Biomarkers In Metastatic Prostate Cancer Research Articles

Charles Brenton Huggins: A historical review of the Nobel laureate's pioneering discoveries.

Androgen deprivation therapy for prostate cancer was pioneered by Charles Huggins, laureate of the Nobel Prize in Medicine in 1966. The authors tried to understand the scientific context and how previous findings paved Huggins way to his discoveries. With the help of summary or review articles on androgen deprivation therapy, the authors identified key publications and used his Nobel Prize speech as a basis to understand his discoveries. Furthermore, they used a recording of the laboratory-talk interview he gave about his findings to guide them to relevant publications. The authors found that the basis for Huggins' discoveries was the isolation of testosterone in 1935, not long before Huggins' 1941 hallmark publication. Huggins' work follows major experiments in the 19th century in orchiectomy done as a treatment for prostate hypertrophy. Researching the etiology of idiopathic hydrocele, Huggins analyzed the composition of prostate fluid. Further research led to the discovery of the influence of castration, testosterone, and estrogen on acid phosphatase. Recently developed methods facilitated the measurement of the phosphatases. He, therefore, had a biomarker for metastatic prostate cancer to measure treatment response. Very early on, he reported clinical improvements after castration in metastatic patients. Although the effect of orchiectomy on prostate hypertrophy was already known, Huggins was the first to show that testosterone stimulated and estrogen decreased the activity of prostate cancer. Huggins also established phosphatases as a tumor marker to measure disease response.

209 Change of the Neutrophil to Lymphocyte Ratio During Treatment: A Potential Prognostic Biomarker in Metastatic Prostate Cancer Treated with Radium-223 Dichloride

209 Change of the Neutrophil to Lymphocyte Ratio During Treatment: A Potential Prognostic Biomarker in Metastatic Prostate Cancer Treated with Radium-223 Dichloride

ZNF750: A Novel Prognostic Biomarker in Metastatic Prostate Cancer

Prostate cancer is the most frequently diagnosed cancer and the fifth leading cause of cancer death among men in 2020. The clinical decision making for prostate cancer patients is based on the stratification of the patients according to both clinical and pathological parameters such as Gleason score and prostate-specific antigen levels. However, these tools still do not adequately predict patient outcome. The aim of this study was to investigate whether ZNF750 could have a role in better stratifying patients, identifying those with a higher risk of metastasis and with the poorest prognosis. The data reported here revealed that ZNF750 protein levels are reduced in human prostate cancer samples, and this reduction is even higher in metastatic samples. Interestingly, nuclear positivity is significantly reduced in patients with metastatic prostate cancer, regardless of both Gleason score and grade group. More importantly, the bioinformatics analysis indicates that ZNF750 expression is positively correlated with better prognosis. Overall, our findings suggest that nuclear expression of ZNF750 may be a reliable prognostic biomarker for metastatic prostate cancer, which lays the foundation for the development of new biological therapies.

Association of whole blood mRNA expression and overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC).

201 Background: Previous studies have evaluated peripheral whole blood mRNA to identify prognostic biomarkers in metastatic prostate cancer, with no consistent genes of prognostic significance between studies and sample collection done at various points of therapy. We aim to identify the prognostic value of 20 previously identified genes in patients mCRPC from a prospective clinical trial. Methods: Between June 2013 and August 2015, whole blood was prospectively collected in PAXgene RNA tubes from 92 men with mCRPC (NCT01953640). Gene expression from samples with RIN > 4.0 were quantified using a customized NanoString CodeSet of 20 candidate genes (C1QA, MCM2, STOM, GABARAPL2, R10K3, HMBS, TFDP1, CDKN1A, ITGAL, TMCC2, TERF2IP, MMP9, SNCA, TIMP1, SLC4A1, SELENBP1, TMEM66, SEMA4D, PROS1, CD22). The raw data from the nCounter Analysis system were normalized to the positive controls and log2 transformed. Univariable Cox proportional hazards models were performed on each target gene sufficiently above negative control (5 times the maximum value of the negative control) to evaluate associations with overall survival (OS). For each gene we considered a linear, quadratic, or categorical model with quantile cutpoints. Categorical models with cutpoints at the 25th percentile for the genes CD22, GABARAPL2, R10K3, and STOM were used as there was a nonlinear relationship between gene expression and death hazard. The remaining genes were modeled with a linear model. Findings were considered statistically significant based on p-values adjusted using the Holm-Bonferroni correction. Results: 18/20 genes were identified and passed quality control (QC) measures, which excluded C1QA and MCM2. 72/92 men had an evaluable pretreatment specimen that passed QC. The median age was 72 years. The study cohort was evenly balanced in terms of Gleason score ( < = 7 v. > 7) and 60% had high volume disease. The median follow-up time was 5.73 years (IQR: 5.39, 6.49) and 58 patients had died. Of the 18 genes evaluated, STOM (Stomatin) [hazard ratio (HR) 3.00, adjusted p = 0.007] and GABARAPL2 (GABA Type A Receptor Associated Protein Like 2) [HR 2.62, adjusted p = 0.033] were significantly associated with overall survival in univariate analysis. In multivariate analysis, after adjusting for volume of metastatic disease and Gleason score, STOM [HR 2.89, adjusted p = 0.014] was significantly associated with overall survival. Conclusions: Elevated whole blood mRNA expression of STOM is adversely associated with OS in mCRPC. Further studies investigating elucidating the molecular significance of STOM in mCRPC are planned. Clinical trial information: NCT01953640 .

Abstract C062: Metabolic rewiring: A role for adenosine-inosine axis in African-American prostate cancer

Abstract African-American (AA) men have a 60% higher incidence of prostate cancer (PCa) compared to European-American (EA) men. An understanding of the altered biological responses and the factors that lead to health disparity in PCa is unclear. Metabolism defines the physiological state of the cell and metabolic reprogramming is a hallmark of cancer. Thus, studying the metabolic landscape will be crucial for understanding the biological changes that might contribute to this disparity. Analysis of 190 metabolites across PCa/benign adjacent tissue pairs from ancestry typed AA and EA men done in our laboratory, revealed altered levels of nucleosides adenosine and inosine. High inosine to adenosine ratio was observed in AA men compared to EA men. In line with this, the enzyme adenosine deaminase (ADA), which converts adenosine to inosine was found elevated in AA men, potentially explaining the high inosine to adenosine ratio in AA PCa. The consequences of the accumulation of these metabolites on AA PCa progression are unknown. This study will address the knowledge gap on the effects adenosine-inosine alterations in AA PCa and attempt to dissect its role in effecting an aggressive phenotype in PCa. To determine the role of elevated ADA in PCa, it was overexpressed in AA(MDA-PCa-2A) and EA PCa (LNCaP) cell lines (termed ADA OE). Phenotypic examination of these cells revealed high ADA enzyme activity decreases the cell-ECM adhesion. Molecular analyses revealed that upon ADA OE there is a reduction in Tenascin C(TNC), a matrix protein known for its anti-adhesive properties. TNC-rich microenvironment facilitates reactive stromal induction and high motility. This TNC-mediated reprogramming enhances the metastatic ability and PCa progression in bone. TNC induction was observed in stromal cells (DPT44) upon treatment with ADA OE conditioned media and inosine addition. PCa progression on bone was assessed using a cancer cell-bone in vitro co-culture system. High inosine and adenosine levels enabled better attachment of PCa cells to the bone. These findings suggest that an altered adenosine/inosine axis could facilitate adhesion decrease and modulate the stromal microenvironment to aid in the metastatic dissemination and migration towards the bone. Adenosine-inosine alterations could serve as a biomarker for metastatic PCa. We will further analyze the inosine and adenosine levels in patient samples and correlate them with various clinical outcomes in PCa. Our study so far shows high inosine to adenosine ratio in biopsy positive patient samples compared to biopsy negative samples. Our next steps of analysis include correlating the metabolite levels with (i)Biochemical recurrence (BCr) (ii)Time to attaining castration resistance (iii)Time to metastasis (iv)Response to Androgen deprivation in patients after BCr. Based on our current findings, we expect the inosine to adenosine ratio in plasma or urine to serve as a predictive marker for PCa incidence or progression in AA men. In addition, the enzyme ADA could serve as a potential therapeutic target for AA PCa. Citation Format: Christy Charles. Metabolic rewiring: A role for adenosine-inosine axis in African-American prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C062.

Novel quantitative software for automatically excluding red bone marrow on whole-body magnetic resonance imaging in patients with metastatic prostate cancer: A pilot study.

To establish a novel quantitative method that automatically excludes the red bone marrow and accurately quantifies the tumor volume on whole-body magnetic resonance imaging using updated imaging software. To also evaluate the association between the quantified tumor volume and the prognosis of patients with metastatic prostate cancer. This prospective analysis included patients diagnosed with metastatic hormone-sensitive or metastatic castration-resistant prostate cancer between 2017 and 2022. We developed an imaging software (Attractive BD_Score) that analyzed whole-body diffusion-weighted and in-phase and opposed-phase T1-weighted images to automatically exclude the red bone marrow. The quantified tumor volume was compared with that quantified by traditional whole-body diffusion-weighted imaging without red bone marrow exclusion. Prostate-specific antigen progression-free survival, time-to-pain progression, and overall survival were evaluated to assess the prognostic value of the quantified tumor volume. The quantified tumor volume was significantly smaller than that quantified by the traditional method in metastatic hormone-sensitive (median: 81.0 ml vs. 149.4ml) and metastatic castration-resistant (median: 29.4 ml vs. 63.5ml) prostate cancer. A highly quantified tumor volume was associated with prostate-specific antigen progression-free survival (p= 0.030), time-to-pain progression (p=0.003), and overall survival (p= 0.005) in patients with metastatic hormone-sensitive prostate cancer and with poor prostate-specific antigen progression-free survival (p= 0.001) and time-to-pain progression (p= 0.005) in patients with metastatic castration-resistant prostate cancer. Our imaging method could accurately quantify the tumor volume in patients with metastatic prostate cancer. The quantified tumor volume can be clinically applied as a new prognostic biomarker for metastatic prostate cancer.

Changes in neutrophile-to-lymphocyte ratio as predictive and prognostic biomarker in metastatic prostate cancer treated with taxane-based chemotherapy

ObjectivesTo assess the predictive and prognostic value of changes in longitudinal neutrophile-to-lymphocyte (NLR) ratios in men receiving taxane-based chemotherapy for metastatic prostate cancer (PC).MethodsRetrospective, unicentric cohort study of patients treated with either docetaxel for metastatic hormone-sensitive PC (mHSPC) or docetaxel or cabazitaxel for metastatic castration-refractory PC (mCRPC) at a tertiary referral hospital between 2010 and 2019. NLR ratios were calculated for each cycle. Next, slopes over the first three (NLR3) and over six cycles (NLR6) were calculated and analysed for biochemical/radiologic response and survival.ResultsA total of 36 mHSPC (docetaxel), 118 mCRPC (docetaxel) and 38 mCRPC (cabazitaxel) patients were included. NLR3 was significantly associated with 1-year-survival, radiographic and biochemical response in mCRPC (docetaxel) in uni- and multivariable analyses. In mCRPC (docetaxel), positive NLR3s were associated with favourable 1-year-survival.ConclusionThis study demonstrated NLR3 as a prognostic marker in men receiving docetaxel for mCRPC. NLR3 might be a clinical tool to reflect the individual’s response to taxane-based chemotherapy. Thereby, NLR3 could complement existing biomarkers and help to early identify treatment failure before complications arise. Further prospective and multicentric studies are needed to extend and confirm the presented results.

Change of the Neutrophil-to-Lymphocyte Ratio during Treatment: A Potential Prognostic Biomarker in Metastatic Prostate Cancer Treated with Radium-223 Dichloride.

Simple SummaryWe analyzed the influence of the neutrophil to lymphocyte ratio (NLR) and its change during therapy as a potential prognostic marker in metastatic prostate cancer patients treated with 223Radium (223Ra) and patients treated with docetaxel. We found that a low NLR at baseline as well as at 12 weeks of treatment was associated with a better overall survival only in patients treated with 223Ra but not in patients treated with Docetaxel. Patients with a baseline NLR ≤ 5 that remained low (NLR ≤ 5) at 12 weeks of treatment had significantly longer median survivals compared to patients whose NLR was low (<5) at baseline and that converted at 12 weeks to >5. The prognostic value of NLR at baseline and 12 weeks will need to be validated in larger prospective cohorts.The neutrophil to lymphocyte ratio (NLR) at baseline has been shown to have prognostic value in metastatic prostate cancer. Little is known about the importance of a change in the NLR during treatment in patients treated with Radium-223 (223Ra). We investigated the prognostic value of the NLR at baseline and during therapy in patients with metastatic prostate cancer treated with 223Ra and also in patients treated with Docetaxel. We reviewed all patients treated with 223Ra in our center and randomly chosen patients treated with Docetaxel. Patients were stratified according to NLR ≤ 5 and >5 at baseline and at 12 weeks of therapy. The relationship between NLR measured at baseline and at 12 weeks and overall survival (OS) were evaluated. A total of 149 patients treated with 223Ra and 170 with Docetaxel were evaluated. For patients treated with 223Ra, overall survival was significantly better in patients that had both an NLR ≤ 5 at baseline and at 12 weeks. No such effect of NLR was found in patients treated with Docetaxel. In the present study, NLR at baseline and after 12 weeks of therapy was found to be prognostic factor in patients treated with 223Ra but not in those treated with Docetaxel.

Liquid Biopsy Based Circulating Biomarkers in Metastatic Prostate Cancer.

Prostate cancer is the most dominant male malignancy worldwide. The clinical presentation of prostate cancer ranges from localized indolent to rapidly progressing lethal metastatic disease. Despite a decline in death rate over the past years, with the advent of early diagnosis and new treatment options, challenges remain towards the management of metastatic prostate cancer, particularly metastatic castration sensitive prostate cancer (mCSPC) and castration resistant prostate cancer (mCRPC). Current treatments involve a combination of chemotherapy with androgen deprivation therapy and/or androgen receptor signalling inhibitors. However, treatment outcomes are heterogeneous due to significant tumor heterogeneity indicating a need for better prognostic biomarkers to identify patients with poor outcomes. Liquid biopsy has opened a plethora of opportunities from early diagnosis to (personalized) therapeutic disease interventions. In this review, we first provide recent insights about (metastatic) prostate cancer and its current treatment landscape. We highlight recent studies involving various circulating biomarkers such as circulating tumor cells, genetic markers, circulating nucleic acids, extracellular vesicles, tumor-educated platelets, and the secretome from (circulating) tumor cells and tumor microenvironment in metastatic prostate cancer. The comprehensive array of biomarkers can provide a powerful approach to understanding the spectrum of prostate cancer disease and guide in developing improved and personalized treatments for patients.

GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling

Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-β-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.

Abstract PO-152: Metabolic rewiring in African-American prostate cancer: A role for adenosine-inosine axis

Abstract African-American (AA) men have a 60% higher incidence of prostate cancer compared to European-American (EA) men and tend to have a more aggressive clinical outcome. An understanding of the altered biological responses and the factors that lead to health disparity in prostate cancer development and progression is unclear. Metabolism defines the physiological state of the cell and metabolic reprogramming is a hallmark of cancer. Thus, studying the metabolic landscape will be critical for understanding the biological changes that might contribute to this disparity. Analysis of 190 metabolites across prostate cancer/benign adjacent tissue pairs from ancestry typed AA and EA men performed in our laboratory, revealed altered levels of adenosine and inosine. High inosine to adenosine ratio is observed in AA men compared to EA men. In line with this finding, the enzyme adenosine deaminase (ADA), which converts adenosine to inosine was found elevated in AA men, potentially explaining the high inosine to adenosine ratio in AA PCa. The effects of these metabolic alterations on AA PCa progression are unknown. The current study will address the knowledge gap on the consequences of elevated ADA activity in AA PCa and attempt to dissect its role in effecting an aggressive phenotype in PCa. To determine the role of elevated ADA in PCa, it was overexpressed in ancestry-typed AA (MDA-PCa-2A) and EA PCa(LNCaP) cell lines (termed ADA OE). Phenotypic examination of these cells revealed increased ADA enzyme activity decreases the cell-ECM adhesion. Molecular analyses revealed a significant reduction in Tenascin C(TNC), a matrix protein known for its anti-adhesive properties. TNC is critical for modulating cell motility and adhesion. TNC is also a marker for the reactive stromal microenvironment. Therefore, we evaluated the effects of altered adenosine-inosine levels on stromal cells. TNC induction was observed in stromal cells upon treatment with ADA OE conditioned media and inosine addition. These molecular findings suggest that high ADA activity could facilitate adhesion decrease and modulate the stromal microenvironment to aid in the metastatic dissemination from the primary tumor. From a translational viewpoint, ADA enzyme activity could serve as a biomarker for metastatic prostate cancer. Therefore, we further look to analyze the inosine to adenosine levels in patient samples and correlate with various clinical outcomes in PCa. Our initial analysis reveals high inosine to adenosine ratio in biopsy positive patient samples compared to biopsy negative samples. Our next steps of analysis include correlating the enzyme activity with (i)Biochemical Recurrence(BCr) (ii)Time to attaining castration resistance in castration-sensitive patients (iii)Time to metastasis (iv)Response to Androgen deprivation in patients after BCr. Based on our current findings, we expect the inosine to adenosine ratio in plasma or urine to serve as a predictive marker for PCa incidence or progression in AA men. In addition, we expect ADA to serve as a potential therapeutic target for AA PCa. Citation Format: Christy Charles. Metabolic rewiring in African-American prostate cancer: A role for adenosine-inosine axis [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-152.

Prediction of potential prognostic biomarkers in metastatic prostate cancer based on a circular RNA-mediated competing endogenous RNA regulatory network.

Recently, studies on competing endogenous RNA (ceRNA) networks have become prevalent, and circular RNAs (circRNAs) have crucial implications for the development and progression of carcinoma. However, studies relevant to metastatic prostate cancer (mPCa) are scant. This study aims to discover potential ceRNAs that may be related to the prognosis of mPCa. RNA-Seq data were obtained from the MiOncoCirc database and Gene Expression Omnibus (GEO). Differential expression patterns of RNAs were examined using R packages. Circular RNA Interactome, miRTarBase, miRDB and TargetScan were applied to predict the corresponding relation between circRNAs, miRNAs and mRNAs. The Gene Ontology (GO) annotations were performed to present related GO terms, and Gene Set Enrichment Analysis (GSEA) tools were applied for pathway annotations. Moreover, survival analysis was conducted for the hub genes. We found 820 circRNAs, 81 miRNAs and 179 mRNAs that were distinguishingly expressed between primary prostate cancer (PCa) and mPCa samples. A ceRNA network including 45 circRNAs, 24 miRNAs and 56 mRNAs was constructed. In addition, the protein–protein interaction (PPI) network was built, and 10 hub genes were selected by using the CytoHubba application. Among the 10 hub genes, survival analysis showed that ITGA1, LMOD1, MYH11, MYLK, SORBS1 and TGFBR3 were significantly connected with disease-free survival (DFS). The circRNA-mediated ceRNA network provides potential prognostic biomarkers for metastatic prostate cancer.

MiR-425-5p as an exosomal biomarker for metastatic prostate cancer

Prostate cancer-related deaths are mostly caused by metastasis, which indicates the importance of identifying clinical prognostic biomarkers. In this study, we evaluated the expression profile of exosomal microRNAs (miRNAs) derived from metastatic prostate cancer (mPCa) cell lines (LNCaP and PC-3). miRNA signatures in exosomes and cells were evaluated by miRNA microarray analysis. Fourteen miRNAs were identified as candidates for specific noninvasive biomarkers. The expression of five miRNAs was validated using RT-qPCR, which confirmed that miR-205-5p, miR-148a-3p, miR-125b-5p, miR-183-5p, and miR-425-5p were differentially expressed in mPCa exosomes. Bioinformatic analyses showed that miR-425-5p was associated with residual tumor, pathologic T and N stages, and TP53 status in PCa samples. Gene ontology analysis of negatively correlated and predicted targeted genes showed enrichment of genes related to bone development pathways. The LinkedOmics database indicated that the potential target HSPB8 has a significant negative correlation with miR-425-5p. In conclusion, this study identified a panel of exosomal miRNAs with potential value as prognostic biomarkers for prostate cancer.

High Monocyte Count and Expression of S100A9 and S100A12 in Peripheral Blood Mononuclear Cells Are Associated with Poor Outcome in Patients with Metastatic Prostate Cancer.

Simple SummaryProstate tumors are heterogeneous with unpredictable outcomes, ranging from harmless to aggressive, metastatic and deadly disease. Current diagnostic methods have limited ability to predict disease aggressiveness. New biomarkers are urgently needed to improve risk stratification, preferably involving non-invasive procedures. The aim of this prospective study was to assess the prognostic value of the inflammation markers S100A9 and S100A12 together with the monocyte count in blood samples from a cohort of 121 prostate cancer patients. We show that high monocyte count and high mRNA levels of S100A9, S100A12 are associated with poor outcome in patients with metastases at diagnosis. Our results suggest that analysis of these factors in blood could identify patients who are in direct need of additional treatment to conventional androgen deprivation therapy (ADT).Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.

Whole blood GRHL2 expression as a prognostic biomarker in metastatic hormone-sensitive and castration-resistant prostate cancer.

BackgroundAs potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined.MethodsIn this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients. Transcripts with statistically significant associations (P<0.05) were further investigated in a metastatic castration-resistant prostate cancer (mCRPC) cohort (n=119) receiving contemporary systemic therapy, exploring associations with PSA >50% response (PSA50), progression-free survival (PFS) and overall survival (OS). Clinical outcomes were prospectively collected in a protected digital database. Kaplan-Meier estimates and multivariable Cox proportional-hazards models assessed associations between gene transcripts and clinical outcomes (mHSPC covariates: disease volume, docetaxel use and haemoglobin level; mCRPC covariates: prior exposure to chemotherapy or ARPIs, haemoglobin, performance status and presence of visceral disease). Follow-up was performed monthly during ARPI treatment, three-weekly during taxane chemotherapy, and three-monthly during androgen deprivation therapy (ADT) monotherapy. Serial PSA measurements were performed before each follow-up visit and repeat imaging was at the discretion of the investigator.ResultsDetection of circulating Grainyhead-like 2 (GRHL2) transcript was associated with poor outcomes in mHSPC and mCRPC patients. Detectable GRHL2 expression in mHSPC was associated with a lower rate of seven-month undetectable PSA levels (25% vs. 65%, P=0.059), and independently associated with shorter TTCR (HR 7.3, 95% CI: 1.5–36, P=0.01). In the mCRPC cohort, GRHL2 expression predicted significantly lower PSA50 response rates (46% vs. 69%, P=0.01), and was independently associated with shorter PFS (HR 3.1, 95% CI: 1.8–5.2, P<0.001) and OS (HR 2.9, 95% CI: 1.6–5.1, P<0.001). Associations were most apparent in patients receiving ARPIs.ConclusionsDetectable circulating GRHL2 was a negative prognostic biomarker in our mHSPC and mCRPC cohorts. These data support further investigation of GRHL2 as a candidate prognostic biomarker in metastatic prostate cancer, in addition to expanding efforts to better understand a putative role in therapeutic resistance to AR targeted therapies.

Quantification of Metastatic Prostate Cancer Whole-Body Tumor Burden with 18F-FDG PET Parameters and Associations with Overall Survival After First-Line Abiraterone or Enzalutamide: A Single-Center Retrospective Cohort Study.

New biomarkers for metastatic prostate cancer are needed. The aim of this study was to evaluate the prognostic value of 18F-FDG PET whole-body tumor burden parameters in patients with metastatic prostate cancer who received first-line abiraterone or enzalutamide therapy. Methods: This was a retrospective study of patients with metastatic castration-sensitive prostate cancer (mCSPC, n = 25) and metastatic castration-resistant prostate cancer (mCRPC, n = 71) who underwent 18F-FDG PET/CT within 90 d before first-line treatment with abiraterone or enzalutamide at a tertiary-care academic cancer center. Whole-body tumor burden on PET/CT was quantified as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and correlated with overall survival (OS) probabilities using Kaplan-Meier curves and Cox models. Results: The median follow-up in survivors was 56.3 mo (interquartile range, 37.7-66.8 mo); the median OSs for patients with mCRPC and mCSPC were 27.8 and 76.1 mo, respectively (P < 0.001). On univariate analysis, the OS probability of mCRPC patients was significantly associated with plasma levels of alkaline phosphatase (hazard ratio [HR], 1.90; P < 0.001), plasma levels of lactate dehydrogenase (HR, 1.01; P < 0.001), hemoglobin levels (HR, 0.80; P = 0.013), whole-body SUVmax (HR, 1.14; P < 0.001), the number of 18F-FDG-avid metastases (HR, 1.08; P < 0.001), whole-body metabolic tumor volume (HR, 1.86; P < 0.001), and TLG (HR, 1.84; P < 0.001). On multivariable analysis with stepwise variable selection, hemoglobin levels (HR, 0.81; P = 0.013) and whole-body TLG (HR, 1.88; P < 0.001) were independently associated with OS. In mCSPC patients, no significant association was observed between these variables and OS. Conclusion: In patients with mCRPC receiving first-line treatment with abiraterone or enzalutamide, 18F-FDG PET WB TLG is independently associated with OS and might be used as a quantitative prognostic imaging biomarker.

Concordance probability as a meaningful contrast across disparate survival times.

The performance of time-to-event models is frequently assessed in part by estimating the concordance probability, which evaluates the probabilistic pairwise ordering of the model-based risk scores and survival times. The standard definition of this probability conditions on any survival time pair ordering, irrespective of whether the times are meaningfully separated. Inclusion of survival times that would be deemed clinically similar attenuates the concordance and moves the estimate away from the contrast-of-interest: comparing the risk scores between individuals with disparate survival times. In this manuscript, we propose a concordance definition and corresponding method to estimate the probability conditional on survival times being separated by at least a minimum difference. The proposed estimate requires direct input from the analyst to identify a separable survival region and, in doing so, is analogous to the clinically defined subgroups used for binary outcome area under the curve estimates. The method is illustrated in two cancer examples: a prognostic score in clear cell renal cell carcinoma and two biomarkers in metastatic prostate cancer.

Abstract PR17: Metabolic re-wiring in African-American prostate cancer: A role of adenosine-inosine axis

Abstract African-American (AA) men have a 60% higher incidence of prostate cancer compared to European-American (EA) men and tend to have a more aggressive clinical outcome. An understanding of the altered biological responses and the factors that lead to health disparity in prostate cancer development and progression is unclear. Metabolism defines the physiological state of the cell and metabolic reprogramming is a hallmark of cancer. Thus, studying the metabolic landscape will be critical for understanding the biological changes that might contribute to this disparity. Analysis of 190 metabolites across prostate cancer/benign adjacent tissue pairs from ancestry typed AA and EA men performed in our laboratory, revealed altered levels of nucleosides adenosine and inosine. High inosine to adenosine ratio is observed in AA men compared to EA men. In line with this finding, the enzyme adenosine deaminase (ADA), which converts adenosine to inosine was found elevated in AA men, potentially explaining the high inosine to adenosine ratio in AA PCa. The consequences of the accumulation of these metabolites on AA PCa progression are unknown. The current study will address the knowledge gap on the consequences of elevated ADA activity in AA PCa and attempt to dissect its role in effecting an aggressive phenotype in PCa. To determine the role of elevated ADA in PCa, it was overexpressed in ancestry-typed AA (MDA-PCa-2A) and EA PCa(LNCaP) cell lines (termed ADA OE). Phenotypic examination of these cells revealed increased ADA enzyme activity decreases the cell-ECM adhesion. This adhesion decrease is facilitated by a decrease in cell adhesion protein integrin β1 (ITGB1). Elevated ADA enzyme activity decreases cAMP which mediates this adhesion decrease by disrupting the Epac-Rap1 pathway. It is postulated that high inosine upon ADA OE activates adenosine receptors A1 and A3, which causes this decrease in cAMP levels. These molecular findings suggest that ADA-mediated adhesion decrease could facilitate metastatic dissemination from the primary tumor. From a translational viewpoint, ADA enzyme activity could serve as a biomarker for metastatic prostate cancer. Therefore, we further look to analyze the inosine to adenosine levels (ADA enzyme activity) in patient samples and correlate with various clinical outcomes in PCa. Our initial analysis reveals high inosine to adenosine ratio in biopsy positive patient samples compared to biopsy negative samples. Our next steps of analysis include correlating the enzyme activity with (i) Biochemical Recurrence (ii) Time to attaining castration resistance in castration sensitive patients (iii) Time to metastasis (iv) Response to Androgen deprivation in patients after BCr. Based on our current findings, we expect inosine to adenosine ratio in plasma or urine to serve as a predictive marker for PCa incidence or progression in AA men. In addition, we expect ADA to serve as a potential therapeutic target for AA PCa. Citation Format: Christy Charles, Jie Gohlke, Stacy Lloyd, Uttam Rasaily, James Henderson, Balasubramanyam Karanam, Brian Simons, Nora Navone, Rick Kittles, Stefan Ambs, George Michailidis, Nagireddy Putluri, Arun Sreekumar. Metabolic re-wiring in African-American prostate cancer: A role of adenosine-inosine axis [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR17.

An Update on the Prognostic and Predictive Serum Biomarkers in Metastatic Prostate Cancer.

Serum biomarkers are molecules produced by normal and abnormal cells. Prostate specific antigen (PSA) is an example of a serum biomarker used widely in the diagnosis and prognostication of prostate cancer. PSA has its limitations as it is organ- but not cancer-specific. The aim of this review is to summarize the current published data on the potential prognostic and predictive biomarkers in metastatic prostate cancer (mPC) that can be used in conjunction with PSA. These biomarkers include microRNAs, androgen receptor variants, bone metabolism, neuroendocrine and metabolite biomarkers, and could guide treatment selection and sequence in an era where we strive to personalized therapy.

In Vivo Detection of Circulating Tumor Cells in High-Risk Non-Metastatic Prostate Cancer Patients Undergoing Radiotherapy.

High-risk non-metastatic prostate cancer (PCa) has the potential to progress into lethal disease. Treatment options are manifold but, given a lack of surrogate biomarkers, it remains unclear which treatment offers the best results. Several studies have reported circulating tumor cells (CTCs) to be a prognostic biomarker in metastatic PCa. However, few reports on CTCs in high-risk non-metastatic PCa are available. Herein, we evaluated CTC detection in high-risk non-metastatic PCa patients using the in vivo CellCollector CANCER01 (DC01) and CellSearch system. CTC counts were analyzed and compared before and after radiotherapy (two sampling time points) in 51 high-risk non-metastatic PCa patients and were further compared according to isolation technique; further, CTC counts were correlated to clinical features. Use of DC01 resulted in a significantly higher percentage of CTC-positive samples compared to CellSearch (33.7% vs. 18.6%; p = 0.024) and yielded significantly higher CTC numbers (range: 0–15 vs. 0–5; p = 0.006). Matched pair analysis of samples between two sampling time points showed no difference in CTC counts determined by both techniques. CTC counts were not correlated with clinicopathological features. In vivo enrichment using DC01 has the potential to detect CTC at a higher efficiency compared to CellSearch, suggesting that CTC is a suitable biomarker in high-risk non-metastatic PCa.