Multigene Profiling of Circulating Tumor Cells (CTCs) for Prognostic Assessment in Treatment-Naïve Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.

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Multi-institutional evaluation of the clinical outcomes and genomic correlates of African Americans with metastatic castration-sensitive prostate cancer (mCSPC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.17 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 17-17

Author(s):

Meredith MI Freeman ◽

Ellen Jaeger ◽

Jason Zhu ◽

Audrey Phone ◽

Roberto Nussenzveig ◽

...

Keyword(s):

Prostate Cancer ◽

Retrospective Analysis ◽

Clinical Outcomes ◽

De Novo ◽

High Volume ◽

Abiraterone Acetate ◽

Phase Iii ◽

Treatment Intensification ◽

Radium 223 ◽

Incidence And Mortality

17 Background: Prostate cancer incidence and mortality is higher in African American (AA) as compared with non-AA men. The outcomes of mCSPC have significantly improved through treatment intensification yet, AA representation in those studies was suboptimal. We aimed to report the clinical, treatment outcomes and genomic data of AA men with mCSPC. Methods: Retrospective analysis of consecutive AA men with mCSPC at six Academic Institutions. The primary objective was to report the baseline characteristics and treatment patterns of mCSPC AA patients. The secondary objectives included the germline and somatic data and the clinical outcomes including PSA response, progression-free survival and subsequent treatments. Results: A total of 71 patients, median age 63 years (range, 41-84) with 58% Gleason 8-10, initial PSA of 69.8 ng/mL (0.02-7650), 59% with de-novo and 55% with high-volume (CHAARTED criteria; 20% visceral) disease, were included in this analysis. Twenty-two patients (31%) were treated with androgen deprivation therapy (ADT; 67% prior to year 2017), while 24%, 45% and 3% received docetaxel (median 6 cycles), abiraterone acetate and enzalutamide, respectively. Two patients received triplet therapy with ADT/docetaxel plus abiraterone or enzalutamide. Undetectable PSA was achieved in 35% after a median of 8.9 months (1.8-22.3). Among patients with mCSPC who received radiation therapy to prostate (n = 8), 89% had low volume disease. At time of cut off, thirty-two patients developed CRPC and the estimated median time to CRPC was 2.9 years (95% CI, 1.6-4.2). Subsequent therapies (n = 29) included abiraterone acetate (41%), enzalutamide (24%), bicalutamide (10%), radium-223 (7%), chemotherapy (7%), sipuleucel-T (3%) and others (7%). Five patients (8%) had pathogenic germline alterations (n = 2 BRCA1; n = 1 HOXB13, PALB2 and PMS2). Additionally, the most common somatic alterations among tested patients (n = 27) included CDK12, SPOP, TMPRSS2-ERG fusion, and TP53, all in 11% frequency. Of note, n = 2 BRCA1 and n = 1 high MSI/TMB. Conclusions: In one of the largest reported cohorts to our knowledge, mCSPC AA presented with a high number of de-novo and high-volume disease and might harbor a different germline and somatic genomic profile. The outcomes were comparable to contemporary phase III trials with treatment intensification, yet 31% were treated with ADT. Despite the known limitations associated with retrospective analysis, these data support prior observations where AA might have better initial PSA responses to ADT-based strategies compared with Caucasians, requiring further validation.

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Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.75.3657 ◽

2018 ◽

Vol 36 (11) ◽

pp. 1080-1087 ◽

Cited By ~ 200

Author(s):

Christos E. Kyriakopoulos ◽

Yu-Hui Chen ◽

Michael A. Carducci ◽

Glenn Liu ◽

David F. Jarrard ◽

...

Keyword(s):

Prostate Cancer ◽

High Volume ◽

Phase Iii ◽

Cancer Trial ◽

Term Survival ◽

Chemohormonal Therapy ◽

Androgen Ablation ◽

Hormone Sensitive ◽

Low Volume

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

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Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial

JCO Precision Oncology ◽

10.1200/po.19.00388 ◽

2020 ◽

pp. 882-897 ◽

Cited By ~ 2

Author(s):

Clare Gilson ◽

Fiona Ingleby ◽

Duncan C. Gilbert ◽

Marina A. Parry ◽

Nafisah B. Atako ◽

...

Keyword(s):

Prostate Cancer ◽

Chromatin Remodeling ◽

Metastatic Prostate Cancer ◽

De Novo ◽

High Volume ◽

Pi3k Pathway ◽

Mismatch Repair Gene ◽

Copy Number Loss ◽

Hormone Sensitive ◽

Low Volume

PURPOSE The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor ( AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences ( AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.

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Application of Microarrays to the Analysis of Gene Expression in Cancer

Clinical Chemistry ◽

10.1093/clinchem/48.8.1170 ◽

2002 ◽

Vol 48 (8) ◽

pp. 1170-1177 ◽

Cited By ~ 86

Author(s):

Pascale F Macgregor ◽

Jeremy A Squire

Keyword(s):

Gene Expression ◽

Early Diagnosis ◽

Molecular Signatures ◽

Therapeutic Approaches ◽

Individual Gene ◽

Prognostic Assessment ◽

Disease Mechanisms ◽

New Gene ◽

Cellular Microenvironments ◽

State Of Activity

Abstract Molecular diagnostics is a rapidly advancing field in which insights into disease mechanisms are being elucidated by use of new gene-based biomarkers. Until recently, diagnostic and prognostic assessment of diseased tissues and tumors relied heavily on indirect indicators that permitted only general classifications into broad histologic or morphologic subtypes and did not take into account the alterations in individual gene expression. Global expression analysis using microarrays now allows for simultaneous interrogation of the expression of thousands of genes in a high-throughput fashion and offers unprecedented opportunities to obtain molecular signatures of the state of activity of diseased cells and patient samples. Microarray analysis may provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments and ultimately may lead to improved early diagnosis and innovative therapeutic approaches for cancer.

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Stratification of Prognoses based on Criteria from Clinical Trials of Metastatic Hormone-sensitive Prostate Cancer

10.21203/rs.3.rs-753861/v1 ◽

2021 ◽

Author(s):

Hyun Kyu Ahn ◽

Jeong Woo Yoo ◽

Kyo Chul Koo ◽

Byung Ha Chung ◽

Kwang Suk Lee

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Liver Metastasis ◽

Bone Metastasis ◽

High Volume ◽

Classification Systems ◽

Oncologic Outcomes ◽

Visceral Metastasis ◽

Hormone Sensitive ◽

Low Volume

Abstract Background: Oncologic outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) are extremely heterogeneous. We aimed to (1) stratify the prognosis in mHSPC patients according to criteria for high-volume disease, as defined in clinical trials, and (2) identify the combinations of unfavorable risk factors.Methods: This retrospective study reviewed 623 patients who were diagnosed with mHSPC between 1996 and 2014. The prognoses of mHSPC patients were stratified by criteria from the GETUG15, CHAARTED, STAMPEDE, and LATITUDE trials. The exclusion criteria were incomplete clinical data, docetaxel chemotherapy with upfront options, and metastatic disease without proper management after initial diagnosis.Results: All 485 patients (median follow-up=36.1 months) were categorized according to stage: M1a (70, 14.4%), M1b (367, 75.7%), and M1c (48, 9.9%). Significant differences in overall survival (OS) and cancer-specific survival (CSS) were found among the groups with low-volume disease, as classified by four clinical trials (log-rank p=0.001 and p<0.001, respectively). Bone metastasis volume and liver metastasis were independent predictors of prognosis. According to disease classification under NCCN guidelines, the prognosis of CSS between low-volume disease patients and M1c patients (no bone metastasis and low-volume bone metastasis) was not significantly different. Additionally, the prognosis of CSS did not significantly differ between M1c (high-volume bone metastasis and visceral metastasis, except liver) and M1b (high-volume bone metastasis) patients.Conclusions: The prognoses of patients with low-volume disease, based on several classification systems, were heterogeneous. Except for lung or liver metastasis, the combination of visceral metastasis with no/low-volume bone disease should be considered as a proxy of less aggressive disease in patients presenting with mHSPC.

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Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.e263 ◽

2015 ◽

pp. e263-e269 ◽

Cited By ~ 1

Author(s):

Leonel F. Hernandez-Aya ◽

Maha Hussain

Keyword(s):

Prostate Cancer ◽

De Novo ◽

High Volume ◽

High Response Rate ◽

Phase Iii ◽

Incurable Disease ◽

Castration Resistant ◽

Castrate Resistant Prostate Cancer ◽

Hormone Sensitive ◽

Castrate Resistant

Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p = 0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p = 0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.

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Cost-effectiveness of docetaxel in high-volume hormone-sensitive metastatic prostate cancer

Canadian Urological Association Journal ◽

10.5489/cuaj.5889 ◽

2019 ◽

Vol 13 (12) ◽

Cited By ~ 1

Author(s):

Jaclyn Beca ◽

Habeeb Majeed ◽

Kelvin K.W. Chan ◽

Sebastian J. Hotte ◽

Andrew Loblaw ◽

...

Keyword(s):

Prostate Cancer ◽

Sensitivity Analysis ◽

Cost Effectiveness ◽

Survival Data ◽

High Volume ◽

Base Case ◽

Castration Resistant Prostate Cancer ◽

Life Years ◽

Hormone Sensitive ◽

The Cost

Introduction: Three pivotal trials have considered the addition of docetaxel (D) chemotherapy to conventional androgen-deprivation therapy (ADT) for the treatment of metastatic hormone-sensitive prostate cancer (HSPC). While an initial small trial was inconclusive, two larger trials demonstrated significant clinical benefit, including pronounced survival benefits (added 17 months) among patients with high-volume metastatic disease. Given the evolving clinical evidence, the cost-effectiveness of this approach warrants exploration. Methods: The cost-effectiveness of six cycles of ADT+D compared to ADT alone to treat patients with high-volume metastatic HSPC was assessed from a Canadian public payer perspective. We included three health states: HSPC, metastatic castration-resistant prostate cancer (CRPC), and death. Survival data were obtained from the CHAARTED trial, which reported outcomes specifically for high-volume disease. We used Ontario costs data and utilities from the literature. Results: In the base case analysis, ADT+D cost an additional $25 757 and produced an extra 1.06 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of $24 226/QALY gained. Results from one-way sensitivity analysis across wide ranges of estimates and a range of scenarios, including an alternate model structure, produced ICERs below $35 000/QALY gained in all cases. Conclusions: The use of D with ADT in high-volume metastatic HSPC appears to be an economically attractive treatment approach. The findings were consistent with other studies and robust in sensitivity analysis across a variety of scenarios.

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End-of-radiation PSA as a novel prognostic factor in patients undergoing definitive radiation for prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.68 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 68-68 ◽

Cited By ~ 1

Author(s):

Phuoc T. Tran ◽

Amol Narang ◽

Ashwin Ram ◽

Scott P. Robertson ◽

Pei He ◽

...

Keyword(s):

Prostate Cancer ◽

Multivariate Analysis ◽

High Risk ◽

Low Risk ◽

Risk Level ◽

Treatment Intensification ◽

Entire Cohort ◽

Kaplan Meier ◽

Risk Patients ◽

Poor Outcomes

68 Background: In patients with localized prostate cancer undergoing radiation therapy (RT) +/- androgen deprivation therapy (ADT), an end of radiation (EOR) PSA obtained during the last week of RT may serve as an early post-treatment predictor of poor outcomes and identify patients in whom to pursue treatment intensification or novel therapies. Methods: We reviewed an IRB-monitored, prospectively acquired database of patients with prostate cancer treated with definitive RT at our institution from 1993-2007 (n=890). Patients with an available EOR PSA were divided into two cohorts and analyzed separately based on inclusion of ADT into the treatment regimen. EOR PSA thresholds of 0.5 ng/mL and 1.0 ng/mL were explored. Multivariate analysis was performed to determine prognostic factors for biochemical failure-free survival (BFFS, Phoenix criteria) and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA thresholds. Results: Median age was 69 years, with an even distribution of NCCN low risk (33.5%), intermediate risk (34.0%), and high risk (32.5%) patients. Median RT dose was 7020 cGy, and 54.5% were treated with ADT. Median follow-up of the entire cohort was 11.7 yrs. EOR PSA level was available for the majority of patients (77.5%). On multivariate analysis, EOR PSA >0.5 ng/mL was significantly associated with worse BFFS (p<0.0001) and OS (p<0.0001). In the subset of patients undergoing RT with ADT for NCCN intermediate/high risk disease, 5 yr BFFS was more disparate based an EOR PSA threshold of 0.5 ng/mL (5 yr BFFS: 87.3% vs. 41.1%, p<0.001), than initial NCCN risk level (5 yr BFFS: 88.7% vs. 76.9%, p=0.038). In NCCN low risk patients undergoing definitive RT alone, an EOR PSA threshold of 1.0 ng/mL was significantly prognostic of outcome (5 yr BFFS: 100.0% vs. 88.6%, p=0.024). Conclusions: For NCCN intermediate/high risk patients undergoing RT with ADT, EOR PSA >0.5 ng/mL may represent a better surrogate for poor outcomes than initial risk group. In addition, NCCN low risk patients undergoing RT alone who obtained an EOR PSA ≤1.0 ng/mL experienced excellent BFFS. Prospective evaluation of the utility of EOR PSA should be explored.

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Early docetaxel-resistance in metastatic hormone-sensitive prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.260 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 260-260

Author(s):

Nedal Bukhari ◽

Kylea R. Potvin ◽

D. Scott Ernst ◽

Lori Sax ◽

Eric Winquist

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Median Overall Survival ◽

High Volume ◽

Outcome Data ◽

Resistant Disease ◽

Docetaxel Resistance ◽

Docetaxel Treatment ◽

Psa Progression ◽

Hormone Sensitive

260 Background: The addition of docetaxel to standard androgen deprivation therapy (ADT) has been shown to improve the survival of men with metastatic hormone-sensitive prostate cancer (MHSPC) (Sweeney 2015, James 2016). We noticed PSA progression in some of our patients (pts) during docetaxel treatment and reviewed their outcomes. Methods: Men with MHSPC treated with docetaxel were identified from an electronic oncology pharmacy database. Eligible pts were prescribed docetaxel for metastatic adenocarcinoma of the prostate within 120 days of initiation of ADT. Pts with castration-resistant disease (CRPC), other histologies, and those without metastatic disease were excluded. Demographic, clinical, treatment and outcome data were extracted retrospectively from electronic medical records. Results: 31 eligible pts with MHSPC treated with docetaxel between August 2014 and July 2016 were identified. Median age was 65 years (53-83) and 28 (90%) had high-volume disease as defined by Sweeney et al (2015). Nadir PSA levels 6-7 months from ADT initiation were < 0.2, 0.2-4, and > 4 ng/mL in 29.0%, 36.7% and 36.7%, respectively. At median follow up of 85 weeks, 45.2% of pts had progressed to CRPC and 22.6% had died. Median time to CRPC was 59 weeks and median overall survival was 85 weeks. Seven pts with high-volume disease (25%) had PSA progression while receiving docetaxel treatment. The median overall survival of this group was 26 weeks (17 to 106+) and six have died. Three had visceral metastases. Nadir PSA was < 0.2 (1 pt), 0.2-4 (2 pts) and > 4 ng/mL (4 pts). After docetaxel 2 pts received BSC alone and 5 pts had 1st-line CRPC therapy. No response to abiraterone/enzalutamide was seen (3 pts). Two pts who discontinued docetaxel immediately at PSA progression and were switched to alternative chemotherapy survived > 1 year. Conclusions: A subset of men with MHSPC has lethal docetaxel-resistant disease characterized by early PSA rise. It is important to recognize these patients, but it is not clear if standard CRPC therapies are effective. An immediate early switch to alternative chemotherapy may be helpful. Further research to predict early docetaxel resistance, characterize response to current therapies and identify more effective treatment is needed.

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A genomic blood test (NETest) identifies neuroendocrine transformation of prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17511 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17511-e17511

Author(s):

Kambiz Rahbar ◽

Mark S. Kidd ◽

Ignat A. Drozdov ◽

Anna Malczewska ◽

Lisa Bodei ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Marker Gene ◽

Castration Resistant Prostate Cancer ◽

Tissue Samples ◽

Blood Gene Expression ◽

Castration Resistant ◽

Hormone Sensitive ◽

Sensitivity Specificity ◽

Real Time Information

e17511 Background: Neuroendocrine-like differentiation (NELD) and an aggressive phenotype are key features of castration-resistant prostate cancer (CRPC). Current blood-based biomarkers cannot detect these treatment-refractory variants. Our aim was to evaluate the NETest, a blood-based 51-marker gene neuroendocrine detection tool, as a CRPC-diagnostic versus prostate cancer (PCA). Methods: In silico evaluation: NETest gene identification in the TCGA-PRAD ( n= 500 PCA) and CRPC RNAseq datasets (cBIOPortal: dbGap-phs000909.v.p1, tissue samples: n= 47, including 15 CRPC). Blood gene expression: PCA: n= 50, CRPC: n= 40, hormone-sensitive PCA: n= 75 and benign prostatic hyperplasia (BPH: n= 41). NETest assay: Normalized gene expression, algorithmically assessed and scored: 0-100. Cut-off 20. PSA: ECLIA diagnostic assay: cut-off 4ng/L, > 10ng/ml = actionable value. Statistics: ANOVA, AUROC analyses and sensitivity/specificity metrics. Data is mean±SEM. Results: RNAseq: Two (4%) of the 51 NETest genes were identified in TCGA-PCA. In contrast, all 51 NETest genes (100%) were identified in CRPC tumors. Thirty-three (65%) were detected as upregulated (1.09-1425-fold vs. normal tissue). Blood-PCR: 49/51 (96%) NETest genes detected in CRPC blood. NELD-gene expression was significantly upregulated ( > 2-fold, p< 0.01) in CRPC vs. PCA ( TPH1, PNMA2, SSTR etc). NETest scores were elevated in CRPC (79±2.8) (ANOVA, p< 0.0001) vs. PCA (22±2) and BPH (23±3). The AUC differentiating CRPC from PCA was 0.93 ( p< 0.0001). NETest was elevated in 94% of CRPC vs. 13% PCA and 15% BPH (both p< 0.001). The diagnostic sensitivities and specificities were 94% and 87%, respectively. PSA: PSA was elevated in CRPC (220±372ng/ml). This was different to PCA (14±20ng/ml, p< 0.0001) and BPH (10.3±5.7ng/ml, p< 0.003). The AUC for CRPC vs. PCA/BPH was 0.70 ( p= 0.10). PSA > 10ng/ml occurred in 70% of CRPC, 60% of PCA ( p= NS) and 39% of BPH ( p< 0.05). The AUC for NETest (0.93) was significantly better than PSA (z-statistic: 4.63, p< 0.0001). Conclusions: The NETest is a liquid biopsy that detects neuroendocrine neoplasia genes in the blood and accurately identifies NELD in castration-resistant prostate cancer. We anticipate that the NETest could be used to provide real-time information relevant to the evolving neuroendocrine status of a PCA during therapy.

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