Stage Prostate Cancer Research Articles

Impacto de la realización de resonancia magnética multiparamétrica (RMmp) antes de la braquiterapia en pacientes con cáncer de próstata

IntroductionBrachytherapy for the treatment of prostate cancer is a well-established option. Use of Multiparametric Magnetic Resonance Imaging (mpMRI) for staging and diagnosis of prostate cancer has come to change the current paradigm. In this study we aim to assess the impact of performing mpMRI to evaluate the presence of extracapsular lesions before brachytherapy in patients with prostate cancer concerning biochemical recurrence and time to nadir. MethodsReview data from 73 patients submitted to brachytherapy. The following factors were evaluated: age, initial PSA, MRI local staging results, ISUP, nadir, time to nadir, PSA at one-year, biochemical recurrence, and time to recurrence. ResultsMedian age was 68years (51-72) and median follow-up 53months (30-72). Concerning imaging modality 30.1% (n=22) patients performed mpMRI. In the mpMRI group, 90.9% (n=20) had at least one suspect lesion on mpMRI. Time to nadir was 27months (3-64) in patients where mpMRI was not performed and 23.5months (2-48) in patients submitted to mpMRI (P=.244). The median value of nadir was 0.42ng/mL (<0.001-2) in patients submitted to mpMRI and vs 0.28ng/mL (<0.001-4) in patients without MRI (P=.062) Recurrence utilizing Phoenix criteria was 9% (n=2) in patients with MRI and 9.2% (n=5) without mpMRI (P=.456), median follow-up of 43months (12-72) for the MRI group with 58months (30-78) for the non-mpMRI group. Both groups were statistically similar. ConclusionOur results allow us to conclude that in our series MRI did not influence biochemical recurrence, time to nadir, or nadir value.

Calcium signalling pathways in prostate cancer initiation and progression.

Cancer cells proliferate, differentiate and migrate by repurposing physiological signalling mechanisms. In particular, altered calcium signalling is emerging as one of the most widespread adaptations in cancer cells. Remodelling of calcium signalling promotes the development of several malignancies, including prostate cancer. Gene expression data from in vitro, in vivo and bioinformatics studies using patient samples and xenografts have shown considerable changes in the expression of various components of the calcium signalling toolkit during the development of prostate cancer. Moreover, preclinical and clinical evidence suggests that altered calcium signalling is a crucial component of the molecular re-programming that drives prostate cancer progression. Evidence points to calcium signalling re-modelling, commonly involving crosstalk between calcium and other cellular signalling pathways, underpinning the onset and temporal progression of this disease. Discrete alterations in calcium signalling have been implicated in hormone-sensitive, castration-resistant and aggressive variant forms of prostate cancer. Hence, modulation of calcium signals and downstream effector molecules is a plausible therapeutic strategy for both early and late stages of prostate cancer. Based on this premise, clinical trials have been undertaken to establish the feasibility of targeting calcium signalling specifically for prostate cancer.

Downregulation of BUD31 Promotes Prostate Cancer Cell Proliferation and Migration via Activation of p-AKT and Vimentin In Vitro.

Among men, prostate cancer (PCa) is the second most frequently diagnosed cancer subtype and has demonstrated a high degree of prevalence globally. BUD31, also known as Functional Spliceosome-Associated Protein 17, is a protein that works at the level of the spliceosome; it is functionally implicated in pre-mRNA splicing as well as processing, while also acting as a transcriptional regulator of androgen receptor (AR) target genes. Clinically, the expression of BUD31 and its functions in the development and progression of PCa is yet to be elucidated. The BUD31 expression was assessed using IHC in a tissue microarray (TMA) constructed from a cohort of 284 patient samples. In addition, we analyzed the prostate adenocarcinoma (TCGAPRAD-) database. Finally, we used PCa cell lines to knockdown BUD31 to study the underlying mechanisms in vitro.Assesment of BUD31 protein expression revealed lower expression in incidental and advanced PCa, and significantly lower expression was observed in patients diagnosed with castrate-resistant prostate cancer. Additionally, bioinformatic analysis and GSEA revealed that BUD31 increased processes related to cancer cell migration and proliferation. In vitro results made evident that BUD31 knockdown in PC3 cells led to an increase in the G2 cell population, indicating a more active and proliferative state. Additionally, an investigation of metastatic processes revealed that knockdown of BUD31 significantly enhanced the ability of PC3 cells to migrate and invade. Our in vitro results showed BUD31 knockdown promotes cell proliferation and migration of prostate cancer cells via activation of p-AKT and vimentin. These results support the clinical data, where low expression of BUD31 was correlated to more advanced stages of PCa.

2022 cancer statistics: Focus on lung cancer.

This is a plain language summary of a medical journal article called 'Cancer statistics, 2022'. The data in this summary provides detailed information about lung cancer and less detailed information about other cancers. The researchers from the original study used data gathered from previous years to produce a cancer forecast, predicting the number of new cancer diagnoses and deaths in the United States in 2022. The review of the data up to 2019 found that compared to previous years: Advanced lung cancer diagnoses had decreased Local stage lung cancer diagnoses had increased Deaths had slowed for lung cancer Deaths continued to reduce for breast cancer, but the rate of this reduction had slowed down Female breast cancer diagnoses were slowly increasing each year Prostate cancer diagnoses stayed similar Local stage prostate cancer diagnoses stayed similar Advanced prostate cancer diagnoses had increased each year The researchers estimated that over 1.9million new cancer cases would be diagnosed and over half a million cancer deaths would occur in the United States in 2022. This figure includes approximately 350 deaths per day from lung cancer, which was found to be the leading cause of cancer death in the United States. The study found that progress in reducing the number of people being diagnosed with breast and prostate cancer has stalled. Although there were fewer lung cancers diagnosed, this reduction was likely caused by changes in screening and advancements in lung cancer treatments. The American Cancer Society recommended that investing more funds in detecting cancers early as well as developing targeted treatments would help to reduce cancer death rates. This would also help to address the differences in access to cancer care that exist based on racial, social and economic inequalities.

Epiregulin expression and secretion is increased in castration-resistant prostate cancer.

In prostate cancer, long-term treatment directed against androgens often leads to the development of metastatic castration-resistant prostate cancer, which is more aggressive and not curatively treatable. Androgen deprivation results in elevated epiregulin expression in LNCaP cells which is a ligand of EGFR. This study aims to reveal the expression and regulation of epiregulin in different prostate cancer stages enabling a more specific molecular characterization of different prostate carcinoma types. Five different prostate carcinoma cell lines were used to characterize the epiregulin expression on the RNA and protein levels. Epiregulin expression and its correlation with different patient conditions were further analyzed using clinical prostate cancer tissue samples. Additionally, the regulation of epiregulin biosynthesis was examined at transcriptional, post-transcriptional and release level. An increased epiregulin secretion is detected in castration-resistant prostate cancer cell lines and prostate cancer tissue samples indicating a correlation of epiregulin expression with tumor recurrence, metastasis and increased grading. Analysis regarding the activity of different transcription factors suggests the involvement of SMAD2/3 in the regulation of epiregulin expression. In addition, miR-19a, -19b, and -20b are involved in post-transcriptional epiregulin regulation. The release of mature epiregulin occurs via proteolytic cleavage by ADAM17, MMP2, and MMP9 which are increased in castration-resistant prostate cancer cells. The results demonstrate epiregulin regulation by different mechanism and suggest a potential role as a diagnostic tool to detect molecular alterations in prostate cancer progression. Additionally, although EGFR inhibitors false in prostate cancer, epiregulin could be a therapeutic target for patients with castration-resistant prostate cancer.

The Role of ERα and ERβ in Castration-Resistant Prostate Cancer and Current Therapeutic Approaches.

Castration-resistant prostate cancer, or CRPC, is an aggressive stage of prostate cancer (PCa) in which PCa cells invade nearby or other parts of the body. When a patient with PCa goes through androgen deprivation therapy (ADT) and the cancer comes back or worsens, this is called CRPC. Instead of androgen-dependent signalling, recent studies show the involvement of the estrogen pathway through the regulation of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in CRPC development. Reduced levels of testosterone due to ADT lead to low ERβ functionality in inhibiting the proliferation of PCa cells. Additionally, ERα, which possesses androgen independence, continues to promote the proliferation of PCa cells. The functions of ERα and ERβ in controlling PCa progression have been studied, but further research is needed to elucidate their roles in promoting CRPC. Finding new ways to treat the disease and stop it from becoming worse will require a clear understanding of the molecular processes that can lead to CRPC. The current review summarizes the underlying processes involving ERα and ERβ in developing CRPC, including castration-resistant mechanisms after ADT and available medication modification in mitigating CRPC progression, with the goal of directing future research and treatment.

A Systematic Review of the Variability in Performing and Reporting Intraprostatic Prostate-specific Membrane Antigen Positron Emission Tomography in Primary Staging Studies

ContextProstate cancer (PCa) remains one of the leading causes of cancer-related deaths in men worldwide. Men at risk are typically offered multiparametric magnetic resonance imaging and, if suspicious, a targeted biopsy. However, false-negative rates of magnetic resonance imaging are consistently 18%; therefore, there is growing interest in improving the diagnostic performance of imaging through novel technologies. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for PCa staging and, more recently, for intraprostatic tumour localisation. However, significant variability has been observed in how PSMA PET is performed and reported. ObjectiveIn this review, we aim to evaluate how pervasive this variability is in trials investigating the performance of PSMA PET in primary PCa workup. Evidence acquisitionFollowing the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed an optimal search in five different databases. After removing duplicates, 65 studies were included in our review. Evidence synthesisStudies dated back as early as 2016, with numerous different source countries. There was variation in the reference standard for PSMA PET, with some using biopsy specimens or surgical specimens, and in some cases, a combination of the two. Similar inconsistencies were noted when studies selected histological definitions of clinically significant PCa, while some omitted their definition altogether. The most significant variations in performing PSMA PET were the radiotracer type, dose, acquisition time after injection, and the PET camera being utilised. Substantial variation in the reporting of PSMA PET was noted, with no consistency in defining what constitutes a positive intraprostatic lesion. Across 65 studies, four different definitions were used. ConclusionsThis systematic review has highlighted considerable variation in obtaining and performing a PSMA PET study in the context of primary PCa diagnosis. Given the discrepancy in how PSMA PET was performed and reported, it questions the homogony of studies from centre to centre. Standardisation of PSMA PET is required for this to become a consistently useful and reproducible modality in the diagnosis of PCa. Patient summaryProstate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for staging and localisation of prostate cancer (PCa); however, there is significant variability in performing and reporting PSMA PET. Standardisation of PSMA PET is required for results to be consistently useful and reproducible for the diagnosis of PCa.

The potential of miR-153 as aggressive prostate cancer biomarker.

Prostate cancer (PC) is one of the most frequently diagnosed cancers in males. MiR-153, as a member of the microRNA (miRNA) family, plays an important role in PC. This study aims to explore the expression and possible molecular mechanisms of the miR-153 action. Formalin-fixed paraffin-embedded (FFPE) tissues were collected from prostatectomy specimens of 29 metastatic and 32 initial stage PC patients. Expression levels of miR-153 were measured using real-time reverse transcription polymerase chain reaction (qRT-PCR). 2-ΔΔCT method was used for quantitative gene expression assessment. The candidate target genes for miR-153 were predicted by TargetScan. Mutations in target genes of miR-153 were identified using exome sequencing. Protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the potential molecular mechanisms of miR-153 in PC. MiR-153 was significantly up-regulated in PC tissues compared to non-cancerous tissues. The analysis of correlation between the expression level of miR-153 and clinicopathological factors revealed a statistically significant correlation with the stage of the tumor process according to tumor, node, metastasis (TNM) staging system (p=0.0256). ROC curve analysis was used to evaluate the predictive ability of miR-153 for metastasis development and it revealed miR-153 as a potential prognostic marker (AUC=0.85; 95%CI 0.75-0.95; sensitivity=0.72, specificity=0.86)). According to logistic regression model the high expression of miR-153 increased the risk of metastasis development (odds ratios=3.14, 95% CI 1.62-8.49; p-value=0.006). Whole exome sequencing revealed nonsynonymous somatic mutations in collagen type IV alpha 1 (COL4A1), collagen type IV alpha 3 (COL4A3), forkhead box protein O1 (FOXO1), 2-hydroxyacyl-CoA lyase 1 (HACL1), hypoxia-inducible factor 1-alpha (HIF-1A), and nidogen 2 (NID2) genes. Moreover, KEGG analysis revealed that the extracellular matrix-receptor (ECM-receptor) interaction pathway is mainly involved in PC. MiR-153 is up-regulated in PC tissues and may play an important role in aggressive PC by targeting potential target genes.

Potential role for protein kinase D inhibitors in prostate cancer.

Protein kinase D (PrKD), a novel serine-threonine kinase, belongs to a family of calcium calmodulin kinases that consists of three isoforms: PrKD1, PrKD2, and PrKD3. The PrKD isoforms play a major role in pathologic processes such as cardiac hypertrophy and cancer progression. The charter member of the family, PrKD1, is the most extensively studied isoform. PrKD play a dual role as both a proto-oncogene and a tumor suppressor depending on the cellular context. The duplicity of PrKD can be highlighted in advanced prostate cancer (PCa) where expression of PrKD1 is suppressed whereas the expressions of PrKD2 and PrKD3 are upregulated to aid in cancer progression. As understanding of the PrKD signaling pathways has been better elucidated, interest has been garnered in the development of PrKD inhibitors. The broad-spectrum kinase inhibitor staurosporine acts as a potent PrKD inhibitor and is the most well-known; however, several other novel and more specific PrKD inhibitors have been developed over the last two decades. While there is tremendous potential for PrKD inhibitors to be used in a clinical setting, none has progressed beyond preclinical trials due to a variety of challenges. In this review, we focus on PrKD signaling in PCa and the potential role of PrKD inhibitors therein, and explore the possible clinical outcomes based on known function and expression of PrKD isoforms at different stages of PCa.

The impact of F-18 PSMA PET imaging on clinical decision-making in prostate cancer across disease states.

63 Background: Piflufolastat F-18 (18F-DCFPyL) PSMA PET imaging was recently approved by the FDA for initial staging, biochemical recurrence (BCR), and restaging of metastatic prostate cancer. Given that the PSMA PET is a next-generation novel imaging modality that carries a higher sensitivity for detecting metastatic disease compared with conventional imaging, we aimed to assess how its integration into clinical care may have impacted the management of patients. Methods: We identified 236 patients who underwent an 18F-DCFPyL PET scan at the University of Minnesota between August 2021 to June 2022. The median PSA at the time of imaging was 1.75 ng/ml (range, 0.02 - 3740 ng/ml). All PSMA PET scans were evaluated by an experienced nuclear medicine physician. Descriptive statistics were used to analyze its impact on the clinical care of 158 patients: 22 for initial staging, 110 with biochemical recurrence, and 26 patients with known metastatic disease. The remaining 78 patients had no information available to assess clinical utility. Results: Metastatic PSMA-avid lesions were detected in 152/236 (64.4%) patients. In patients undergoing initial staging of high-risk prostate cancer, 17/40 (42.5%) patients had metastatic lesions outside the prostate involving 10 regional and 5 non-regional lymph nodes, 1 visceral site, and 10 bone metastases. 17/40 (42.5%) of the scans were unremarkable. 6/40 (15%) had equivocal scan results. For the patients with available clinical information, 12/22 (54.5%) had a change in their treatment plan post-DCFPyL, while 10/22 (45.5%) had no change. In the biochemical recurrence cohort, 93/151 (61.6%) had positive lesions: 28 local recurrences, 47 regional and 22 non-regional lymph nodes, 5 visceral and 28 bone metastases. Equivocal and negative scans accounted for 13/151 (8.6%) and 45/151 (29.8%) cases, respectively. 44/110 (40%) of the patients with clinical information had a change in their treatment plan, while the plan did not change for 66/110 (60%) cases. In patients with known metastatic prostate cancer undergoing restaging, 42/45 (93.3%) had DCFPyL-positive lesions; 12 local recurrences, 20 regional and 16 non-regional, 9 visceral, and 29 bone metastases. Equivocal and negative scans accounted for 2/45 (4.4%) and 1/45 (2.2) of cases, respectively. Only 11/26 (42.3%) of those with clinical information had their tentative treatment plan adjusted post-DCFPyL. No change in the treatment plan was made in 15/26 (57.7%) cases. Conclusions: Integration of the F-18 PSMA PET imaging substantially impacted clinical decision-making, especially for initial staging of high-risk localized disease (treatment change in 55%) and for biochemical recurrence (treatment change in 40%). It remains to be seen if this would translate into superior survival outcomes.

Association between sociodemographic factors and diagnosis of advanced prostate cancer in early life.

32 Background: A subset of patients are diagnosed with lethal prostate cancer early in life, before PSA screening is typically initiated. To identify opportunities for improved detection we evaluated patient clinical and sociodemographic factors associated with advanced versus localized prostate cancer diagnosis across the age spectrum. Methods: We conducted a retrospective cohort study using the National Cancer Database, identifying patients diagnosed with prostate cancer in 2004-2016. We compared characteristics of patients diagnosed at advanced (cN1 or M1) versus localized (cT1-4N0M0) stage. Using multivariable logistic regression, we evaluated the associations among patient clinical and sociodemographic factors and advanced diagnosis, stratifying patients by age as &lt;55 (before screening is usually initiated), 55-65, 65-75, and &gt;75 years. Results: We identified668,486 patients who met inclusion criteria (mean age at diagnosis=64.6 years), including 33,455 (5.0%) with advanced disease at diagnosis. Uninsured (odds ratio, OR=3.78, 95% confidence interval, CI 3.56-4.02) and Medicaid-insured (OR 2.84, 95% CI 2.70-3.00) versus commercially insured patients were more likely to be diagnosed with advanced disease, however this effect was more pronounced for younger patients. Among patients &lt;55 years, uninsured (OR 4.63, 95% CI 4.08-5.25) and Medicaid (OR 3.59, 95% CI 3.22-3.99) versus commercial insurance were associated with greater odds of advanced cancer at diagnosis. Similarly, residence in the lowest versus highest income quintile (OR 1.21, 95% CI 1.04-1.40) was associated with increased odds of advanced prostate cancer in patients &lt;55 years. Black versus White race was associated with increased odds of advanced prostate cancer at diagnosis later in life (OR 1.15, 95% CI 1.11-1.19), however race was not significantly associated with stage of prostate cancer in those &lt;55 years (p=0.29). Conclusions: Sociodemographic disparities in advanced stages of prostate cancer diagnosis were more pronounced in younger patients, particularly with respect to insurance status. These findings may support greater attention to differential use of early prostate cancer screening by health insurance.

“It just makes sense to me”: Patient experiences with prostate MRI during prostate cancer active surveillance.

334 Background: Although prostate MRI is commonly used in the diagnosis, staging and active surveillance of prostate cancer, little is known about patient perspectives on MRI imaging. Methods: We performed a qualitative descriptive study consisting of in-depth, semi-structured interviews of patients with low and intermediate risk prostate cancer managed with active surveillance. Interviews focused on experiences with prostate MRI and MRI-ultrasound fusion biopsy during active surveillance monitoring. We purposively sampled patients who received prostate MRI as part of their clinical care, over-sampling Black and Latino men, and conducted interviews until thematic saturation. We performed conventional content analysis to analyze data. Results: The mean sample (n=20) age was 68 years (range 51-79). Fourteen (70%) participants identified as White, 5(25%) as Black, and 2(10%) as Hispanic/Latino. At diagnosis, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 tumor. Overall, participants viewed prostate MRI as a valuable tool that accurately localizes and monitors prostate cancer over time. Prostate MRI was seen as central to active surveillance monitoring. We identified five thematic categories: (1) the experiential aspects of undergoing an MRI scan; (2) the experience of visualizing one’s own prostate and prostate cancer; (3) adequacy of provider explanations of MRI results; (4) confidence in prostate MRI in decision-making; and (5) the role of prostate MRI in longitudinal follow-up during active surveillance, including an interest using MRI to modify the timing of, or replace, prostate biopsy. Conclusions: These findings reveal that patients highly value prostate MRI as a tool that enhances the confidence in the initial diagnosis and monitoring of prostate cancer. This work can inform future studies to optimize the patient experience, education and counseling during active surveillance for prostate cancer.

Inherited risk for prostate cancer (PCa): Following the natural history of men with high-risk genetics using multiparametric MRI (mpMRI).

390 Background: PCa has inherited risk factors including high genetic risk variants such as BRCA1/2, HOXB13, and DNA mismatch repair genes. mpMRI has been shown to be effective for detection and staging of localized PCa. This study follows participants (prts), born biologically male, without a diagnosis of PCa with known germline pathogenic or likely pathogenic variants (PV) in BRCA1/2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C/D, BRIP1, or FANCA-FANCM (NCT03805919). Methods: Up to 500 eligible prts 30-75 years old (yo) with a documented germline PV will enroll. Prts undergo biennial clinical exam and mpMRI, and annual PSA monitoring and are followed at 12-month intervals to determine PSA, prostate cancer diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes clinical or imaging findings. Biopsy specimens undergo molecular analyses. Results: To date, 175 prts have been enrolled: 169 (97%) White, 3 Hispanic (2%), 1 African American (1%), 1 Asian (1%), and 1 biethnic (1%). Median age is 47 yo. The most common monoallelic PV are: 48.6% BRCA2, 25.1% BRCA1, 6.3% CHEK2 and 5.7% MSH2. PVs in ATM, PALB2, HOXB13, PMS2, MLH1, MSH6, BRIP1, EPCAM and RAD51D are ≤4%. One subject carries three distinct PVs ( BRCA2, CHEK2, BRIP1). Indication for biopsy was found in 26.3% of prts with 22/46 (47.8%) with a PIRADS 4 lesion, 6/46 (13.0%) PIRADS 3 lesion, 12/46 (26.1%) elevated PSA (median=2.8 ng/mL) or 6/46 (13.0%) due to clinical discretion. Adenocarcinoma was diagnosed on 13/39 (33.3%) biopsies with median age at diagnosis=59 yo. 9/13 (69%) prts had a PSA &lt;3 ng/ml at diagnosis. Nine prts were diagnosed with ISUP Grade Group (GG) 1, 3 with GG2, and 1 with GG3. Eight prts opted for active surveillance (AS), 2 for radiation therapy (RT), and 3 for prostatectomy (RP). Two prts on AS converted to definitive treatment (one RP and one RT) due to progression in GG on the year 1 AS biopsy. Conclusions: mpMRI screening in men with germline PV can be used for diagnosis and monitoring of PCa and facilitates detection below conventional PSA thresholds in a high genetic risk setting. Access to genetic testing and other variables need to be addressed in underrepresented minorities. Correlative studies, including cfDNA and PBMCs, are ongoing. Clinical trial information: NCT03805919 . [Table: see text]

Perioperative outcomes of radical prostatectomy for advanced stage, node positive, and metastatic prostate cancer.

270 Background: Historically, surgical management with radical prostatectomy (RP) has been a definitive treatment option only for localized prostate cancer (PCa). However, recent studies suggest an overall survival benefit to treating the primary tumor with radiation therapy in metastatic PCa (mPCa). Therefore, RP may have a role in treating mPCa, but the perioperative safety of that remains unclear. Here, we aim to compare the perioperative outcomes of RP for locally advanced, node positive, and metastatic PCa using the National Surgical Quality Improvement Project (NSQIP) database. Methods: RPs performed between 2019-2020 were identified in NSQIP and the corresponding Prostatectomy-Targeted Participant Use File. Cases were grouped into six distinct categories: T1N0M0-T2N0M0; T3N0M0; T4N0M0; T1-3N1M0; T4N1M0; and T1-4N0-1M1. Baseline age, race, and medical comorbidities were compared between the groups. Patients were then further grouped into T1-2N0M0 versus T3-4N0M0 cases to compare the effect of locally advanced disease, TanyN1M0 versus TanyN0M0 to compare the effect of node-positivity, and TanyN0M1 versus TanyN0M0 to compare the effect of metastases. 30-day outcomes, operative time, hospital length-of-stay, 30-day mortality, readmissions, reoperations, major complications, minor complications, and surgery-specific complications were compared between groups. Results: Pathologic staging was available for 5,248 RPs. Baseline demographics were largely similar, with the exceptions of increased Black race, diabetes, and smoking in the node-positive-group and increased age in the T4 group. There was a slightly higher rate of minor complications in the locally advanced (T3-4N0M0) versus localized (T1-2N0M0) group, but no significant difference in major complications, 30-day mortality, readmissions, or rectal injuries. In comparison to node-negative patients (T1-4N0M0), node-positivity (T1-4N1M0) was associated with longer operative time, LOS, and incidence of 30-day renal failure, but was otherwise not associated with a higher rate of any complication. Compared to non-metastatic cases (T1-4N0M0), metastatic cases (T1-4N0M1) were associated with a higher rate of bleeding, prolonged-NG-tube use, ureteral obstruction, and LOS. Conclusions: RP for patients with locally advanced, node positive, and metastatic prostate cancer appears to be safe; it is not associated with significantly higher rates of 30-day mortality or major complications compared to RP for localized prostate cancer. Given the potential survival benefit in treating the primary tumor in advanced disease, there may be a role for RP in treating patients with advanced PCa.

Predictor of adverse pathology in patients who underwent deferred radical prostatectomy following active surveillance: Results from multi-institutional prospective observational cohort in the PRIAS-JAPAN.

350 Background: Intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic pathologies among early stage prostate cancer patients; however, predictors of adverse pathology, including these types, remain unknown. In men who opted for active surveillance (AS), we aimed to examine the association between adverse pathology and patient characteristics, utilizing radical prostatectomy (RP) specimens. Methods: We re-reviewed available RP specimens from 1035 men prospectively enrolled in the PRIAS-JAPAN cohort between January 2010 and September 2020. We defined adverse pathology on RP specimen as Gleason grade group of ≥3, pT-stage≥T3, pN positivity, or the presence of IDC-P or invasive cribriform. And, we examined the predictive factors associated with adverse pathology, using factors at AS enrollment and before RP. Results: Out of 162 men underwent RP, available 137 RP specimens were analyzed. The percentage of adverse pathology was 48.9% (67 patients), including 8.8% in IDC-P and 29.9 % in invasive cribriform. Men with adverse pathology had lower prostate specific antigen recurrence-free survival than those without them (log rank P = 0.0189). On multivariate logistic regression analyses, increasing age at AS enrollment and before RP were the predictive factors for adverse pathology (Odds ratio [OR], 1.1; 95% confidence interval [CI]: 1.02-1.19, P = 0.0178, OR, 1.12; 95% CI: 1.02-1.22, P=0.0126), not magnetic resonance imaging findings. Conclusions: Aging is significantly associated with adverse pathology including IDC-P or cribriform. The results suggest that relaxing scheduled examinations during AS depending on age is not practical. Clinical trial information: UMIN000048095 .

Plasma proteome landscape and impact of the circulatory proteome on clinical outcomes in metastatic prostate cancer.

237 Background: We performed plasma-based high-plex proteomic profiling for identifying classifiers of clinical outcomes in metastatic prostate cancer (PC). Olink Explore NGS-based proteome profiling platform was used for high-precision analysis of 736 cancer associated plasma proteins in plasma samples from non-metastatic stage prostate cancer (PC), metastatic hormone-sensitive PC (mHSPC) and metastatic castrate resistant PC (mCRPC) states. Methods: Plasma was collected prospectively in a cohort of 108 PC patients (24 with non-metastatic PC; 28 mHSPC; 56 mCRPC of which 37 patients were collected before starting any mCRPC treatments). Proteomic data were generated with Proximity Extension Assay (PEA) on the Olink platform from 100 µL plasma per sample. Levels of 736 cancer-associated protein assays were denoted as normalized protein expression (NPX) units through a QC and normalization process developed and provided by Olink. Data generation of NPX consists of normalization to the extension control, log2 -transformation, and level adjustment using the plate control (plasma sample). Temporal trends of differentially expressed assays in non-metastatic PC, mHSPC and mCRPC states were identified using linear mixed effects model (FDR with Benjamini-Hochberg (BH) adjustment; q-value&lt;0.05, R version 4.1.2.). Clinical outcomes included in mCRPC state overall survival (calculated as time from turning mCRPC to death) and in mHSPC early failure of ADT-based therapies defined as progression within 12.5 months. Cox proportional hazard regression was performed for proteins associated with mHSPC and mCRPC states and clinical endpoint of interest. Results: After BH adjustments, 105 protein assays were differentially expressed across non-metastatic, mHSPC and mCRPC states of which 73 assays differed between non-metastatic and metastatic states (q&lt;0.05). 83/105 assays differed between mHSPC and mCRPC states (q&lt;0.05). Of the 83 plasma proteins, 77 were over-expressed in mCRPC. 19/37 mCRPC patients who had collections performed before mCRPC treatments had died. The median time to death was 29 months (Range: 1.9-119 mths). After adjustment for serum Alkaline phosphatase (ALP) levels in these 37 mCRPC patients 32/77 were significantly associated with overall survival. After performing an enrichment analysis the oxidative phosphorylation pathway with specific proteins assays (IMMT, COX5B and FXN, p = 5.1e-4, FDR = 2.55 e-2) were significantly overexpressed in patients with poor survival. Conclusions: A global plasma proteomic profiling of cancer related proteins revealed significant differences in expression in different states of cancer progression. Overexpressed proteins related to oxidative phosphorylation pathway in mCRPC in specific are associated with poor survival.

Natural killer cell activity in patients with metastatic castration-resistant prostate cancer treated with enzalutamide.

255 Background: Metastatic castration resistant prostate cancer (mCRPC) is the lethal stage for most patients with prostate cancer (PCa). The need for more reliable prognostic and predictive markers for the management of mCRPC is still unmet. The aim of this study was to elucidate the correlation between Natural Killer cell activity (NKA) and treatment outcome in mCRPC patients. Methods: Blood samples were collected prospectively from 87 patients with mCRPC who were treated by enzalutamide as first line treatment. Samples were collected, in NK Vue tubes, at baseline, and prior to each treatment cycle until treatment change. Tubes were placed in an incubator at 37°C within 15 minutes of sampling. Following 20-24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured, by ELISA (NK Vue) as a surrogate for NKA. Outcomes data were included as endpoints. Results: At the time of biochemical response, plasma IFNγ decreased significantly compared to levels detected at baseline (z-score= 2.334, p=0.019). Additionally, the level of IFNγ was significantly lower at radiological response compared to values at biochemical progression (z-score=2.168, p=0.030). Regarding outcome data, the whole cohort was divided into four groups. In group 1 (n=41) the IFNγ level remained within a normal range (&gt;250 pg/mL), while in group 2 (n=8) it increased from an abnormal (&lt;250 pg/mL) to a normal level. In group 3 (n=13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n=17). There was a significant difference between patients in group 2 and patients in the other three groups regarding both overall survival, radiological free survival and time to next treatment (HR= 3.98, p= 0.012, HR= 6.10, p=&lt; 0.001 and HR= 6.521, p= &lt; 0.001, compared to group 1 respectively). Conclusions: An inverse correlation between NKA and both treatment response and outcome was observed, suggesting a unique role of NK cells in late stage PCa treated with enzalutamide.

Correlation of age and the tumor transcriptomic profile in patients (pts) with advanced prostate cancer (PCa).

233 Background: In general, older pts are likely to have an advanced stage PCa, hence poor overall survival (PMID: 18660852). Owing to increased awareness and better diagnostics, the incidence of PCa has steadily increased amongst older adolescents and young adult pts (PMID: 31553489). Recent reports suggest that younger pts often are staged less adequately, present with more advanced stages, and could have worse outcomes than older pts (PMID: 33575208). Hence, elucidating the underlying molecular biology of PCa by age may unravel specific biologic features and distinct genomic expressions specific to young-age PCa, and help investigate new therapeutic targets. Methods: In this IRB-approved retrospective study, eligibility criteria included pts diagnosed with advanced PCa with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on the cohort's age cut-off points (&lt; 65 vs. ≥65 years). DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. The statistical significance level was predetermined at 0.05. Results: 80 pts were eligible: &lt; 65 (n=44) vs ≥65 years (n=36). No differences in Gleason score (&lt;8/≥8), baseline PSA levels, and disease volume (high/low) between the cohorts (Table). As compared to pts ≥65 years; in young pts, (1) the three most upregulated significant pathways were oxidative phosphorylation (OXPHOS), bile acid, and fatty acid metabolism pathways, and (2) the three most downregulated significant pathways were tumor necrosis factor-alpha (TNFα) via NF-Κb, transforming growth factor-β (TGF β), and inflammatory response pathways. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show distinct genomic pathways to be upregulated in younger pts vs. older pts with advanced PCa and may guide further drug development, e.g., OXPHOS inhibitors in younger pts vs. drugs targeting inflammatory response in older pts. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with PCa. [Table: see text]

Routine practice data of three cancer entities: Comparison among cancer registry and health insurance data

IntroductionClaims data and cancer registry data are valuable secondary data sources for addressing health service research questions. This study provides a thorough insight into the comparability of data from health insurance companies and cancer registries in Germany regarding breast, prostate, and lung cancer patients and their treatment. MethodsFor this study claims data of the InGef database and data of the Cancer Registry of Rhineland-Palatinate were used to identify patients living in Rhineland-Palatinate with an incident breast, prostate, or lung cancer diagnosis between Jan. 1, 2018 and Dec. 31, 2019. Both datasets were compared for patient and tumour characteristics as well as treatment strategy. For the descriptive analysis of tumour localisation and treatment all patients were followed up for a maximum of two years. ResultsA total of 1,470 incident cancer cases were identified in the InGef database and 1,694 in the Cancer Registry. Data on sex, age, and tumour localisation matched well for all cancer entities in the cohorts. Data for early UICC stages I+II varied between the cohorts for prostate cancer (84% InGef, 66% Cancer Registry) and lung cancer (29% InGef, 20% Cancer Registry). Larger deviations were found for antihormonal treatment (breast 54% vs. 44%, prostate 32% vs. 18%). Significant differences were found for surgery (breast and lung) and radiation (breast and prostate), respectively. DiscussionAge at diagnosis, tumour localisation, and treatment for breast cancer was well documented in both databases. Tumour-specific deviations were observed for tumour localisations (lung cancer), UICC stage (prostate and lung cancer) and treatment options. ConclusionBoth databases show very good completeness across cancer entities, but at the same time have minor limitations where they could readily complement each other. Individual linkage of claims and registry data could be an important step to improve oncological studies with routine practice data and to overcome the limitations identified.

Micro-Ultrasound: Current Role in Prostate Cancer Diagnosis and Future Possibilities.

Prostate Cancer (PCa) is the second most common cancer in men. Population screening using prostate specific antigen (PSA) blood test and digital rectal exam (DRE) is recommended by the NCCN, EAU and other prominent clinical guidelines. While MRI is the recommended initial test in men at risk for PCa, micro-Ultrasound (MicroUS) is a novel high resolution ultrasound technology that has shown promise in PCa detection. This article provides a narrative review of the studies to date which have been conducted to evaluate the functionality and efficacy of MicroUS within the patient care pathway for prostate cancer. A total of 13 relevant publications comparing detection of csPCa between MicroUS and mpMRI were selected. An amount of 4 publications referring to use of MicroUS for other indications were found. Each publication was evaluated for risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool. The studies reviewed conclude that MicroUS detection rates for clinically significant prostate cancer diagnosis are comparable to the detection rates of mpMRI guided biopsy procedures. While the existing literature indicates that MicroUS should replace conventional TRUS for prostate imaging and biopsy, it is not yet clear whether MicroUS should be used on its own or in conjunction with mpMRI for augmenting prostate cancer detection. The ongoing OPTIMUM trial will provide evidence on how best to utilize this new technology. Early data also suggest this flexible new imaging modality has a place in local staging and active surveillance of prostate cancer as well as in bladder cancer staging.