Early Stage Prostate Cancer Research Articles

1411P Development and validation of a novel six-gene signature to accurately risk stratify men with early-stage prostate cancer to aid in treatment decision making

Prostate cancer (PCa) is the second-most common non-cutaneous cancer in men with over 1.2 million men diagnosed worldwide annually. A large proportion of these men have indolent PCa and can safely defer treatment with active surveillance. Despite that, many patients are commonly treated with surgery (radical prostatectomy, RP) or radiation therapy, which are associated with a significant reduction in quality of life. In the past ten years, molecular signatures have been developed to assist clinicians in stratifying patients based on risk of aggressive PCa; while these have shown promise, there remains a significant opportunity for improving prognostic capacity.

Differential effects of omega-3 PUFAS on tumor progression at early and advanced stages in TRAMP mice.

In vitro studies evidenced antitumor effects of omega-3 polyunsaturated fatty acids ([n-3]PUFAs), but their effects on prostate cancer (PCa) remain controversial in epidemiological studies. Here we investigated whether an (n-3) PUFA-enriched diet affects tumor progression in transgenic adenocarcinoma of the mouse prostate (TRAMP), at early (12 weeksage) and advanced stages (20 weeksage). TRAMP mice were fed with standard rodent diet (C12, C20) or (n-3) PUFA-enriched diet containing 10% fish oil (T12, T20). A group of 8 weeksage animals fed standard diet was also used for comparison (C8). The ventral prostate was processed for histopathological and immunohistochemical analyses and serum samples submitted to biochemical assays. At early stages, (n-3) PUFA increased the frequency of normal epithelium (3.8-fold) and decreased the frequency of high-grade intraepithelial neoplasia (3.3-fold) and in situ carcinoma (1.9-fold) in the gland, maintaining prostate pathological status similar to C8 group. At advanced stages, 50% of the animals developed a large primary tumor in both C20 and T20, and tumor weight did not differ (C20: 2.2 ± 2.4; T20: 2.8 ± 2.9 g). The ventral prostate of T12 and of T20 animals that did not develop primary tumors showed lower cell proliferation, tissue expressions of androgen (AR) and glucocorticoid (GR) receptors, than their respective controls. For these animals, (n-3) PUFA also avoided an increase in the number of T-lymphocytes, collagen fibers, and αSMA immunoreactivity, and preserved stromal gland microenvironment. (n-3) PUFA also lowered serum triglycerides and cholesterol, regulating the lipid metabolism of TRAMP mice. (n-3) PUFAs had a protective effect at early stages of PCa, delaying tumor progression in TRAMP mice, in parallel with reductions in cell proliferation, AR, and GR and maintenance of the stromal compartment of the gland. However, (n-3) PUFAs did not prevent the development of primary tumors for the T20 group, reinforcing the need for further investigation at advanced stages of disease.

Interplay of Developmental Hippo-Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer.

Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related ‘hubs’ such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR–Hippo–Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.

Isolation of Circulating Tumor Cells from Seminal Fluid of Patients with Prostate Cancer Using Inertial Microfluidics.

Simple SummaryProstate cancer (PCa) is notoriously difficult to diagnose owing to the lack of reliable biomarkers and the invasiveness of obtaining a tissue biopsy from the prostate. As an alternative, we developed a liquid biopsy technique, based on isolating tumor cells from semen samples via a microfluidic device. To optimize the device, we first attempted to recover PCa cells from semen samples spiked with PCa cell lines, achieving an average efficiency of >87% cell recovery at the chosen flow rate. We then transitioned to a clinical setting using semen samples from PCa patients. The yield of isolated clinical PCa cells varied between 67 and 307 cells per mL of semen (in 15 cancer patients). These cells were stained and compared to the standard prognostic parameters such as Gleason score and PSA serum level. This study presents a potential liquid biopsy technique to augment the existing diagnosis and prognosis of PCa.Prostate cancer (PCa) diagnosis is primarily based on prostate-specific antigen (PSA) testing and prostate tissue biopsies. However, PSA testing has relatively low specificity, while tissue biopsies are highly invasive and have relatively low sensitivity at early stages of PCa. As an alternative, we developed a technique of liquid biopsy, based on isolation of circulating tumor cells (CTCs) from seminal fluid (SF). The recovery of PCa cells from SF was demonstrated using PCa cell lines, achieving an efficiency and throughput as high as 89% (±3.8%) and 1.7 mL min−1, respectively, while 99% (±0.7%) of sperm cells were disposed of. The introduced approach was further tested in a clinical setting by collecting and processing SF samples of PCa patients. The yield of isolated CTCs measured as high as 613 cells per SF sample in comparison with that of 6 cells from SF of healthy donors, holding significant promise for PCa diagnosis. The correlation analysis of the isolated CTC numbers with the standard prognostic parameters such as Gleason score and PSA serum level showed correlation coefficient values at 0.40 and 0.73, respectively. Taken together, our results show promise in the developed liquid biopsy technique to augment the existing diagnosis and prognosis of PCa.

Opportunistic Virus BKV: Racial Disparities in Prostate Cancer

Prostate cancer (PCa) is the most common malignancy and the second most leading cause of cancer death among men in the United States. More specifically, African American (AA) men are at 1.6 times higher risk of being diagnosed and 2 times higher risk of death from PCa, compared to European-American (EA) men or other ethnicities. BKV is an emerging opportunistic pathogen that infects 90% of the human population and is known to reactivate in immune-compromised hosts and has been implicated as a cofactor in early stages of PCa. Reactivated BKV may be a more virulent strain that emerges in the absence of host immune response. Therefore, it is plausible that BKV genetic diversity within immune-compromised cancer hosts may allow more virulent strains to reactivate to opportunistically cause disease.BKV replication is orchestrated by a regulatory protein large T antigen (LTag) which binds products of tumor suppressor genes (pRb family, p53) and interferes with the strategic checkpoints of the cell cycle of infected cells, thereby resulting in transformation and cancer progression. The association of viruses and their evolutionary dynamics in human disease is critical for advancement in tumor biology therapeutics and clinical diagnoses. This review article describes to better understand racially derived differences in PCa and a potential role for BKV as a cofactor in PCa progression..

Isolation and Characterization of Urinary Extracellular Vesicles from Healthy Donors and Patients with Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting.

Prostate cancer screening - is it time to change approach?

Prostate adenocarcinoma (CaP) is one of the most common malignancies in men in Slovakia and in the world. The disease accounts for more than 22% of all tumors in the male population. Screening studies show an increase in the diagnosis of CaP without improvement in overall or CaP-specific mortality. The main goal of the work is to evaluate the incidence of CaP in the group of patients examined and treated during the period from 2014 to 2019 at the urological outpatient clinic of the Railway Hospital (RH) in Košice, and to evaluate the risks and treatment options. Men aged 40 to 75 years underwent a preventive examination in 2014-2019 at the urology outpatient clinic, RH Košice. The number of screened patients was 3,943. Epidemiological parameter, diagnosis-related examinations (prostate specific antigen - PSA examination, digital rectal examination, and ultrasonography examination) as well as the frequency of examinations were monitored during the specified period on the basis of documentation. The number of prostate biopsies, incidence of prostate cancer and relation to PSA values were also monitored, as well as the classification of prostate cancers according to the degree of risk. Initial treatment in individual patients was also evaluated. PSA values in patients who underwent biopsy ranged from 3.6 ng/mL to 2,000 ng/mL. We observed positive digital rectal examination in 52 patients. Of the number of patients examined, 231 (61.28%) were positive biopsies. There were negative biopsies with the finding of benign prostatic hyperplasia in 92 patients or chronic prostatitis in 54 patients, i.e., 146 (38.72%). According to the criteria for risk assessment based on the PSA value and the result of the histological examination, we diagnosed 109 low-risk patients, 57 medium-risk patients and 24 high-risk patients. CaP is detected by prevention about 10 years before it develops clinically. The main aim of preventive examinations should be to detect, in particular, high-risk forms of early-stage prostate cancer and to improve the quality of life of men. Due to the results of extensive studies, it is necessary to continue the active search for prostate cancer. This reduces the risk of metastatic forms of CaP.

Abstract 3220: Patient communication efficacy, information seeking, and treatment regret among early-stage prostate cancer survivors

Abstract Background: Most men with prostate cancer lack sufficient knowledge of their illness at the time they are diagnosed to make informed decisions about treatment. The ways patients interact with physicians can influence the quality of treatment-related information that is received and impact emotional well-being. Regret is a common negative affect that patients, providers, and care givers seek to avoid. This study investigated the relationship between patient communication efficacy, treatment information seeking behaviors, and decision regret within a sample of early-stage prostate cancer survivors. Methods: Sixty-three men diagnosed with early-stage prostate cancer (Stage T1 or T2) completed self-administered questionnaires. Men who were actively monitoring or undergoing definitive treatment were eligible for inclusion. The 67-item data collection tool captured patient demographics, cancer treatment information seeking behaviors, and psychosocial characteristics. Communication efficacy was measured using the validated Perceived Efficacy Patient Physicians Interaction (PEPPI-10, α=.94) scale. Decision regret was assessed using a validated 5-item measure (Brehaut et al., 2003). Descriptive and comparative analyses were conducted using SPSS Version 25. Results: A majority of participants were White (58.7%), married/partnered (79.4%), privately insured (54.2%) and graduated college (75.0%). More than two-thirds (77.8%) wanted to assume an active role during treatment decision-making. Most respondents (58.1%) fell within the high efficacy communication group (+/- 1/2 s.d. of the mean). A majority of men did not regret their initial treatment choice (82.5%). Men who regretted their initial treatment choice reported significantly more unmet treatment information needs (Mean= 5.63) than those who did not regret (Mean= 2.78) their treatment decision [t(60) = 2.084, p = .041]. Independent samples t-test results showed a statistically significant relationship between regret and communication efficacy [t(60) = -2.38, p =.021]. The two situations where men who regretted their decisions reported lower levels of communication efficacy were getting doctors to pay attention to what they have to say [t(60) = -3.39, p = .001] and making the most of their visit with the doctor [t(60) = -2.22, p = .030]. Perceived communication efficacy marginally differentiated men who regretted and did not regret their treatment decisions in two more clinical situations [t(60) = -1.92, p = .060; t(60) = -1.97, p = .054]. Conclusion: Communication efficacy appears to impact patient treatment information seeking behaviors and decision regret. Communication interventions need to be developed to increase early stage prostate cancer patients’ level of confidence when seeking treatment information to enhance their emotional well-being and quality of life. Citation Format: Levi Ross, Jordan S. Young, Jala Lockhart, Torhonda Lee, Ashley Bowers, Guleer Shabab, Michael A. Preston. Patient communication efficacy, information seeking, and treatment regret among early-stage prostate cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3220.

Abstract 393: Targeting MCT inhibition to overcome enzalutamide resistance in prostate cancer

Abstract Prostate cancers (PCa) exhibit a unique metabolic profile with reliance on different forms of glucose metabolism at different stages of disease progression. Early stage PCa cells use the more efficient TCA cycle, while metastatic PCa cells switch to glycolysis (Warburg effect), leading to the accumulation of lactate. Lactate is exported out of the cells by monocarboxylate transporters (MCTs) to maintain redox balance. Such metabolic reprogramming can lead to gain-of-function mutations and affect drug sensitivity. Enzalutamide is a second-generation antiandrogen used for the treatment of metastatic castration-resistant PCa. However, resistance to Enzalutamide develops in most patients within 9-15 months. Since Warburg effect is a hallmark of metastatic PCa, we sought to understand whether lactate transport has any effect on Enzalutamide-resistance in PCa. We measured the expression of MCTs in parental and Enzalutamide-resistant C4-2B and 22RV1 cells and found that they are overexpressed in the Enzalutamide resistant subtypes. Based on this observation, we hypothesized that targeting lactate transport might be a potential strategy to overcome Enzalutamide-resistance in PCa cells. Using cell survival and cell proliferation assays, we found that MCT antagonists resensitized Enzalutamide resistant C4-2B and 22Rv1 cells to treatment with Enzalutamide. Using the Seahorse based glycolytic rate assay we found that these combination treatments significantly reduced the extracellular acidification rate by reducing the level of glycolysis in the Enzalutamide-resistant PCa cells. We also found that treatment with these antagonists either singly, or in combination with Enzalutamide suppressed xenograft growth in SCID mice bearing subcutaneously injected parental or Enzalutamide-resistant C4-2B cells. These findings led to the conclusion that targeting MCTs could be an attractive strategy to overcome Enzalutamide resistance in prostate cancer. Citation Format: Sayani Bhattacharjee, Jonathan P. Doan, Rebecca Wynn, Nagalakshmi Nadiminty. Targeting MCT inhibition to overcome enzalutamide resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 393.

Diagnostic Value of Magnetic Resonance Susceptibility-Weighted Imaging Scanning in Different Types of Early Prostate Cancer.

To investigate the cost of MRI-sensitive imaging (SWI) for early-stage prostate cancer. In 2019, the research group included a total of 60 leukemia patients, all of whom were diagnosed with prostate-specific antigen (PSA). According to the range of PSA values, they were group A (18 cases), group A 0-44 mg/ml (18 cases), and group B 4-1010 mg/ml (26 cases). 10 mg/ml was divided into C group (16 cases). Another 60 patients with benign prostatic hyperplasia treated at the same time served as a control group. All patients underwent sensitive MRI scanning, followed by diagnostic and clinical evaluation of weighted MRI scanning to diagnose various types of prostate cancer. The results showed that there was no difference in Ve levels among the three groups (P > 0.05); the SUSE score and Ktrans and Kep levels of the patients in group C were higher in groups B, A, and A (P < 0.05). In patients with early leukemia, SUSE score was significantly correlated with Ktrans and Kep levels (P < 0.05), but not with Ve and P > 0.05 levels. Magnetic resonance imaging can be used to diagnose prostate cancer. It can differentiate and diagnose different types of prostate cancer early. This is important for evaluating the benefits of prostate cancer screening and treatment.

Urine Cell-Free MicroRNAs in Localized Prostate Cancer Patients.

Simple SummaryUrine cell-free microRNAs (cfmiRs) are promising biomarkers for the detection of prostate cancer (PCa) and may replace or complement prostate-specific antigen screening. This pilot study aims to demonstrate the diagnostic utility of urine cfmiRs for early-stage PCa using a robust microRNA (miR) panel based on next-generation sequencing. We assessed urine, plasma, and formalin-fixed paraffin-embedded tumor tissue samples obtained from patients diagnosed with pT2 PCa. Differentially expressed miRs were found in urine, plasma, and tumor samples obtained from PCa patients. Through bioinformatic analysis, several miRs were found as potential cfmiRs with utility for the detection of PCa. Our results showed that specific cfmiRs in urine samples from PCa patients may have potential utility in the detection of early-stage PCa.Prostate cancer (PCa) is the most common cancer in men. Prostate-specific antigen screening is recommended for the detection of PCa. However, its specificity is limited. Thus, there is a need to find more reliable biomarkers that allow non-invasive screening for early-stage PCa. This study aims to explore urine microRNAs (miRs) as diagnostic biomarkers for PCa. We assessed cell-free miR (cfmiR) profiles of urine and plasma samples from pre- and post-operative PCa patients (n = 11) and normal healthy donors (16 urine and 24 plasma) using HTG EdgeSeq miRNA Whole Transcriptome Assay based on next-generation sequencing. Furthermore, tumor-related miRs were detected in formalin-fixed paraffin-embedded tumor tissues obtained from patients with localized PCa. Specific cfmiRs signatures were found in urine samples of localized PCa patients using differential expression analysis. Forty-two cfmiRs that were detected were common to urine, plasma, and tumor samples. These urine cfmiRs may have potential utility in diagnosing early-stage PCa and complementing or improving currently available PCa screening assays. Future studies may validate the findings.

Diet and Health-related Quality of Life Among Men on Active Surveillance for Early-stage Prostate Cancer: The Men’s Eating and Living Study (Cancer and Leukemia Group 70807 [Alliance

BackgroundHealth-related quality of life (HRQoL) among patients with localized prostate cancer (PC) on active surveillance (AS) and whether it may be improved through lifestyle-focused interventions remain underdefined. ObjectiveTo assess longitudinal changes in HRQoL in patients who received and those who did not receive a behavioral intervention that increased vegetable intake. Design, setting, and participantsA secondary analysis of participants in the Men’s Eating and Living (MEAL) study (Cancer and Leukemia Group 70807 [Alliance]), a randomized trial of vegetable consumption in patients on AS, was conducted. Outcome measurements and statistical analysisPatient-reported outcomes (PROs) included the Memorial Anxiety Scale for Prostate Cancer (MAX-PC), the Expanded Prostate Cancer Index Composite 26 (EPIC-26), and the Functional Assessment of Cancer Therapy Scale—Prostate (FACT-P). Areas under the curves (AUCs) were used to summarize serial HRQoL. Results and limitationsPROs were completed in 87% (n = 387) of the intention-to-collect population. Baseline characteristics of patients completing HRQoL measures did not differ significantly from the entire study population or between groups. Baseline scores were high for all PROs and remained stable over 24 mo, with no significant differences from baseline at any time point. In adjusted analyses, there were no significant differences in summary AUC measures comparing control with intervention for the total MAX-PC score (p = 0.173); EPIC-26 domains of urinary incontinence (p = 0.210), urinary obstruction (p = 0.062), bowel health (p = 0.607), sexual health (p = 0.398), and vitality (p = 0.363); and total FACT-P scores (p = 0.471). ConclusionsAmong men with localized PC on AS enrolled in a randomized trial, HRQoL was high across multiple domains at baseline, remained high during follow-up, and did not change in response to a behavioral intervention that increased vegetable intake. Patient summaryPatients with localized prostate cancer enrolled on active surveillance experience minimal cancer-associated anxiety, suffer low levels of cancer-associated symptoms, and perceive high physical and emotional well-being.

Development and Evaluation of a PSMA-Targeted Nanosystem Co-Packaging Docetaxel and Androgen Receptor siRNA for Castration-Resistant Prostate Cancer Treatment.

Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) during androgen deprivation therapy (ADR) in early stages of prostate cancer. Thus, rather than blocking the androgen-related pathway further, docetaxel (DTX)-based therapy has become the most effective and standard first-line chemotherapy for CRPC. Although the therapy is successful in prolonging the survival of patients with CRPC, chemotherapy resistance develops due to the abnormal activation of the androgen receptor (AR) signaling pathway. Thus, to optimize DTX efficacy, continued maximum suppression of androgen levels and AR signaling is required. Here, we designed a prostate-specific membrane antigen (PSMA)-targeted nanosystem to carry both DTX and AR siRNA (Di-PP/AR-siRNA/DTX) for CRPC treatment. Specifically, DTX was encapsulated into the hydrophobic inner layer, and the AR siRNA was then condensed with the cationic PEI block in the hydrophilic outer layer of the PEI-PLGA polymeric micelles. The micelles were further coated with PSMA-targeted anionic polyethylene glycol-polyaspartic acid (Di-PEG-PLD). In vitro and in vivo results demonstrated that the resulting Di-PP/AR-siRNA/DTX exhibited prolonged blood circulation, selective targeting, and enhanced antitumor effects. Consequently, Di-PP/AR-siRNA/DTX holds great potential for efficient CRPC treatment by combining chemotherapy and siRNA silencing of androgen-related signaling pathways.

Sex steroid hormones in urinary exosomes as biomarkers for the prediction of prostate cancer

BackgroundAlthough they are involved in the progression of PCa, the use of sex steroid hormones in urinary exosomes as biomarkers for PCa remains obscure. Here, the potential use of sex steroid hormones in urinary exosomes as biomarkers was investigated for the prediction of early-stage PCa to assist in clinical diagnosis. MethodsTwo hundred and eighty-six participants were randomly recruited, 231 patients with PCa and 55 healthy controls. According to their Gleason scores (GSs), the patients with PCa were divided into two groups, mild PCa (GS6) (n = 116) and severe (≥GS7) group (n = 115). The concentrations of 8 sex steroid hormones in urinary exosomes were quantitated using liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization (LC-APCI–MS/MS). ResultsThe results showed that the levels of 7 out of 8 sex steroids including dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulfate (DHEAS), androstenedione (A4), testosterone (T), progesterone (P), dihydrotestosterone (DHT), and estrone (E1), but not estradiol (E2) in urinary exosomes, were not only distinguished the PCa patients from healthy controls, can also differentiate between patients with mild and severe PCa. Of the 8 selected urinary exosomal biomarkers, DHEA, DHEAS, T, and DHT were finally screened further to build the regression model, and the detection method of the 4 biomarkers-combined achieved an area under the ROC curve (AUC) of 0.854 and predictive accuracy of 78.2%. ConclusionOur data showed the use of exosomal sex steroids in urine could be as biomarkers for predicting PCa for the first time. This finding would supply a novel insight for PCa diagnosis.

The Prognostic Value of PI-RADS Score in CyberKnife Ultra-Hypofractionated Radiotherapy for Localized Prostate Cancer.

Simple SummaryMagnetic resonance imaging is commonly used in pre-treatment prostate cancer diagnostics. The assessment includes a five-stage scale classification called Prostate Imaging-Reporting and Data System (PI-RADS), routinely used to describe the probability of finding a clinically significant cancer. Less is known about the association of PI-RADS score with patients’ prognosis. Our retrospective study aimed to assess the association between pre-treatment PI-RADS score and risk of developing metastases, based on a cohort of 152 patients treated with ultra-hypofractionated CyberKnife radiotherapy for low or intermediate-risk group prostate cancer. PI-RADS score and the size of the target lesion proved to be significantly associated with the risk of developing metastases, suggesting that the introduction of PI-RADS score to initial risk assessment could improve the patient-tailored management of prostate cancer.Prostate Imaging-Reporting and Data System (PI-RADS) has been widely implemented as a diagnostic tool for significant prostate cancer (PCa); less is known about its prognostic value, especially in the setting of primary radiotherapy. We aimed to analyze the association between PI-RADS v. 2.1 classification and risk of metastases, based on a group of 152 patients treated with ultra-hypofractionated stereotactic CyberKnife radiotherapy for localized low or intermediate risk-group prostate cancer. We found that all distant failures (n = 5) occurred in patients diagnosed with a PI-RADS score of 5, and axial measurements of the target lesion were associated with the risk of developing metastases (p < 0.001). The best risk stratification model (based on a combination of greatest dimension, the product of multiplication of PI-RADS target lesion axial measurements, and age) achieved a c-index of 0.903 (bootstrap-validated bias-corrected 95% CI: 0.848–0.901). This creates a hypothesis that PI-RADS 5 and the size of the target lesion are important prognostic factors in early-stage PCa patients and should be considered as an adverse prognostic measure for patients undergoing early treatment such as radiation or focal therapy.

Contemporary outcomes of a systematic prostate cancer active surveillance program: Results from the Niagara Health System, Ontario, Canada.

241 Background: Surgery and radiotherapy are standard therapies for patients with early-stage prostate cancer (PrCa). However, studies show that patients with low-risk localized PrCa (Gleason 6; Grade Group (GG) 1 and prostate-specific antigen (PSA) &lt;10) could be safely monitored with active surveillance (AS), if intense patient follow up and re-biopsy schedules are utilized. Here, we reviewed clinical outcomes of AS of a program associated with the Niagara Health System (NHS) PrCa diagnostic program, which provides centralized diagnosis, systematic follow up, re-biopsy and multi-disciplinary consultation clinics for all patients in the Niagara region, Ontario, Canada. Methods: After receiving appropriate ethics approval, NHS databases were searched for patients that underwent more than one biopsy of the prostate in the period Jan. 2015 (program inception) to Dec. 2020. Cases were reviewed for clinical stage, biopsy results and treatment record data. Data were then codified for anonymity and analyzed. Criteria for inclusion into the analysis involved, i) a minimum of two PrCa biopsies before treatment and ii) detailed reporting of biopsy and clinical results (number of positive cores, % of core involvement, and PSA). Results: A total of 343 AS patient cases were identified in the initial search. Of those 52 cases did not meet inclusion criteria. The baseline GG score distribution in the 291 cases included in the analysis was, GG0: 27 (cases with negative biopsies but high PSA), GG1: 247 and GG2: 17 (patients refusing treatment). A total of 144 cases (49.5%) progressed at re-biopsy. Rates of progression to higher GG category in the three groups were 100%, has 46.5% and 50%, respectively. The average time to progression was 23.3+15.5 months. The rate of progression to treatment after entering AS was 39.17% (114/291). Average time from first biopsy to treatment was (28.4+14.5 months). Amongst those that received treatment the overall rate of progression to high-intermediate or high-risk PrCa, was 29.8%, with 20.8% of cases (30/144) progressing to GG&gt;3 (Gleason Score 7: 4+3 or higher) and 9.0% (13/144) progressing to PSA &gt; 20. Of the treated patients, 70 (61.4%) patients received radiotherapy, 42 (36.8%) combined radiotherapy and androgen deprivation therapy and (31.3%) underwent radical prostatectomy. Conclusions: This retrospective study provides contemporary real-world systematic AS outcomes from a Canadian program with unique features of systematic urological follow up and centralized diagnosis and multi-disciplinary patient assessment. We observe increased rates of disease progression and need for earlier utilization of treatment compared to those reported by other studies. Further analysis examines factors predicting increased risk for disease progression.

Impact of COVID-19 on the incidence of prostate cancer among White and Black Veterans.

29 Background: Early-stage prostate cancer (PCa) is typically detected on prostate-specific antigen (PSA) screening and subsequent prostate biopsy, healthcare interventions that are considered routine elective procedures. The COVID-19 pandemic disrupted routine healthcare screenings and interventions. We sought to determine whether delayed screening and diagnostic workup of PCa was associated with increased rates of incident PCa, high-grade Gleason, and metastatic disease at diagnosis. Methods: We used the Corporate Data Warehouse of the Veterans Health Administration to collect PSA, prostate biopsy, PCa diagnosis, Gleason score, and metastasis information of White and Black Veterans aged 40 years or older newly diagnosed with PCa from January 2019 through June 2021. For each month, we calculated rates of PSA, prostate biopsy, and incident PCa per 100,000 men and plotted monthly rates by race. We performed descriptive analyses to compare age at first PSA, age at diagnosis, baseline PSA, Gleason scores, and metastasis pre- and post-January 2020, the month in which the U.S. declared COVID-19 a public health emergency. Results: The decrease in the rate of PSA screening immediately after January 2020 was similar in both White and Black Veterans (7% vs. 6%). However, the magnitude of reduction in the rate of prostate biopsy and the rate diagnosis of incident PCa were five times larger among Black Veterans compared to White Veterans (11% vs. 2% for both biopsy and diagnosis rates). Among the 17,771 White and 9,610 Black Veterans with incident PCa, the rate of Gleason of 4+3 or greater and the rate of metastatic disease at diagnosis increased three months after the pandemic in both race groups with comparable magnitude (2-3% increase in high-grade Gleason, 1% increase in metastatic disease). Conclusions: Utilization patterns indicated that while the decrease in PSA screening after the pandemic was similar in White and Black Veterans, reductions in prostate biopsy and diagnosis of incident PCa were five times greater in Blacks than Whites. Further research including risk-adjusted modeling is needed to determine whether Black Veterans were disproportionately affected by the pandemic-related disruptions in PSA screening and diagnostic workup of prostate cancer.[Table: see text]

Virtual genetics board for enhancing knowledge and practice of prostate cancer genetic testing: The ENGAGEMENT study.

184 Background: With the increasing indications for germline testing for prostate cancer (PCA), there is a growing need for a spectrum of providers to develop working knowledge and understand considerations of germline testing and genetic counseling. A virtual genetics board was developed to provide case-based discussion of PCA germline testing, standard of care and clinical trial management, hereditary cancer management, and genetic counseling. Methods: A virtual genetics board was launched including experts in GU medical oncology, prostate cancer genetics, radiation oncology, urology, clinical trials, genetic counseling, and molecular oncology. Conferences are held monthly, with cases covering metastatic PCA, high-risk disease, early-stage PCA, or PCA screening. Participants complete a baseline survey of demographic information and cancer genetics knowledge. Post-conference survey includes retaking knowledge questions and feedback on cases and Zoom format. Results: At the time of this report, 57 participants have engaged in the virtual genetics board. Participants include genetic counselors (21%), nurse practitioners (21%), medical oncologists (14%), researchers/scientists (14%), nurses (9%), urologists (5%), radiation oncologists (4%), and other specialties. Practice settings include academic centers (49%), public hospitals (16%), private hospitals (11%), and other settings. The baseline survey was completed by 55 participants, and post-conference survey by 34 participants. Knowledge scores increased regarding cancer inheritance, rates of mutations in metastatic PCA, BRCA2-related cancers, risk of PCA for HOXB13 carriers, and risk for PCA in African American males. Feedback was positive, with over 90% favorable responses on usability of technology, usefulness of case discussions, and relevance to informational needs. Conclusions: Initial results support a virtual genetics board to increase PCA genetic evaluation knowledge. The ENGAGEMENT study is ongoing with monthly live case discussions that are also recorded for on-demand viewing; registration is available at www.prostategenetics.com/engagement.[Table: see text]

Immunotherapy to prevent progression on active surveillance study (IPASS): A phase II, randomized, double-blind, controlled trial of PROSTVAC in prostate cancer patients who are candidates for active surveillance.

249 Background: Immunotherapy could potentially prevent disease progression for early-stage prostate cancer. In this randomized Phase 2 clinical trial, we evaluated the clinical effects of PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy that contains PSA and three T-cell costimulatory molecules, in patients with localized prostate cancer. Methods:154 patients with clinically localized, low- or favorable intermediate-risk prostate cancer active surveillance were randomized (2:1) to receive 7 doses of subcutaneous PROSTVAC or placebo (empty fowlpox vector) over 140 days. Post-intervention prostate biopsy was performed 7-14 days after the last dose. Participants were followed for 6 months post-treatment. The primary outcome was change from baseline to post-vaccination in CD4 and CD8 T cell infiltration in biopsy tumor tissue. Secondary outcomes included changes in prostate biopsy Gleason grade (Grade Group) and serum PSA. Results: There were no differences in CD4 and CD8 densities (count of cells/mm2) in post-treatment biopsy tumor tissue between groups ( p = 0.63 and p = 0.75, respectively). Compared to placebo, patients who received PROSTVAC were less likely to demonstrate upgrading at follow-up biopsy, but this difference did not attain significance (22% vs. 40%, p= 0.08). There was no difference in the change of PSA from baseline to 6 months post-treatment between arms ( p= 0.30). Conclusions: In this first-of-kind trial of immunotherapy for localized prostate cancer, PROSTVAC was well tolerated but did not elicit significant prostate tissue T-cell responses compared to placebo. The favorable post-treatment biopsy grade findings in PROSTVAC patients merit further evaluation and longer-term clinical follow-up. Clinical trial information: NCT02326805.

The Classification Power of Classical and Intra-voxel Incoherent Motion (IVIM) Fitting Models of Diffusion-weighted Magnetic Resonance Images: An Experimental Study.

This study aims at investigating the classification power of different b-values of the diffusion-weighted magnetic resonance images (DWI) as indicator of prostate cancer. This paper investigates several techniques for analyzing data from DWI acquired at a range of b-values for the purpose of detecting prostate cancer. In the first phase of experiments, we analyze the available data by producing two main parametric maps using two common models, namely: the intra-voxel incoherent motion (IVIM) model and the mono-exponential ADC model. Accordingly, we evaluated the benign/malignant tissue classification potential of several parametric maps produced using different combinations of b-values and fitting models. In the second phase, we utilized the maps that performed best in the first phase of experiments to design a machine learning-based computer-assisted diagnosis system for the detection of early stage prostate cancer. The system performance was cross-validated using data from 20 patients. On a fivefold cross-validation scheme, a maximum accuracy and an area under the receiver operating characteristic (AUC) of 90% and 0.978, respectively, was achieved by a system that uses ADC maps fitted using the mono-exponential model at 11 different b-values. The results suggest that the proposed machine learning-based diagnosis system is potentially powerful in differentiating between malignant and benign prostate tissues when combined with carefully generated ADC maps.