reported that high levels of NUCB2 mRNA and protein are a potent prognostic factor for prostate cancer, endometrial carcinoma, and breast cancer. Suzuki et al.described high NUCB2 immunoreactivity in patients with breast cancer, and NUCB2 protein expression associated significantly with lymph node metastasis and an increased risk of recurrence. They found that NUCB2 significantly increased tumor cell proliferation, migration, and invasion, suggesting that NUCB2 plays a crucial role in the metastatic process of breast cancer. Several researchers have reported that the expression level of NUCB2 was significantly higher in prostate cancer tissues than in non-cancerous tissues, and was associated with lymph node metastasis and shorter survival. However,theclinicopathologicalsignificance of NUCB2 expression in gastric cancer has still not beenelucidated. Therefore, we examined NUCB2 expression in a large number of gastric cancer patients, using immunohistochemistry, to explore its clinicopathologicalsignificance. To explore this, we aimed to investigate the NUCB2 expression in gastric cancer tissues and adjacent non-tumor tissues and its potential relevance to clinicopathological factors and prognosis using immunohistochemistry analysis. In our study, NUCB2 level in gastric cancertissues was higher than in non-tumor tissues. A high expression of NUCB2 is significantly associated with tumor depth, lymph node metastasis, lymphatic invasion, venous invasion and clinical stage. Furthermore, the expression level of NUCB2 protein was independent predictor of progression-free survival. In summary, NUCB2 might play a crucial role in gastric cancerdevelopment and could serve as an independent predictor of prognosis of gastric cancerpatients.

Prognostic Factors in Prostate Cancer for Patients Treated by Watchful Waiting

Prognostic Factors in Prostate Cancer for Patients Treated by Watchful Waiting

RRBP1 is highly expressed in prostate cancer and correlates with prognosis.

Objective: Recently, ribosome binding protein 1 (RRBP1) is reported to be involved in tumorigenesis. However, the expression and clinical significance of RRBP1 in prostate cancer (PCa) remains unknown. This study is aimed to investigate the expression and clinical significance of RRBP1 in PCa. Materials and methods: RRBP1 expression was firstly detected in 6 cases of PCa and matched adjacent non-cancerous prostate tissues by reverse transcription-quantitative PCR (RT-qPCR) and Western blot. Then, RRBP1 expression was further detected in 127 cases of PCa and 40 cases of non-cancerous prostate tissues by immunohistochemistry (IHC). The relationship of RRBP1 with clinical-pathological characters and patients’ prognosis was analyzed in PCa.Results: RT-qPCR and Western blot analysis showed that RRBP1 expression levels in PCa tissues were significantly higher compared with those in matched adjacent non-cancerous prostate tissues. IHC results shown that the high-expression rate of RRBP1 in PCa was 69.3%, which was significantly greater than those in non-cancerous prostate tissues (15.0%, P<0.001). RRBP1 expression was significantly associated with T stage, lymph node metastasis, PSA and Gleason score in PCa. Survival analysis indicated that patients with RRBP1 low-expression presented longer survival time compared with those with RRBP1 high-expression. Moreover, RRBP1 as well as T stage, lymph node metastasis and Gleason score could serve as independent prognostic factors in PCa.Conclusion: RRBP1 is highly expressed in PCa and correlates with prognosis, which may serve as a potential biomarker in PCa.

EP-1921 Phase II AIRC-IG13218: Association of MRIbased radiomics with prognostic factors in prostate cancer

EP-1921 Phase II AIRC-IG13218: Association of MRIbased radiomics with prognostic factors in prostate cancer

Prostatic Adenocarcinoma: A Grading from Gleason to the New Grade-Group System: A Historical and Critical Review

The introduction of the Gleason grading system revolutionised prognostic parameters and determination of patient treatment regiments for prostatic adenocarcinomas, and has become synonymous with prostate cancer, almost universally applied in clinical settings to predict radical prostatectomy specimen findings, potential biochemical failure, local recurrences, lymph nodes or distant metastases in patients not receiving any treatment as well as those receiving treatment including radiation therapy, surgical treatment such as radical prostatectomy and other therapies etc,. However, characterisation and classification of prostate cancer is very different compared to 40-50 years ago when Gleason scores were first introduced. Despite this radical shift in classification, the Gleason system has remained one of the most important prognostic factors in prostate cancer, only possible as a result of timely and appropriate modifications to this characterisation system made in 2005 and 2014. However, even after these modifications, certain limitations of the Gleason system remain, due to which a new prostate cancer prognostic grade group system was introduced in 2014, which was widely accepted in the 2014 ISUP consensus conference, and incorporated into the WHO classification of thetumor of the Urinary System and Male Genital Tract in 2016. Herein, this article will discuss how this new prognostic grade group system, which is regarded as simpler and more accurate than the Gleason system risk stratification groups, will be used in conjunction with the Gleason system to improve patient prognosis and treatment.

A nuclear shift of GSK3β protein is an independent prognostic factor in prostate cancer.

Glycogen synthase kinase 3ß (GSK3ß) regulates many cancer relevant cellular processes and represents a potential therapeutic target. GSK3ß overexpression has been linked to adverse tumor features in many cancers, but its role in prostate cancer remains uncertain. We employed immunohistochemical GSK3ß expression analysis on a tissue microarray with 12,427 prostate cancers. Cytoplasmic and nuclear GSK3ß staining was separately analyzed. GSK3ß staining was absent in normal prostate epithelium, whereas 57% of 9,164 interpretable cancers showed detectable GSK3ß expression. Cytoplasmic staining was considered weak, moderate, and strong in 36%, 19.5% and 1.5% of tumors and was accompanied by nuclear GSK3ß staining in 47% of cases. Cytoplasmic GSK3ß staining as well as nuclear GSK3ß accumulation was associated with advanced tumor stage, high Gleason grade, presence of lymph node metastasis and early biochemical recurrence (p < 0.0001 each for cytoplasmic staining and nu-clear accumulation). Prognosis of GSK3ß positive cancers became particularly poor if nuclear GSK3ß staining was also seen (p < 0.0001). The prognostic impact of nuclear GSK3ß accumu-lation was independent of established preoperative and postoperative parameters in multivari-ate analyses (p < 0.0001). The significant association of GSK3ß expression with deletions of PTEN, 3p13 (p < 0.0001 each), 5q21 (p = 0.0014) and 6q15 (p = 0.0026) suggest a role of GSK3ß in the development of genomic instability. In summary, the results of our study identify GSK3ß as an independent prognostic marker in prostate cancer.

Early predicting factor for biochemical failure for patients with intermediate and high-risk prostate cancer treated by definitive radiotherapy.

52 Background: The prostate-specific antigen nadir (nPSA), a strong prognostic factor for prostate cancer, does not occur until several years after definitive radiotherapy. Our aim was to assess an early predictive factor for biochemical failure (BCF) in patients with intermediate- and high-risk prostate cancer treated with definitive radiotherapy. Methods: Between 2007 and 2017, 97 patients with localized prostate cancer underwent radiotherapy at two institutions. We used a pelvic lymph node involvement risk of 15% as the cutoff value, calculated using the Roach formula, to decide whether to deliver prostate and seminal vesicle only radiotherapy (PORT) or whole-pelvis radiotherapy (WPRT). Twenty-seven patients (27.8%) underwent PORT with the prostate receiving 45 Gy (4.5 Gy per fraction) and the other 70 patients (72.2%) underwent WPRT with the prostate receiving 72 Gy (2.4 Gy per fraction). The median equivalent dose in 2 Gy fractions to the prostate was 80.3 Gy based on the assumption that the α/β ratio is 1.5 Gy. Sixty-two patients (63.9%) were treated with androgen deprivation therapy (ADT). Results: The median follow-up time was 40 (range, 10 to 133) months. The 4-year BCF-free survival (BCFS) rate was 87.0%. In the univariate analysis, the nPSA, the nPSA within 12 months (nPSA12), and ADT use were significant predictive factors for BCF. nPSA ( p = 0.003) and ADT use ( p = 0.041), but not nPSA12 ( p = 0.485), were independent predictive factors for BCF in the multivariate analysis. However, there was a strong correlation between nPSA and nPSA12 in this study ( r = 0.854, p &lt; 0.001). The receiver operating characteristic curve identified 0.47 ng/ml as the optimal cutoff value of nPSA12 for predicting BCF. The 4-year BCFS rate in patients with nPSA12 &lt; 0.47 ng/ml was 100% in contrast to 71.3% in patients with nPSA12 ≥ 0.47 ng/ml. Conclusions: The nPSA12 has a strong correlation with nPSA and is a considerable predictor of BCF. Therefore, the treatment outcome can be predicted early using nPSA12. Furthermore, ADT can significantly reduce BCF in patients with intermediate- and high-risk prostate cancer.

MicroRNAs as Diagnostic, Prognostic, and Therapeutic Biomarkers in Prostate Cancer.

Prostate cancer is the most prevalent nonskin cancer and a major cause of cancer-related deaths worldwide. Prostate-specific antigen (PSA) testing is routinely used for screening and early detection of prostate cancer; however, it does not reduce death from prostate cancer. Moreover, PSA is not specific for prostate cancer and results in high false-positive rates, and it is poorly correlated with cancer stage. Therefore, the need for another diagnostic and prognostic factor in prostate cancer is apparent. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs which are involved in modulation of gene expression posttranscriptionally. Multiple lines of evidence indicate that miRNAs play key roles in various physiological events. Deregulation of miRNAs is related to initiation and development of various diseases such as prostate cancer. It has been shown that various miRNAs (miR-34, miR-21, miR-155, miR-221, miR-222, and let-7) exert their effects by targeting a variety of cellular and molecular pathways (c-Myc, EZH2, c-RSC, BCL2L2, E2F6, ZEB, HMGA251, and CCND2) involved in prostate cancer pathogenesis. Hence, it seems that miRNA expression profiles can be seen as potential candidates for prognosis, diagnosis, and treatment of prostate cancer. Here, we summarize various miRNAs as prognostic, diagnostic, and therapeutic biomarkers for prostate cancer therapy.

GBX2 Methylation Is a Novel Prognostic Biomarker and Improves Prediction of Biochemical Recurrence Among Patients with Prostate Cancer Negative for Intraductal Carcinoma and Cribriform Architecture

BackgroundTumor intraductal carcinoma/cribriform architecture (IDC/C) is associated with an unfavorable prognosis and biochemical recurrence (BCR) in prostate cancer (PCa). Up to 70% of PCa patients are IDC/C-negative, but it is estimated that 20% of these cases still experience BCR. Thus, biomarkers for better detection of aggressive disease in IDC/C-negative patients are required. ObjectiveTo investigate tumor-specific methylation of the transcription factor GBX2 as a novel prognosticator and predictor of BCR in PCa patients stratified by histopathologic features including IDC/C. Design, setting, and participantsUsing genome-wide methylome profiling, we identified higher GBX2 methylation in grade group (GG) 4 tumors compared to GG1 (discovery cohort). The prognostic nature of GBX2 methylation was validated in silico using The Cancer Genome Atlas data (n=478) and a quantitative methylation assay for radical prostatectomy samples (n=254). Regulation of GBX2 methylation was investigated in prostate cells using methyl-CpG-binding domain sequencing and methylation analysis in functional knockouts of TET2, a key epigenetic player in prostate carcinogenesis. Outcome measurements and statistical analysisThe association of GBX2 methylation with Gleason score (GS), pathologic stage (pT), IDC/C, and BCR was analyzed using Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression analyses were used to predict BCR. ResultsGBX2 methylation was associated with GS (p<0.05), pT (p<0.01), and BCR (p<0.05). GBX2 methylation (p=0.004), GS (p<0.001), pT (p=0.012), and prostate-specific antigen (p=0.005) were independent predictors of BCR. Among IDC/C-negative patients, GBX2 methylation improved prediction of BCR (p=0.002). Loss of TET2 in prostate cells resulted in greater GBX2 methylation. ConclusionsWe identified GBX2 methylation as a novel prognostic factor in PCa and an independent predictor of BCR. We demonstrated the additive value of GBX2 methylation in predicting BCR among IDC/C-negative patients and elucidated a novel TET2-mediated upstream epigenetic regulatory mechanism of GBX2. Patient summaryWe identified GBX2 methylation as a promising prognostic biomarker that could improve the identification of prostate cancer patients at higher risk of biochemical recurrence.

Quantum dot-based immunofluorescent imaging and quantitative detection of DNER and prognostic value in prostate cancer.

DNER, Delta/Notch-like epidermal growth factor (EGF)-related receptor, is a neuron-specific transmembrane protein carrying extracellular EGF-like repeats. The prognostic value of DNER in prostate cancer has not been evaluated. Here we showed that the up-regulation of DNER protein was observed in prostate cancer detected by immunohistochemistry (IHC) and quantum dot-based immunofluorescent imaging and quantitative analytical system (QD-IIQAS). However, a higher accuracy of measurements of DNER expression in prostate cancer was found by QD-IIQAS than by IHC (AUC = 0.817 and 0.617, respectively). DNER was significantly higher in patients undergoing bone metastasis (P = 0.045, RR = 3.624). In addition, DNER overexpression was associated with poor overall survival (OS) (P = 0.028, adjusted HR = 8.564) and recurrence-free survival (RFS) (P = 0.042, adjusted HR = 3.474) in patients suffering prostate cancer. Thus, QD-IIQAS is an easy and accurate method for assessing DNER and the DNER expression was an independent prognostic factor in prostate cancer.

Abstract A079: MicroRNA-139 regulates prostate cancer aggressiveness by targeting IGF1R

Abstract Background: Dysregulated microRNA (miRNA) expression has been implicated in prostate cancer progression. We previously identified a panel of five miRNAs associated with biochemical recurrence and metastasis following prostatectomy based on NGS-based whole miRNome discovery and qPCR-based validation analysis. In this analysis, we examine the effect of miR-139-5p, one of the downregulated miRNAs identified in the panel, in greater detail. Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 for functional assays. Finally, we examined pathways through which miR-139 may function using prediction algorithms and confirmed targets by Western blotting and reporter assays. Results: MiR-139 downregulation was significantly associated with a variety of accepted prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis was significantly lower among patients with high miR-139 expression (p=0.0004 and 0.038, respectively). After adjusting for known prognostic factors, patients with high miR-139 expression had significantly lower risk of recurrence (HR 0.77, 95% 0.58-1.04). Validation in the TCGA dataset showed a significant association between dichotomized miR-139 expression and biochemical recurrence (OR 0.52, 95% CI 0.33-0.82). Overexpression of miR-139 in PC3 and DU145 prostate cancer cells led to a significant reduction in cell proliferation and migration compared to control cells. IGF1R was identified as a potential target of miR-139 based on previous work in colorectal and non-small cell lung cancers. Reduced luciferase reporter activity was observed upon co-transfection of the 3′ UTR of IGF1Rβ with miR-139 mimic compared to co-transfection with control mimic. Furthermore, Western blotting of PC3 cells overexpressing miR-139 revealed reduced IGF1Rβ protein expression, as well as reduced expression of its downstream pathway proteins pAKT and pERK. Cell cycle analysis indicated a significantly increased number of cells arrested in G2/M phase in PC3 cells overexpressing miR-139. This was accompanied by an increase in β-galactosidase stained senescent cells and p21 protein expression. Conclusions: miR-139 is associated with improved prognosis in patients with localized prostate cancer. This appears to be mediated through an IGF1R pathway leading to increased p21 expression, resulting in prostate cancer cell senescence from G2 arrest. Citation Format: Yutaka Amemiya, Christopher J. Wallis, Tania Benatar, Elizabeth Kobylecky, Linda Sugar, Christopher Sherman, Robert Nam, Arun K. Seth. MicroRNA-139 regulates prostate cancer aggressiveness by targeting IGF1R [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A079.

Early Versus Delayed Initiation of Salvage Androgen Deprivation Therapy and Risk of Prostate Cancer-Specific Mortality.

Background: This study sought to ascertain whether there is an association between prostate cancer (PC)-specific mortality (PCSM) and timing of salvage androgen deprivation therapy (ADT) among men with short versus long prostate-specific antigen doubling times (PSA-DTs). Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. A total of 54 men who received salvage ADT for PSA failure after a median follow-up of 18.72 years following randomization defined the study cohort. The Fine-Gray competing risks regression model was used to analyze whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (interquartile range, 3.05-9.56) following salvage ADT, 49 of the 54 men (91%) died, of which 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate (per month increase) was associated with a decreasing risk of PCSM (adjusted hazard ratio [HR], 0.33; 95% CI, 0.13-0.82; P=.02). Among men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA level >12 ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (adjusted HR, 8.84; 95% CI, 1.99-39.27; P=.004), whereas for those with a short PSA-DT (<6 months; adjusted HR, 1.16; 95% CI, 0.38-3.54; P=.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA failure in men with a PSA-DT of ≥6 months may reduce the risk of PCSM.

Increased KIF4A expression is a potential prognostic factor in prostate cancer.

The kinesin super-family protein (KIF) 4A gene is reported to be overexpressed and associated with poor clinical prognosis in human cancers; however, its clinical significance in prostate cancer (PCa) has not been well studied. The present study performed dataset analyses and revealed that KIF4A expression was significantly increased in castration-resistant PCa patients. Additionally, KIF4A expression was significantly highly expressed in PCa tissues compared with non-cancerous tissues, particularly in advanced PCa pathological stages. Upregulated KIF4A mRNA expression in PCa tissues was significantly correlated with shorter overall survival and prostate-specific antigen failure. Furthermore, both univariate and multivariate analyses revealed that upregulated KIF4A may predict poor biochemical recurrence (BCR)-free survival. The data suggested that KIF4A may play a key role in PCa progression. Notably, increased KIF4A expression may potentially predict poor BCR-free survival in PCa patients.

Brachytherapy-Based Radiotherapy and Radical Prostatectomy Are Associated With Similar Survival in High-Risk Localized Prostate Cancer.

Purpose There are no randomized trials to guide treatment decisions between radiotherapeutic and surgical options for patients with high-risk localized prostate cancer. Comparative studies have been limited by their ability to match patients on the basis of pretreatment prognostic variables and to adjust for the cancer-related, medical, and socioeconomic differences between patients who choose radiotherapeutic or surgical approaches. Methods We analyzed the outcome of all patients in the National Cancer Database with high-risk, clinically localized prostate cancer with complete prognostic data who were treated with either radical prostatectomy (RP), external beam radiotherapy (EBRT) combined with androgen deprivation (AD), or EBRT plus brachytherapy with or without AD. Inverse probability of treatment weighting was used to adjust for covariable imbalance among treatment groups. The weighted time-dependent Cox proportional hazards model was then used to estimate the effects of treatment groups on survival, accounting for differential treatment initiation times. A predictive model of pathologic nodal (pLN) status was built using prostate-specific antigen level, Gleason score, and clinical T stage; predicted pLN status was used to repeat the inverse probability of treatment weighting and time-dependent Cox proportional hazards model. Results A total of 42,765 patients were analyzed. There was no statistically significant difference in survival between RP and EBRT plus brachytherapy with or without AD (hazard ratio [HR], 1.17; 95% CI, 0.88 to 1.55). However, EBRT plus AD was associated with higher mortality than RP (HR, 1.53; 95% CI, 1.22 to 1.92). Adjustment for predicted pLN status did not yield statistically different results. A sensitivity analysis showed that EBRT plus AD ≥ 7920 cGy narrowed the difference, but a significantly higher mortality remained (HR, 1.33; 95% CI, 1.05 to 1.68). Conclusion After comprehensively adjusting for imbalances in prostate cancer prognostic factors, other medical conditions, and socioeconomic factors, this analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival.

Low testosterone at first PSA failure and assessment of the risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials.

45 Background: Low testosterone at prostate cancer diagnosis has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at first PSA failure following definitive therapy and prior to the documentation of metastatic disease has not been elucidated and was studied. Methods: Between 1995 to 2001, 58 men with unfavorable-risk prostate cancer treated on clinical trials with radiation and androgen deprivation therapy (ADT) had testosterone levels at PSA failure available. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone at PSA failure was associated with the risk of prostate cancer-specific, other-cause and all-cause mortality (PCSM, OCM, ACM) adjusting for age, salvage ADT use and known prostate cancer prognostic factors. Results: After a median follow-up of 6.68 years following first PSA failure, 31 men (53.4%) died; 10 from prostate cancer (32.3%), of which 8/11 (72.7%) versus 2/47 (4.3%) occurred in men with low versus normal testosterone at PSA failure, respectively. A significant increase in the risk of ACM (adjusted hazard ratio, AHR [2.54, 95% CI 1.04-6.21]; P = 0.04) and PCSM (AHR [13.71, 95% CI 2.4-78.16]; P = 0.003), with a reciprocal trend toward decreased risk of OCM (AHR [0.18, 95% CI 0.02-1.55]; P = 0.12) was observed in men with low versus normal testosterone at first PSA failure. Conclusions: Low testosterone at first PSA failure confers a very poor prognosis. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic prostate cancer and possibly in men with localized high-risk prostate cancer provides rationale to support their use with ADT in men with low testosterone at PSA failure in the setting of a phase II trial.

Survival after surgical or radiotherapeutic treatment for high-risk localized prostate cancer: A National Cancer Database analysis with comprehensive treatment group imbalances adjustments.

55 Background: There are no randomized trials to guide a high-risk localized prostate cancer patient’s treatment decision between radiotherapeutic and surgical options. Comparative studies have been limited by their ability to match patients based on pre-treatment prognostic variables and to adjust for the cancer–related, medical and socioeconomic differences between patients who choose radiotherapeutic or surgical approaches. Methods: We analyzed the outcome of all patients in the National Cancer Database with high-risk clinically localized prostate cancer with complete prognostic data who were treated with either radical prostatectomy (RP), external beam radiotherapy (EBRT) combined with androgen deprivation (AD) or EBRT+brachytherapy (brachy)±AD. Inverse probability of treatment weighting (IPTW) was used to adjust for covariate imbalance between treatment groups. Time-dependent Cox proportional hazards (TDCPH) model was then used to evaluate differences between treatment groups. Because of imbalances in the frequency of pathologic lymph node sampling between the treatment groups, a predictive model of pathologic nodal (pLN) status was built using PSA, Gleason score and clinical T stage and predicted pLN status was used to repeat the IPTW and TDCPH model. Results: 42,765 patients were analyzed. There was no statistically significant difference in survival between RP and EBRT+brachy±AD (HR 1.17 (0.88, 1.55)). However, EBRT+AD was associated with higher mortality than RP (HR 1.53 (1.22, 1.92)). Adjustment for predicted pLN status did not change the results. Subset analysis of EBRT+AD patients who received ≥7920 cGy narrowed the difference but remained significant (HR 1.32 (1.02, 1.66)). Conclusions: After comprehensively adjusting for imbalances in prostate cancer prognostic factors, other medical conditions and socioeconomic factors, this analysis showed no difference in survival between patients treated with RP vs. EBRT+brachy±AD. EBRT+AD was associated with lower survival. Randomized trials comparing these three methods of treatment are urgently needed.

Early versus delayed initiation of salvage androgen deprivation therapy and the risk of prostate cancer-specific mortality.

189 Background: We sought to ascertain whether there is an association between prostate cancer (PC)-specific mortality (PCSM) and salvage androgen deprivation therapy (ADT) timing amongst men with short versus long prostate-specific antigen doubling times (PSA-DT)s. Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC who were randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. Fifty-four men who received salvage ADT for PSA failure after a median follow up of 18.72 years following randomization defined the study cohort. Fine-Gray competing risks regression analyzed whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (IQR 3.05 - 9.56) following salvage ADT 49 of the 54 men (91%) died, 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate was associated with a decreasing risk of PCSM (adjusted hazard ratio [AHR] 0.33, 95% CI 0.13, 0.82; P=0.02). Amongst men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA&gt;12ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (AHR 8.84, 95% CI 1.99-39.27; P=0.004); whereas for men with a short (&lt;6 months) PSA-DT (AHR 1.16, 95% CI 0.38-3.54; P=0.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA recurrence in men with a PSA-DT of 6 months or more may reduce the risk of PCSM, arguing against the unproven assumption that patients with a short PSA-DT are those most likely to benefit from early initiation of salvage ADT. Clinical trial information: NCT00116220.

The prognosis of different distant metastases pattern in prostate cancer: A population based retrospective study.

The present of metastases is a poor prognostic factor in prostate cancer, but the prognostic impact of different distant metastases pattern is unclear. The aim of this study is to investigate the impact of different distant metastases pattern on the survival of patients with stage IV prostate cancer. Data queried for this study include prostate cancer (2010-2014) from the Surveillance, Epidemiology, and End Results (SEER) program. Metastatic distribution information was provided for bone, brain, liver and lung. The overall survival was calculated by the Kaplan-Meier method. Multivariable Cox regression models were used to analyze survival outcome and risk factors. A total of 265 900 eligible patients were identified from SEER database. Among these patients, stage of IV prostate cancer accounted for 7.53% (20 034/265 900) at diagnosis. Patients who suffered metastasis to either one of the four organs occupied 61.24% (12 268/20 034) in stage of IV patients. Comparing with other three single metastases, the patients with liver metastasis exhibited worst OS whose mean survival was 17.529 months (P < 0.001). The mean survival of metastases with bong and lung was 25.238 months, which was the best survival of the six forms with two metastatic sites (P < 0.001). The results of univariate survival analysis showed that metastatic forms, race, N-classification and differentiated grade did not have impact on the overall survival of patients with three metastatic sites (all, P > 0.05). In analysis of both one and two metastatic sites, patients with liver metastasis seemed to have worse survival outcome. On the other hand, bone metastasis had better outcome than other three visceral metastases. Knowledge of these differences in metastatic patterns may help to better guide pre-treatment evaluation of prostate cancer and make determination regarding curative-intent interventions.