Metastatic Prostate Adenocarcinoma Research Articles

Role of Panax Ginseng as an Antioxidant and Hepatoprotective after Liver Toxicity caused by Flutamide in Adult Male Rats

Aim: This study was conducted to determine antioxidant, hepatoprotective and anti – inflammatory effects of panax ginseng extract against hepatotoxic effect of flutamide, a drug widely used in the treatment of metastatic prostate adenocarcinoma. Materials and Methods: Thirty rats (weight 200-300 g) were used and had access to water and food in the animal house for two week. The rats were divided randomly into six equal groups: group (A): received normal saline as control, group(B): received flutamide (25 mg/kg b.wt) orally for 7 days, group (C): injected p. ginseng extract (200 mg / kg b.wt) intraperitonialy daily for 30 days, group (D):injected p. ginseng extract (400mg/kg b.wt) intrapretonialy daily for 30 days, group (E):received flutamide (25mg/kg b.wt) orally for 7 days with p. ginseng extract (200 mg / kg b.wt) intrapretonialy daily for 30 days, group (F): received flutamide (25mg/kg b.wt) orally for 7days with p. ginseng extract (400 mg/kg b.wt) intrapretonialy daily for 30 days. In this study, we assessed the hepatoprotective effect of red ginseng in rats treated with flutamide. Serum concentrations of the hepatic marker enzymes alanine amino transferase (ALT), aspartate amino transferase (AST) and histopathological analysis have been performed for this purpose. The hepatic antioxidant status was assessed using measurement of GSH levels. Results: Administration of flutamide to adult male rats causes severe hepatic injury. Hepatosomatic index, ALT and AST were significantly increased in comparison with control and ginseng treated groups. While a significant decrease in the contents of reduced hepatic glutathione (GSH) was observed Histological examination of liver tissues showed that flutamide caused significant increase in the diameter of central vein, bloody congestion in the central vein with infiltration of Inflammatory cells, swelling of hepatocytes, narrowing of blood sinusoids and vacoules appear inside the hepatocytes. Conclusion: The results of this current study indicate that the administration of ginseng (200,400 mg / kg b.w) to flutamide treated animals resulted in an improvement in the histological picture of the liver as well as biochemical parameters, mainly through down regulation of oxidative stress and inflammatory response.

Integrative clinical transcriptome analysis reveals TMPRSS2-ERG dependency of prognostic biomarkers in prostate adenocarcinoma.

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene-signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa are characterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for their association with event-free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)-three of which are included in commercially available prognostic tests-whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa.

Prevalence of homologous recombination deficiency (HRD)-related signatures indicates that a wider range of prostate cancer patients may benefit from PARP-inhibitor therapy

Abstract Background Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP-inhibition and platinum-based chemotherapy. Currently targeted sequencing of key HR genes serves as an indicator of homologous recombination deficiency (HRD) in prostate cancer. It is well known, however, that other mechanisms, such as suppression of expression, rare mutations of HR-related genes can also cause HRD. Methods HRD levels can be estimated using various mutational, genomic signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n = 311) and whole exome sequencing data (n = 498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed. Results Known BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. The signs HRD present low intratumor heterogeneity and in most cases, the metastasis’s HRD-status is similar to the primary tumor’s. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD. Conclusions Based on the HRD associated mutational and genomic scar signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations). The prioritization of these patients for clinical trials, extending PARP-inhibitor therapy to all cases with HRD associated mutational signatures, even to those without BRCA1/2 mutations, will likely increase the efficacy of this treatment. Legal entity responsible for the study The authors. Funding Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 to Z.S.); Breast Cancer Research Foundation (BCRF-17-156 to Z.S.) and the Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant (NNF15OC0016584 to Z.S.), Department of Defense through the Prostate Cancer Research Program (award number is W81XWH-18-2-0056) to Z.S. and M.F. The Danish Cancer Society grant (R90-A6213 to MK). Z.S. and J.B. was supported by Velux Foundation 00018310 grant. Disclosure Z. Szallasi: Licensing / Royalties: Inventor on a patent used in the myChoice HRD assay: Myriad. All other authors have declared no conflicts of interest.

1634 Extracolonic Neoplasm From Colonic Polyps: A Case of Metastatic Prostate Cancer Diagnosed From a Colonic Polyp

INTRODUCTION: Prostate Cancer is the 2nd most common cancer among men in the US. Prostate Cancer frequently metastasizes to the bones, lymph nodes, lungs, liver, and brain. Very rarely, patients can develop metastases to the GI tract. We are presenting a patient that was diagnosed with metastatic prostate cancer after a colon biopsy. CASE DESCRIPTION/METHODS: A 61-year-old gentleman with no significant past medical history, presented with constipation, weak urinary stream, in addition to remote fall followed by lower back pain, trouble ambulating, and an unintentional 40 lb weight loss. He did not have any history of melena, hematochezia, abdominal pain or family history of cancers Examination was only evident of tenderness overlying lumbar vertebrae. He underwent CT Abdomen/Pelvis which showed sclerotic vertebral bone lesions in addition to abnormal thickening of the mid to lower rectal wall with adjacent perirectal soft tissue masses suspicious for rectal cancer with adjacent conglomerate lymphadenopathy/tumor. Colonoscopy revealed diminutive sigmoid sessile polyps which was removed by cold snare and cold biopsy in addition to an area of ulceration in the proximal rectum. Surprisingly the pathology of the polyps and rectal ulceration was consistent with metastatic prostate adenocarcinoma. He is planned to be started on chemotherapy with Docetaxel. DISCUSSION: Prostate cancer may invade the rectum however it remains rare to have metastatic colonic polyps from a prostate cancer. It has been reported to discover metastatic colonic polyps from breast, lung, skin (melanoma) cancer, however the finding of metastatic colonic polyps from a prostate cancer is rare and portends a sinister prognosis. In the light of this infrequent finding it becomes imperative to consider an extracolonic cause as the source of a colonic polyp especially in patients with known or in suspicion for a primary cancer. The mechanism of metastasis to the colonic is thought to be by hematogenous or lymphatic spread, however, rectal involvement often occurs by local tissue invasion. The clinical scenario in our patient is peculiar since there were no prior diagnoses of primary cancer. An extracolonic metastatic polyp may sometimes be the earliest sign of recurrent prostate cancer.

2711 A Rare Cause of Hematemesis: Metastatic Prostate Cancer to the Stomach

INTRODUCTION: Prostate cancer is a malignancy that constitutes the third most common type of cancer in males. Present day its mortality rate is decreasing with better screening in the form of prostate specific antigen (PSA). The most common site of metastasis is the bone. Rarely will this form of malignancy metastasize to the gastrointestinal tract. Here we present a rare case of advanced prostate cancer with gastric metastasis. CASE DESCRIPTION/METHODS: Patient is an 81 year old male with a medical history of hypertension and prostate cancer (on anti-androgen therapy) who presented to our emergency department with altered mental status, aphasia, and left sided hemiparesis. Given his poor neurologic status and inability to maintain oxygenation the patient was intubated. Notable imaging included a computed tomography (CT) scan of the brain showing findings consistent with acute infarct of the left middle cerebral artery. Notable laboratory workup included a hemoglobin 7.8 gm/dL. Physical exam was notable for a cachectic male with left sided weakness in the left upper extremity and left lower extremity. He was then admitted to the intensive care unit (ICU) where he was noted to have an acute drop in hemoglobin to 5.0 gm/dL with coffee ground emesis. An esophagogastroduodenoscopy (EGD) was then performed which showed a large infiltrative, ulcerated, friable mass lesion with contact oozing in the gastric body along the greater curvature which was biopsied. The pathology results of the biopsy specimen returned with positive staining to prostate specific antigen (PSA) consistent with metastatic prostatic adenocarcinoma in the gastric mucosa. During his hospital course at our facility, the patient's condition worsened and his family decided to withdraw care. The patient then underwent palliative extubation and expired peacefully. DISCUSSION: There are multiple primary malignancies that have the potential for metastasis to the stomach. Of these, the most common cancers include those of the lung, breast, kidney, esophagus and finally, cancers of the head and neck. Rarely will prostate cancer present with gastric metastasis. Symptoms of metastatic lesions to the stomach mimic those of primary gastric cancers and include abdominal pain, nausea, vomiting and hematemesis. Treatment of metastatic prostate cancer is best managed with androgen deprivation therapy. If this fails, alternate treatment options include chemotherapy or immunotherapy with androgen receptor antagonists or androgen synthesis inhibitors.

Metastatic prostate cancer presenting as a retroperitoneal mass: a case report and review of literature.

Prostate cancer (PCa) is the second most common cancer diagnosed in men globally, after lung cancer. Many patients with PCa are asymptomatic until the tumor has progressed. The prognosis of PCa mainly depends on the presence of metastatic spread. It usually metastasizes to the bone, lung, and liver. Retroperitoneum is an exceedingly rare site for metastatic PCa to occur. We describe a case of a 68-year-old male patient presented for left flank pain and lower limb edema. A retroperitoneal mass was identified on imagery. This mass was found to be due to metastatic prostate adenocarcinoma based on immunohistochemical studies. Knowledge of this atypical presentation of metastatic PCa will reduce the diagnostic delay and allow the appropriate timely treatment.

A Phase 2 Trial for Men With Metastatic Prostatic Adenocarcinoma

A Phase 2 Trial for Men With Metastatic Prostatic Adenocarcinoma

Expression of CDX2 in metastatic prostate cancer.

SummaryThe intestinal marker CDX2 has recently been found to stain a small percentage of primary prostate adenocarcinomas, but little is known of its expression in metastatic prostate cancers. We present a case of metastatic prostate adenocarcinoma that stained for CDX2 and highlight the confusion this may create when evaluating a carcinoma of unknown primary.

Abstract 134: Immunogenomic landscape of neuroendocrine prostate cancer (NEPC)

Abstract Background: NEPC is a histological subtype of advanced prostate cancer, predominantly arising clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance. Given current immunotherapeutic strategies only showing modest clinical benefit in prostate cancer patients and NEPC having clinical features aligned with small cell lung carcinoma (SCLC) we investigated the immune landscape of NEPC in relation to prostate cancer subtypes and SCLC to identify potential targets. Methods: We evaluated RNA-seq from a 190 patient cohort including benign prostate (n=29; 25 PCa matched), localized prostate adenocarcinoma (PCa; n=68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n=11), CRPC (n=54), NEPC (n=25; 11 de novo) with follow-up data, and SCLC (n=28) (Rudin et al., Nat Gen 2012). Additionally, 234 prostate cancer patients had tumor mutational burden (TMB) determined by WES. Unsupervised clustering of FPKMs was performed to identify a 232 gene, immune-rich cluster, used to categorize immune status and prioritize validation of targets by IHC. Results: Prostate cancer is known to have a relatively low TMB. Similarly, the median TMB of NEPC is akin to CRPC (38.0 vs 37.0 p = 0.44) while significantly lower than SCLC (38.0 vs 142.5, p <0.001). Unsupervised assessment identified a predominantly ‘cold’ immune status across subtypes, with ‘hot’ tumors (n=8) associated with metastatic tumors of the LN and bone and ‘intermediate’ NEPC tumors (n=9) associated with de novo cases. Worse overall survival was associated with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p <0.001). Further analysis of NEPC showed lower expression of cytokines (p<0.01) as well as variation in checkpoint markers. Specifically, NEPC tumors had significantly lower expression of PD1 in relation to CRPC (p = 0.0001) and SCLC (p = <0.0001), higher PDL1 expression than CRPC (p = 0.05) but comparable with SCLC (p = 0.93) and lower PDL2 expression than PCa and SCLC (p = 0.03; <0.001, respectively). Conclusion: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. Association of colder tumors with treatment-induced disease, inverse correlation between survival outcome and immune infiltration, as well as novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC. Citation Format: Alison M. Ferguson, Bhavneet Bhinder, Vincenza Conteduca, Michael Sigouros, Andrea Sboner, David Nanus, Scott Tagawa, David Rickman, Olivier Elemento, Himisha Beltran. Immunogenomic landscape of neuroendocrine prostate cancer (NEPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 134.

METASTATIC NEUROENDOCRINE PROSTATE CANCER, AN AGGRESSIVE PROSTATE MALIGNANCY: A REPORT OF TWO CASES WITH ORAL MANIFESTATIONS

Objectives Neuroendocrine prostate cancer (NEPC) is a lethal prostate malignancy with a median survival of less than 1 year from time of detection. NEPC can occur de novo or more commonly as a treatment emergent phenomenon (t-NEPC). t-NEPC occurs in a subset of patients with metastatic-castration resistant prostate cancer. Two cases of t-NEPC with oral manifestations are presented highlighting the pathologic features and the varied clinical context in which these lesions presented. Patients and Methods Case 1) A 79 year-old man with a history of prostate adenocarcinoma undergoing hormone treatment presented with a fungating mass of the right maxilla and palate, clinically suspicious for squamous cell carcinoma. Biopsy revealed a high grade neuroendocrine carcinoma. Case 2) A 76 year-old man with a history of metastatic prostate adenocarcinoma receiving zoledronic acid and denosumab treatment for bony metastases, presented with mandibular fracture. A segmental resection without reconstruction with debridement was performed with a clinical diagnosis of medication-related osteonecrosis of the jaw (MRONJ). The pathology revealed a high grade neuroendocrine cell tumor. Both cases were positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, and stained negative for prostate specific antigen (PSA) and prostate specific acid phosphatase (PSAP). Both tumors demonstrated a proliferative index (Ki-67) of 60-70%. An extended panel of immunostains appeared to eliminate other entities from consideration. Conclusions Awareness of t-NECP is of importance to correctly diagnosis the entity, recognizing that tumor markers such as PSA and PSAP are negative, and standard serum markers for prostate carcinoma may be stable or show no increase with progression of disease. Neuroendocrine carcinoma in the setting of medication related osteonecrosis of the jaw in a patient with prostate carcinoma needs to be included in the differential diagnosis.

Utility of NKX3.1 Immunostaining in the Detection of Metastatic Prostatic Carcinoma on Fine-Needle Aspiration Smears.

NK3 homeobox 1 (NKX3.1) has been increasingly used to diagnose metastatic prostatic carcinoma in histologic samples. However, its utility and reliability in cytologic direct smears have not been studied. A total of 59 fine-needle aspiration (FNA) cases with a definitive diagnosis of metastatic carcinoma from the prostate were included. The cases were grouped based on different Gleason score in their corresponding primary tumors and morphologic variants. For each case, tumor cells were immunostained with NKX3.1, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP) on cell-transferred smears. NKX3.1 was strongly and diffusely positive in all 40 metastatic prostatic adenocarcinomas, including those with ductal features, but negative for the 19 small cell carcinoma (SmCC) cases. NKX3.1 had a better detection rate than PSA (13/50, 26%) and PAP (0/47, 0%). NKX3.1 immunostaining on FNA smears is highly reliable for detecting metastatic prostatic carcinomas of conventional and ductal types but not for SmCC.

IMPACT: Immunotherapy in patients with metastatic cancers and CDK12 mutations.

TPS5091 Background: Tumors with biallelic CDK12 loss have been identified as a distinct subtype in metastatic castration resistant prostate cancer (mCRPC) and other cancer types. The CDK12 biallelic loss mCRPC genomic signature, distinct from homologous recombination deficient (HRD) and ETS fusion signatures, is characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens, and increased tumor T cell infiltration. Early clinical experience with anti-PD-1 immunotherapy in CDK12 loss mCRPC patients (pts) is notable for deep and sustained PSA as well as radiographic responses. We hypothesize that CDK12 biallelic loss is a potential biomarker of immune checkpoint immunotherapy (ICI) efficacy in mCRPC and other cancers. Methods: IMPACT (NCT03570619) is a multi-center, open label, phase 2 study of pts with metastatic cancers that harbor CDK12 biallelic loss. mCRPC pts will be enrolled in cohort A (n = 25) in a Mini-Max Simon Two-Stage design, and all other pts in single-stage cohort B (n = 15). All pts will receive induction therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks (up to 52 weeks in total). Eligible pts must have identified biallelic CDK12 loss on any CLIA/CAP approved next generation sequencing assay and a histologic diagnosis of metastatic prostate adenocarcinoma or other metastatic carcinoma. No prior ICI is allowed. The primary endpoint is the overall response rate (ORR) in cohort A per PCWG3 criteria. An ORR of 30% is targeted in cohort A. Secondary endpoints include safety, secondary efficacy measures, quality of life, and survival measures. Exploratory objectives include tumor whole exome analysis and changes in immune profiles with therapy. Comprehensive and serial monitoring of peripheral blood immune cell populations will be performed via T cell clonal diversity assessment and multi-parametric flow cytometry. Changes in myeloid and lymphoid populations will be assessed from whole blood. Polarization and effector function of T cells and activation of antigen presenting cells will be further characterized from isolated peripheral blood mononuclear cells. Study accrual is ongoing. Clinical trial information: NCT03570619.

MON-500 A Case of Tumor-Induced Osteomalacia Caused by Metastatic Prostate Cancer

Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia due to renal phosphate wasting. An overproduction of the phosphatonin fibroblast growth factor 23 (FGF-23) has been implicated in TIO pathogenesis. FGF-23 increases renal phosphate excretion by reducing the expression of sodium-dependent phosphate co-transporters NPT2a and NTP2c in the proximal tubules. TIO is most commonly associated with mesenchymal tumors. Epithelial tumors are estimated to account for only 5% of reported cases of TIO. Here we report a rare case of TIO associated with castration resistant metastatic prostate cancer. Clinical Case: A 59 year old male with high grade castration-resistant metastatic prostate adenocarcinoma presented with worsening fatigue and bone pain. Nine years before presentation, he was treated with prostatectomy, pelvic radiation, and taxotere followed by one year of luteinizing hormone-releasing hormone (LHRH) agonist. Bony metastases were identified 8 years later, and he was treated with a combination of LHRH agonist, RANK-ligand inhibitor denosumab, antiandrogenic therapy abiraterone and prednisone. Due to refractory disease, he received three cycles of sipuleucel-T, a cell-based cancer immunotherapy, and was enrolled in a phase 1B clinical trial involving enzalutamide. Laboratory evaluation included phosphorus 1.2 (2.5-4.5 mg/dL), urine phosphate excretion 1984 (400-1300 mg/24 hour), parathyroid hormone 110 (15-65pg/mL), calcium7.9 (8.7-10.2 mg/dL), vitamin D-25 85.3 (30-100mg/dL), inappropriately low vitamin D 1,25 40 (19.9-79.3 mg/dL) and FGF-23 387 (44-215 ref units/mL). Whole body scan showed widespread osteoblastic metastatic lesions. He was treated with high-dose calcitriol, vitamin D, calcium carbonate, and potassium phosphate with improvement in hypophosphatemia and bone pain. Clinical Lessons: Hypophosphatemic osteomalacia in the setting of advanced prostate cancer was first reported in 1975. The role of FGF-23 as a phosphatonin in such cases has since emerged, due to advancement of laboratory assays and improved understanding of the pathophysiology of TIO. Review of existing literature reveals five reported cases of prostate cancer-associated TIO with associated elevated FGF-23. This condition poses a diagnostic challenge, as TIO-related bone pain and weakness can be mistaken for that associated with bony metastases. Given the inability to resect widely metastatic disease, treatment of such cases consists of reducing tumor burden with chemotherapy and radiation and supplementation with calcitriol and phosphorus. While other FGF pathways have been implicated in prostate cancer-related angiogenesis, drug resistance, and metastases, the role FGF23 may play in an aggressive disease course warrants further investigation, particularly given it may represent a treatment target.

Immunogenomic landscape of neuroendocrine prostate cancer (NEPC).

224 Background: Prostate cancer (PCa) shows limited clinical benefit from current immunotherapy strategies. NEPC is a histologic subtype of advanced PCa that most often arises clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance, but shares pathologic, clinical, and molecular features with small cell lung carcinoma (SCLC). We investigated the immune landscape of NEPC in relation to other PCa subtypes and SCLC to identify potential immunological targets. Methods: We evaluated RNA-seq from 190 patients comprising benign prostate (n = 29; 25 PCa matched), localized PCa (n = 68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n = 11), CRPC (n = 54), NEPC (n = 25) with follow-up data, and SCLC (n = 28) (Rudin et al., Nat Gen 2012). Additionally, 290 patients had WES data available for tumor mutational burden (TMB). Unsupervised clustering of FPKMs was performed to identify an immune rich cluster of 232 genes, which was used to categorize immune status and prioritize validation of select targets by IHC. Results: Median TMB of NEPC was similar to CRPC (38.0 vs 37.0 p= 0.44) but significantly lower than SCLC (38.0 vs 142.5, p< 0.001). Unsupervised assessment of T-cell related gene expression identified a predominantly cold immune status across subtypes, with hot (n = 8) tumors associated with metastatic tumors of the LN and bone. Worse overall survival was seen with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p < 0.001). Further analysis of NEPC showed lower expression of cytokines ( p< 0.01) and variation in checkpoint markers. Specifically, NEPC had significantly lower expression of PD1 in relation to CRPC ( p= 0.0001) and SCLC ( p = < 0.0001), higher PDL1 than CRPC ( p= 0.05) but comparable with SCLC ( p= 0.93) and lower PDL2 than PCa and SCLC ( p= 0.03; < 0.001, respectively). Conclusions: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. The inverse correlation between survival outcome and immune infiltration, as well as the novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC.

Metacure: Multi-arm multimodality therapy for very high risk localized and low volume metastatic prostatic adenocarcinoma.

TPS349 Background: Therapeutic advances in the management of metastatic castration-resistant prostate cancer (mCRPC) have not been matched in non-castrate states. A key obstacle is the traditional paradigm in which therapies with significant benefit in mCRPC are then studied in patients (pts) with localized, rising PSA or early metastatic disease using time-to-event (TTE) outcomes (e.g. biochemical recurrence, radiographic progression or death). These trials are costly, lengthy and often give inconclusive results that do not change practice nor provide a methodology to rank regimens based on efficacy. A new strategy is needed that gives a rapid efficacy readout and prioritizes approaches for large-scale testing. Methods: Metacure is a multi-arm, multi-stage randomized Phase 2 trial in which novel systemic therapies are studied in the context of a multimodality approach, which includes radical prostatectomy + pelvic and retroperitoneal lymph node dissection, if applicable, stereotactic radiotherapy (RT) to osseous metastases, and an option for adjuvant RT based on risk factors. The arms include combinations of ADT + apalutamide +/- abiraterone acetate and prednisone. Non-castrate prostate cancer pts with high probability of relapse or death from disease ranging from very high risk localized to low-volume metastatic disease are eligible. The primary endpoint is pathologic complete response and minimal residual disease. The secondary endpoint is undetectable PSA with non-castrate levels of testosterone. Both are binary endpoints that circumvent interpretations of the clinical relevance of TTE outcomes, providing a read-out of success or failure in a shorter time frame with fewer pts. The uniform entry criteria and continuous randomization enables ranking and prioritization of the strategies evaluated for further development in large-scale trials so that only the most effective ones move forward. This multicenter trial is managed by the Prostate Cancer Clinical Trials Consortium, funded by Janssen and is currently open and actively accruing. Future plans include opening a cohort of pts with aggressive non-castrate disease harboring DNA damage repair alterations. Clinical trial information: NCT03436654.

Health-Related Quality of Life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate adenocarcinoma (mPCa) and urothelial carcinoma (mUC).

478 Background: HRQOL outcomes are increasingly used to guide patient-centered care and health policy decisions, especially when treatment has a limited impact on survival. Our aim was to systematically evaluate the quality of HRQOL reporting in phase III RCTs of mPCa and mUC. Methods: A systematic literature review identified phase III RCTs evaluating palliative systemic therapies for castrate sensitive or castrate resistant mPCa (excluding androgen-deprivation therapy) and mUC, published in English between 1985 and 2018. Supplementary material and companion publications on HRQOL were also reviewed. RCTs reporting HRQOL outcomes were scored by the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (range 0-11). Results: Of 44 RCTs in mPCa, 25 (56.8%) reported HRQOL outcomes. BPI-SF or BPI (14 RCTs) and McGill-Melzack pain questionnaire (6 RCTs) were the most commonly used generic instruments, whereas FACT-P (16 trials), validated in advanced PCa, was the most commonly used disease-specific instrument. Average score of HRQOL reporting in mPCa was 6.7. Of 21 RCTs in mUC, 7 (33.3%) reported HRQOL. EORTC QLQ-C30 (6 RCTs) was the most commonly used generic instrument. Only 1 trial used a disease-specific instrument, FACT-BL, which lacks validation in mUC. Average score in mUC was 6.6. Conclusions: Robust HRQOL data from phase III RCTs in mPCa and mUC remain limited, and most HRQOL reports had methodologic shortcomings. Although the disease-specific FACT-P questionnaire being used is validated in advanced PCa, mUC RCTs have yet to use a culturally validated instrument to assess HRQOL. Quality of HRQOL reporting has improved over time but needs to be better harmonized across trials. [Table: see text]

Prostate Metastasis Presenting as Primary Colon Cancer

Prostate cancer is the second most common cancer, and the second leading cause of cancer death in US men. Prostate cancer has high metastatic potential, with 20% having metastatic disease upon diagnosis. Here we describe a rare case of a metastatic prostate cancer to the rectosigmoid initially presenting as a colon polyp. A 74 yo man with a history of prostate cancer and radical prostatectomy 15 years ago was referred for evaluation of colon cancer and pericolonic abscess. He had mild suprapubic pain and constipation. He was diagnosed with subacute diverticulitis and pericolonic abscess after CT Abdomen and Pelvis showed a sigmoid/pericolonic fistula extending to the bladder. Diagnostic flexible sigmoidoscopy found a sigmoid polyp which was positive for poorly differentiated carcinoma of undetermined origin. He was then directed to our facility for a second opinion.His vitals and physical exam, including rectal exam, and PSA were normal. He was still taking Leuprolide every 6 months. A CT Chest Abdomen and Pelvis showed a 5 cm mottled mass between the sigmoid and the bladder with clouding of omental fat suggesting an inflammatory vs peritoneal metastatic disease. There was thickening of the ileocecal valve and focal segments of the distal colon. On colonoscopy there were several small adenomatous/hyperplastic polyps. However, a rectosigmoid polyp was positive for mucosal adenocarcinoma with stains consistent with metastatic prostate adenocarcinoma, not primary colon adenocarcinoma as originally thought. The tumor cells stained positive for AE1/3, PSA, PSAP, and mucicarmine, and negative for CD56, synaptophysin, chromogranin S-100, and Melan A. The case presented here highlights the importance of thoroughly evaluating masses found in the colon and the importance of specialized GI pathologists. Rectal involvement by prostatic cancer is rare and only occurs in approximately 4% of patients. Of those 4%, only 3% present as separate metastasis to the rectosigmoid, as shown in this case. Upon literature review, few accounts of metastatic spread to the colon have been published, and even rarer is the presentation of prostate cancer as a colon polyp. While rare, it is still essential to confirm the diagnosis by histopathology with appropriate immunohistochemical stains. Distinguishing between primary and metastatic tumors is essential as major surgical intervention may be avoided in favor of less invasive treatments, such as hormonal or radiological therapies.1519_A Figure 1. Rectosigmoid polyp positive for metastatic prostate adenocarcinoma.1519_B Figure 2. CT scan showing mass with central mottled contents between the bladder and sigmoid.

A Unique Diagnosis of Metastatic Prostate Adenocarcinoma

Prostate adenocarcinoma is the most common non-skin cancer that affects men in the United States. Although its prevalence is high with 1/6 men being diagnosed with prostate cancer in their lives, the prognosis is often promising with only 1/36 men dying from prostate cancer. The prognosis of this cancer, like many, is based on the presence or absence of metastases. Gastroenterologists rarely encounter this malignancy as the primary is located in a genitourinary organ and the most common sites of metastasis are bone and lung, as well as local lymph nodes. However, there are rare cases when new or recurrent diagnoses of metastatic prostate cancer can be established via fine needle aspiration (FNA) of abnormal mediastinal lymph nodes under endoscopic ultrasound (EUS). An 80 year old man had a previous history of prostate adenocarcinoma that had been treated with radiation and adjuvant androgen deprivation therapy. About 18 months after completing treatment, steadily uptrending prostate serum antigen values prompted a PET scan. This showed increased uptake in multiple retroperitoneal lymph nodes, prompting a concern for metastasis. In addition, there were multiple mediastinal lymph nodes with increased uptake. Given the rare occurrence of mediastinal lymph node metastases in prostate malignancy, there was significant concern for a second malignancy. The patient underwent EUS to further evaluate (see image 1) and an FNA showed pathology consistent with prostate adenocarcinoma (see images 2 and 3). EUS FNA is a commonly used modality for concerning lymph nodes or masses noted on PET scans or other types of imaging. Similarly, prostate cancer is a common diagnosis, especially in elderly men. However, EUS FNA is very rarely used to confirm a diagnosis of metastatic prostate cancer. This case is unique because it highlights the potential for prostate adenocarcinoma to metastasize outside of its common sites of bone, lung, liver and retroperitoneal lymph nodes. It also illustrates the associated utility of EUS FNA. Case reports have described this method of diagnosis in only a select few cases. It is far more common for lymph node involvement above the diaphragm to be associated with lung, esophageal or head/neck cancers. Recognizing and sampling concerning mediastinal lymph nodes is vital to ensure that the correct primary malignancy is identified and appropriate chemotherapy or radiation regiments can be determined.2140_A Figure 1. EUS image showing an enlarged mediastinal lymph node (circled in red) prior to FNA.2140_B Figure 2. Papanicolaou stain showing a cohesive cluster of pleomorphic malignant cells (x200)2140_C Figure 3. Prostate specific antigen (PSA) immunohistochemical stain showing positive staining in the malignant cells, consistent with metastatic prostate adenocarcinoma (x200).

The U Shape of Prostate-specific Antigen and Prostate Cancer-specific Mortality in High-grade Metastatic Prostate Adenocarcinoma

BackgroundAccumulated evidence suggests that metastatic prostate cancer (mPCa) with a low prostate-specific antigen (PSA) level may be a unique entity. However, its clinical features and prognosis have not been fully evaluated. ObjectiveTo investigate the clinical features of low-PSA mPCa and the impact of low PSA level on overall survival (OS) and PCa-specific mortality (PCSM) of mPCa. Design, setting, and participantsA total of 8479 mPCa patients were retrieved from the Surveillance, Epidemiology, and End Results program (2010–2015). The median follow-up was 18 mo. Outcome measurements and statistical analysisCox regression and Fine-Gray competing risk were used to calculate the hazard ratio (HR) and subdistribution hazard ratio (sHR) for OS and PCSM, respectively. Results and limitationsA higher rate of T4 stage disease (19.8%) and visceral metastasis (18.2%) and the shortest median OS (34 mo) were observed in mPCa patients with Gleason 8–10 and PSA ≤4ng/ml. In the Cox regression model, PSA ≤4ng/ml was a significant predictor of OS for Gleason 8–10 disease. The distribution of PCSM by PSA was U-shaped for Gleason score 8–10 (PSA 4.1–10ng/ml as the referent), with an adjusted sHR of 1.52 for PSA ≤4.0ng/ml (95% confidence interval: 1.17–1.96) versus 0.99 for PSA 10.1–20ng/ml and 1.35 for PSA >20ng/ml. In contrast, the distribution of PCSM by PSA was linear for Gleason 5–7. Sensitivity analyses showed similar results in Gleason 9–10 and Gleason 10 subgroup. The study is limited by its retrospective design. ConclusionsLow PSA, high-grade mPCa has a higher proportion of T4 stage disease, visceral metastasis, and PCSM. Patient summaryWe found that 2.8% of high-grade metastatic prostate cancer has a prostate-specific antigen level ≤4ng/ml at diagnosis. This population has aggressive clinical features and a poor cancer-specific outcome. Our results highlighted this under-reported population, and the management of these patients warrants further research.

Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient-derived xenograft (PDX) models.

While it has been challenging to establish prostate cancer patient-derived xenografts (PDXs), with a take rate of 10-40% and long latency time, multiple groups throughout the world have developed methods for the successful establishment of serially transplantable human prostate cancer PDXs using a variety of immune deficient mice. In 2014, the Movember Foundation launched a Global Action Plan 1 (GAP1) project to support an international collaborative prostate cancer PDX program involving eleven groups. Between these Movember consortium members, a total of 98 authenticated human prostate cancer PDXs were available for characterization. Eighty three of these were derived directly from patient material, and 15 were derived as variants of patient-derived material via serial passage in androgen deprived hosts. A major goal of the Movember GAP1 PDX project was to provide the prostate cancer research community with a summary of both the basic characteristics of the 98 available authenticated serially transplantable human prostate cancer PDX models and the appropriate contact information for collaborations. Herein, we report a summary of these PDX models. PDX models were established in immunocompromised mice via subcutaneous or subrenal-capsule implantation. Dual-label species (ie, human vs mouse) specific centromere and telomere Fluorescence In Situ Hybridization (FISH) and immuno-histochemical (IHC) staining of tissue microarrays (TMAs) containing replicates of the PDX models were used for characterization of expression of a number of phenotypic markers important for prostate cancer including AR (assessed by IHC and FISH), Ki67, vimentin, RB1, P-Akt, chromogranin A (CgA), p53, ERG, PTEN, PSMA, and epithelial cytokeratins. Within this series of PDX models, the full spectrum of clinical disease stages is represented, including androgen-sensitive and castration-resistant primary and metastatic prostate adenocarcinomas as well as prostate carcinomas with neuroendocrine differentiation. The annotated clinical characteristics of these PDXs were correlated with their marker expression profile. Our results demonstrate the clinical relevance of this series of PDXs as a platform for both basic science studies and therapeutic discovery/drug development. The present report provides the prostate cancer community with a summary of the basic characteristics and a contact information for collaborations using these models.