High gastrin levels may help to explain the association between several conditions and osteoporosis, such as pernicious anemia, the use of proton pump inhibitors, and atrophic gastritis. This study aimed to determine whether administering a gastrin receptor antagonist (GRA) to older women would lower their bone turnover markers (BTM) and, therefore, be a suitable preventive measure for osteoporosis. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy, safety, and tolerability of an oral GRA (netazepide) 100 mg administered daily for 90 d in postmenopausal women. Our primary endpoint was the change in the BTM plasma CTX (automated immunoassay analyzer) at days 0, 7, 28, 56, and 90. We also measured other BTMs, and gastrin and group I pepsinogens (ELISA assays). We studied the effect of the drug on the log-transformed baseline scaled ratio for BTM and gastric markers using mixed-model ANOVA for the fixed effects of treatment, time, and the treatment-by-time interaction, with the baseline value included as a covariate. We studied 99 women, with a mean age of 60 yr and bone mineral density (BMD) T-scores for the spine and total hip (TH) of −0.96 and −0.09, respectively. We found that gastrin increased by 90% in response to GRA as early as 7 d (p-value for treatment: .0008), and group I pepsinogens decreased by 15% as early as 7 d (p-value: .0002). There was no significant change in plasma CTX. A high percentage of women (81/99) completed the study, and the GRA was well tolerated. Gastrin receptor antagonist had the expected effects on the gastric markers with an increase in gastrin and a decrease in group I pepsinogens. However, the absence of any change in the bone resorption marker plasma CTX was a bit surprising. Based on this study, it appears that short-term gastrin receptor antagonism is unlikely to be a successful strategy in the prevention of osteoporosis. However, this is a preliminary exploration of a novel hypothesis and larger studies might be needed.

Objective:To describe the evolution of management strategies for neuroendocrine liver metastases (NE LM) and trends in patient outcomes over the preceding 3 decades.Background:Liver metastases are common in neuroendocrine neoplasms and impair prognosis. A broad therapeutic armamentarium has evolved over recent decades, but there remains uncertainty regarding optimal treatment selection and sequencing.Methods:Retrospective cohort study pooling data from 4 specialist centers of excellence in the United Kingdom and Germany for individuals diagnosed with neuroendocrine liver metastases between January 1, 1990, and December 31, 2020. We explored trends in theranostic strategies over 3 decades and quantified overall survival (cohort, and by decade-defined temporal periods).Results:We identified 551 individuals with NE LM with a median age at diagnosis of 59.1 years; 453 (82.2%) had synchronous metastases, and 402 (73.0%) underwent multimodal therapy. In all centers, somatostatin receptor-based PET/CT and MRI were the preferred imaging techniques. There were significant trends in the use of somatostatin analogs and peptide receptor radionuclide therapy, but the number of surgical resections remained stable. Overall survival (OS) at 5 and 10 years was 77.5% and 58.1%, respectively. Across the 3 time periods, 5-year OS significantly improved-period I: 45.2%, period II: 66.0%, and period III: 75.7%. Ten-year OS showed overlapping confidence intervals for period I (23.5%) and period II (18.3%) but doubled in period III (55.5%). On multivariable analysis, the use of multimodal therapy strategies was significantly associated with improved overall survival (HR=0.59, 95% CI: 0.40-0.88, P=0.009).Conclusions:Improved imaging modalities and modifications in specific therapies as components of multimodal treatment concepts are concordant with significantly improved survival outcomes in NELM over 30 years. The use of multimodal therapy improved overall survival in patients with NE LM. Future studies should determine optimal treatment selection and sequencing and the role of novel biomarkers to guide these.

Following the Food and Drug Administration's approval of Lutathera and Pluvicto in 2018 and 2022, respectively, we predicted that 120,000 and 30,000 radiopharmaceutical therapy (RPT) cycles would soon be administered annually in the United States to treat prostate cancer (PC) and neuroendocrine

Gastric cancer is still a prevalent and lethal cancer. Gastric hypoacidity and gastritis have long been recognized in the pathogenesis. The identification of Helicobacter(H.) pylori as the main cause of gastritis leading to peptic ulcer disease and gastric cancer was a breakthrough. H. pylori was the first bacterium accepted as a carcinogen. The mechanism was not found before H. pylori was shown to predispose to cancer only after having induced oxyntic atrophy incriminating reduced killing of microorganisms and/or secondary hypergastrinemia. H. pylori has an uncertain carcinogenic role in cardia cancer, making microbes more unlikely. Gastrin has a trophic effect on the oxyntic mucosa, particularly on the enterochromaffin like cell carrying the gastrin receptor. Every condition with long-term hypergastrinemia in whatever species predisposes to gastric neoplasia. All observations on gastric neoplasia connected to H. pylori gastritis (the protective effect of duodenal ulcer, increased risk with oxyntic atrophy and preserved risk after loss of H. pylori in complete oxyntic atrophy) may be explained by gastrin. The role of gastrin in gastric carcinogenesis is also reflected by autoimmune gastritis and profound long-term gastric acid inhibition.

TPS4225 Background: Gastro-entero-pancreatic (GEP) neuroendocrine tumours (NET) are steadily increasing in incidence and prevalence. About 65%-95% of GEP NET show hepatic metastases. Surgery is the mainstay of treatment for NE LM. While macroscopically complete resection for NE LM is associated with favourable overall survival (OS), recurrence rates of up to 70% at 3 years and up to 95% at 5 years are reported. These results call for adjuvant treatment concepts which have not yet been established. Methods: A prospective open-label, multicentre randomised parallel-group trial was conducted in patients with resected GEP NE LM. Adjuvant treatment with 177 Lu-DOTA 0 -Ty 3 -ocreotate ( 177 Lu-DOTATATE) (total administered activity 14.8 GBq) is compared with standard of care (SOC). The frequency of administration is 2 cycles (8±1weeks between each cycle). The first cycle is applied 8±2 weeks after liver resection. The control arm consists of SOC. Main inclusion criteria are well differentiated grade 1 or grade 2 (Ki67 < 20%) GEP NET, R0 or R1 resection of NE LM, primary tumour already resected or resected synchronously with LM, 68 Ga DOTATATE PET/CT prior to surgery confirming LM and no extrahepatic disease (except resectable perihilar lymph node involvement and/or primary tumour, if still in place). Main exclusion criteria are high grade NET, neuroendocrine carcinoma, R2 resection of LM, peptide receptor radionuclide therapy at any time prior to randomisation in the study, and any type of liver directed therapy within 12 weeks prior to randomisation in the study. Primary endpoint are disease-free survival (DFS) at 3 years after liver resection. The sample size of 106 patients in total is powered to detect an HR of 0.27, reflecting a 44% DFS probability at 3 years post-surgery in the 177 Lu-DOTATATE arm compared with a 25% in the SOC arm. Secondary endpoints OS, time to tumour recurrence, time to administration of subsequent antineoplastic therapy, safety and tolerability of 177 Lu-DOTATATE, health-related quality of life, patient reported outcomes, and cost effectiveness. Ancillary objectives explore the clinical utility of novel molecular based biomarkers in identification of residual microscopic disease and early detection of recurrent disease. Enrolment has begun. Follow-up data will be collected for 5 years overall from the date of randomisation of the last patient. Discussion: The NELMAS trial aims to investigate the efficacy of adjuvant therapy with 177 Lu-DOTATATE (2 cycles) compared to standard of care in preventing tumour recurrence in patients following R0/R1 resection of LM of well differentiated GEP NET. Clinical trial information: NCT05987176 .

INTRODUCTION:We describe the development of a molecular assay from publicly available tumor tissue mRNA databases using machine learning and present preliminary evidence of functionality as a diagnostic and monitoring tool for prostate cancer (PCa) in whole blood. MATERIALS AND METHODS:We assessed 1055 PCas (public microarray data sets) to identify putative mRNA biomarkers. Specificity was confirmed against 32 different solid and hematological cancers from The Cancer Genome Atlas (n = 10,990). This defined a 27-gene panel which was validated by qPCR in 50 histologically confirmed PCa surgical specimens and matched blood. An ensemble classifier (Random Forest, Support Vector Machines, XGBoost) was trained in age-matched PCas (n = 294), and in 72 controls and 64 BPH. Classifier performance was validated in two independent sets (n = 263 PCas; n = 99 controls). We assessed the panel as a postoperative disease monitor in a radical prostatectomy cohort (RPC: n = 47). RESULTS:A PCa-specific 27-gene panel was identified. Matched blood and tumor gene expression levels were concordant (r = 0.72, p < 0.0001). The ensemble classifier ("PROSTest") was scaled 0%-100% and the industry-standard operating point of ≥50% used to define a PCa. Using this, the PROSTest exhibited an 85% sensitivity and 95% specificity for PCa versus controls. In two independent sets, the metrics were 92%-95% sensitivity and 100% specificity. In the RPCs (n = 47), PROSTest scores decreased from 72% ± 7% to 33% ± 16% (p < 0.0001, Mann-Whitney test). PROSTest was 26% ± 8% in 37 with normal postoperative PSA levels (<0.1 ng/mL). In 10 with elevated postoperative PSA, PROSTest was 60% ± 4%. CONCLUSION:A 27-gene whole blood signature for PCa is concordant with tissue mRNA levels. Measuring blood expression provides a minimally invasive genomic tool that may facilitate prostate cancer management.

OBJECTIVE:To describe the evolution of management strategies for neuroendocrine liver metastases (NE LM) and trends in patient outcomes over the preceding 3 decades. BACKGROUND:Liver metastases are common in neuroendocrine neoplasms and impair prognosis. A broad therapeutic armamentarium has evolved over recent decades, but there remains uncertainty regarding optimal treatment selection and sequencing. METHODS:Retrospective cohort study pooling data from 4 specialist centers of excellence in the United Kingdom and Germany for individuals diagnosed with neuroendocrine liver metastases between January 1, 1990, and December 31, 2020. We explored trends in theranostic strategies over 3 decades and quantified overall survival (cohort, and by decade-defined temporal periods). RESULTS:We identified 551 individuals with NE LM with a median age at diagnosis of 59.1 years; 453 (82.2%) had synchronous metastases, and 402 (73.0%) underwent multimodal therapy. In all centers, somatostatin receptor-based PET/CT and MRI were the preferred imaging techniques. There were significant trends in the use of somatostatin analogs and peptide receptor radionuclide therapy, but the number of surgical resections remained stable. Overall survival (OS) at 5 and 10 years was 77.5% and 58.1%, respectively. Across the 3 time periods, 5-year OS significantly improved-period I: 45.2%, period II: 66.0%, and period III: 75.7%. Ten-year OS showed overlapping confidence intervals for period I (23.5%) and period II (18.3%) but doubled in period III (55.5%). On multivariable analysis, the use of multimodal therapy strategies was significantly associated with improved overall survival (HR=0.59, 95% CI: 0.40-0.88, P =0.009). CONCLUSIONS:Improved imaging modalities and modifications in specific therapies as components of multimodal treatment concepts are concordant with significantly improved survival outcomes in NELM over 30 years. The use of multimodal therapy improved overall survival in patients with NE LM. Future studies should determine optimal treatment selection and sequencing and the role of novel biomarkers to guide these.

386 Background: A critical clinical concern after radical prostatectomy for prostate cancer (PCa) is the timely identification of residual disease. Recurrent disease (biochemical recurrence: BCR) develops in approximately 30% of radical prostatectomies within 5 years of surgery. Currently, clinicopathological variables, including pathological tumor stage (pT-stage), Gleason score and PSA, or algorithmic combinatorial calculations (e.g., CAPRA-S) are used to predict BCR. Early and objective prediction of individuals at high risk of BCR would enable stratification of follow-up strategies and facilitate therapeutic therapy. To achieve these goals, we developed a liquid biopsy, the PROSTest, to identify PCa. This is a 27 multigene algorithmic signature with a high sensitivity and specificity (>90%) for PCa detection. We investigated if the PROSTest had utility as a predictive biomarker for BCR. Methods: Prospective recruitment of 60 PCa for radical prostatectomy with assessment of standard pathological, clinical and biomarker (PSA) data. D’Amico Risk scores and CAPRA-S were calculated. Blood was collected for PROSTest measurement pre-surgery. Target genes were amplified using qPCR and scored (0-100) using algorithmic analysis. Pre-surgical PROSTest scores were evaluated as predictors of BCR and compared with standard criteria as well as DR and CAPRA-S scores. Data was evaluated using Mann-Whitney U-test, multiple regression analyses, Kaplan-Meier survival analysis and Cox-proportional modeling. All data: median (range). Results: Consent was obtained in 48 (80%) patients. Median age (range) was 64 (50-82). Gleason was predominantly 7 (85%; 26: 7A, 15: 7B); TNM was primarily T2c (48%) and T3a (32%) with nodal disease evident in 8% and 0% cM1 disease. Resections were R0 (85%) and 7 R1. The median follow-up was 42 days (range: 14-782). Early BCR occurred in 8 (17%) patients. This included 3/7 (43%) of R1 and 5/41 (12%) R0 resections. PSMA imaging confirmed 3 LN recurrences and new visceral ( n=1) and bone ( n=1) disease. D’Amico Risk scores were mostly “high” (88% with risk score ≥50%) and were not associated with early BCR. CAPRA-S scores were higher in those who developed early BCR (5: 1-9) than in those who did not (2: 0-5). Pre-surgical PROSTest scores were elevated in all (median 59: 15-81). Multiple regression analysis identified only PROSTest score ≥60 and nodal status were associated with BCR. The median Recurrence Free Survival (mRFS) was 89 days compared to undefined in those with baseline PROSTest scores ≥60 (HR: 9.7; 95%CI: 2.16-43.7; p=0.003). No recurrences were identified in those with scores <60. Conclusions: Early biochemical recurrence (within 3 months of surgery) can be accurately predicted by elevated (≥60) pre-surgical PROSTest blood gene expression scores. This suggests the marker could be used as a stratification tool for neoadjuvant therapy, or to guide the frequency of monitoring during follow-up.

183 Background: Radionuclide therapy targeting the prostate specific membrane antigen (177Lu-PSMA therapy) has proven to be an effective treatment in men with metastatic castration resistant prostate cancer (mCRPCs). Despite representing a significant therapeutic breakthrough, a critical unmet need in 177Lu-PSMA therapy, is a prognostic biomarker for treatment optimization. Imaging and standard biomarkers have limited value. The PROSTest is a new 27-gene algorithmic signature originally developed for prostate adenocarcinoma diagnosis (0 to 100, positive score ≥20). We hypothesized that PROSTest would be elevated in mCRPCs and could have utility as a biomarker for mCRPC management. Methods: Prospective enrollment of 113 mCRPC for 177Lu-PSMA therapy (KlbB-5338-0302021 study). Pathology, clinical and biomarker data were available as was PSMA-PET/CT. Blood samples were collected for PROSTest prior to therapy. Target genes were isolated and amplified using qPCR. PROSTest scores (0-100) were obtained following algorithmic analysis. Scores were correlated with mCRPC diagnosis and baseline information. Scores and standard clinical measures were evaluated as prognostic factors with survival as endpoint. Mann-Whitney U-test, Kaplan-Meier survival and Cox proportional hazards regression analysis were utilized. All data: median (IQ range). Results: 89 (79%) patients were evaluable. Age was 75 (68-80). Disease characteristics at time of diagnosis included Gleason scores 8-10 (70%) and TMM: T3-T4 tumors (67%), N1 (53%), M1 (45%). At the time of therapy all patients were metastatic and all exhibited PSMA-positive disease. The highest tumor SUVmax was 51 (28-78). PSA levels were 69ng/mL (18-305). The PROSTest score was 89 (81-92). PROSTest scores were weakly correlated with age (r=0.33, p=0.0015) but not with baseline histopathological parameters (e.g., Gleason score, TNM) or pretreatment imaging results (e.g., SUVmax). Twenty-four (27%) patients have perished. Treatment and follow-up (5 months, 3-18) are ongoing. The mOS was 15 months. No factors were associated with death as an outcome except for the PROSTest score. PROSTest scores ≥79 (based on ROC analysis) were associated with significantly increased risk for mortality (HR: 2.9, 95% CI: 1.5-7.4). The mOS was 14 months in patients with pre-therapy PROSTest scores >79 compared to mOS not reached for PROSTest scores <79 ( p=0.02). In the COX model, baseline PROSTest was confirmed to be significantly predictive of death despite therapy (β = 1.51, p=0.01). Conclusions: The PROSTest blood gene expression score is elevated in mCRPCs. Levels are not associated with baseline clinical, histopathological, pretreatment PSA or imaging parameters. Elevated expression (≥79) of this biomarker prior to treatment was associated with a lower survival and could be used to predict survival in patients undergoing 177Lu-PSMA.

252 Background: A crucial requirement in prostate cancer (PCa) management is an accurate, easily measurable, liquid biopsy that can define the molecular pathology of an individual PCa. We report the development and clinical validation of a novel PCa-specific, multi-genomic biomarker. Methods: We identified candidate mRNA biomarkers in PCa-Adeno transcriptomes ( n=1,159) using several strategies: co-expression networks, differential expression, and functional enrichment. mRNA transcripts were screened in an independent tumor tissue ( n=50) set and validated as biomarkers in the TCGA-PRAD ( n=500) dataset. An amalgam of Random Forest, Gradient Boosted Machines and Support Vector Machines, all standard machine learning classifiers, was used to develop a classification algorithm and probability score in a peripheral blood gene expression test cohort ( n=430). This multigene biomarker was validated in two independent clinical blood sample sets (Set I: PCa n=77, controls n=54; Set II: PCa n=132, controls/BPH n=99) to determine as PCa-specificity and diagnostic efficacy Clinical utility was evaluated versus Gleason scores, T-staging and PSA ( n=209) and in a prostatectomy cohort ( n=47). Results: The pipeline identified 27 of PCa gene markers in the tumor tissue set and TCGA-PRAD dataset. Gene expression was significantly correlated ( r=0.72, p<0.0001) in matched tissue/blood samples. The PROSTest (scale: 0-100) ensemble algorithm (developed in blood) had a sensitivity for PCa of 92.2% (95% CI: 83.8-97.1%; Set I) and 95.0% (95% CI: 89.9-98%. Set II). The specificity was 100% for Set I (95% CI: 93.4-100%) and 100% for Set II (95% CI: 96.3-100%). PCa scores were significantly ( p<0.0001) lower for controls (Set I: 17±4; Set II: 18±4) and BPH (19±6) to PCa; 82±19 (Set I) and 80±19 (Set II). The AUROC was 0.98±0.01. PROSTest scores were elevated ( p<0.05) in T2-4 and were significantly correlated with Gleason ( r=0.93, p<0.02). In contrast, PSA from matched samples was not associated ( p=NS) with clinically significant disease (Gleason 7-10 or T2-4 tumors). In head-to-head comparisons, the PROSTest was considerably more accurate than PSA for detecting significant disease (z-statistic: 2.43, p=0.015). In the R0 prostatectomy cohort, all scores were elevated (72±7) and significantly decreased post-surgery (26±8, p<0.0001, n=37). Individuals with residual disease ( n=10) exhibited elevated (60±4) post-surgical scores. Conclusions: The PROSTEst is a multigenomic blood-based PCR tool that accurately (>90%) identifies prostate cancer. It is significantly more accurate than PSA for the detection and stratification of clinically significant prostate disease. A multigenomic liquid biopsy for PCA provides a real-time, non-invasive method for detection of a PCa and may facilitate the early identification of residual/recurrent disease.

The birth of radionuclide therapy can properly be ascribed to Saul Hertz who initiated the experimental work that led to the development of radioiodine therapy in thyroid disease. This also paved the way for the development of novel thyroid diagnostics and ushered in new paradigms of radioisotope therapy. The latter included antigen-directed radioimmunotherapy and more recently, receptor targeted therapy (PRRT) directed at neuroendocrine tumors and more recently prostate cancer. This strategy was based upon radiation (typically 177Lutetium) coupled to peptides (either somatostatin analogs for NETs or PMSA for prostate cancer) that targeted specific receptors overexpressed by the tumor. The strategy of using isotopes both for diagnostic and therapeutic purpose has been denominated as theranostics. Although radionuclide therapies have efficacy, it has long been apparent that not all patients or tumors respond equally. Clinical features have only a limited ability to define efficacy or toxicity. Recent investigation has identified that factors intrinsic to the tumor and the host itself appear to determine the response to different treatments and the susceptibility to toxicity. The modulators of the responses to radionuclide therapy include diverse genomic regulators of biologic processes including metabolomics and the cancer determinants of proliferation, metastasis and immune response. Delineation of this diverse array of genomic regulators and their biologic pathway determinants have enabled identification of molecular biomarkers e.g., gene expression panels, that have utility as tools to determine a variety of clinical applications including patient stratification, the prediction of toxicity and the monitoring of disease. Previously such information was mostly obtained by clinical assessment or tissue analysis. The former strategy has limited application and the latter is invasive, cannot be undertaken repetitively and involves random sampling of heterogeneous tumors, thereby obviating its clinical utility. In recent times, the use of blood-based multi-genomic assessment, liquid biopsies e.g., NETest, PPQ, has provided molecular strategies effective in real-time, non-invasive evaluation of radionuclide therapy. Current investigation indicates that mapping the genomic and metabolic basis of radionuclide therapy remains a critical future objective to optimize, patient selection, predict therapeutic efficacy, assess outcome ad predict toxicity. Future refinements and advances of radionuclide therapy require the genomic delineation of the tumor and host to provide personalized therapy and optimize outcome.

The recent development of peptide receptor radionuclide therapy (PRRT) into an accepted treatment allows for consideration of the requirements to move beyond the mere concept of tumor therapy. This chapter addresses the limitations of the “huff and puff” theory of tumor destruction by critically applying the knowledge of radionuclide therapy.

In respect of carcinoid disease, one might well ask, why have we failed so miserably? In 1907, Oberndorfer described “karzinoide” and yet more than a century later, most diagnoses still reflect incurable metastatic disease. Attempts to address the biology and mechanistic basis of neuroendocrine tumors (NETs) have lacked logic, balanced oversight, or linearity. Governance appears directed to the support of countless clinical trials, often so underpowered and scientifically improbable as to seem based more on marketing premise than medicine. Much science is devoted to the development of potentially commercial applications rather than the elucidation of the mechanisms of neoplastic biology. A variety of organizations with quasi-scientific or commercial interests purport to drive research and diverse studies with no apparent focus or prioritization. Goals more often appear to seek popular acclaim and to accommodate the vogue of public debate by enthusiastic and often uninformed advocates of progress (sic) than to logically address the acquisition of information necessary to facilitate diagnosis and effect cure. Innumerable iterations of tumor nomenclature have been pondered over and discarded as if semantics might effect a cure or theological debate might inform science. Publications are often permutations and commutations of previous work and do little more than plump up personal bibliographies. Innumerable “disease observations” continue to be published, much in the mode of the reports of the early discovers of the globe-like sightings of exotic apparitions or more often, merely “me too” reflections. Treatments have been almost completely co-opted from other cancers and, in the most part, found to be wanting or misleading in their efficacy. Guidelines, eminence based and society based, continue to be presented with metronomic regularity and adopted by “followers”; more remindive of religious exhortations to the faithful endlessly in pursuit of Hippocratic grail. Some progress has been made—somatostatin receptor identification (40 years ago), sundry quasi-effective drugs, theranostics, and receptor targeting—but unfortunately, the molecular mechanistic basis of NETs remains so inadequately defined as to obviate any intervention based on a plausible hypothesis. There needs to be input from persons wise in science, clinical medicine, and strategy development to define rational steps forward to a series of defined goals rather than an interface of the marketplace and client dialog. Short-, intermediate-, and long-term goals need to be defined and developed rather than random excursions into the hinterland of an uncharted disease. Overall, what is obligatory for advance is the development and integration of novel technologies—molecular, mathematical, multianalytic, and genomic based—to provide the biological basis for elucidation of the disease and the development of personalized clinical management. The neuroendocrine community must move beyond the endless and relatively ineffective iterations of known knowledge and define new ways forward. Some work of noble note may yet be done; T’is not too late to seek a newer world, but strong in will to strive, to seek, to find (Adapted from Alfred Lord Tennyson, 1842).

Pheochromocytomas and paragangliomas (PHEOs/PGLs) represent diagnostically challenging and complex neuroendocrine tumors (NETs). Current biomarker tests for PHEOs/PGLs are technically complex or limited. We assessed the diagnostic utility of a NET-specific 51-marker gene blood assay (NETest) in patients with PHEOs/PGLs (n = 81), including ten pediatric patients, and age-/gender-matched controls (n = 142) using a prospective case:control (1:2) analysis. mRNA was measured (qPCR), and results were scaled from 0 to 100 (upper limit of normal < 20). Receiver operating curve (ROC) and non-parametric (Mann–Whitney) tests were used for analyses (two-tailed). All data are presented as mean ± s.e.m. NETest accuracy for PHEO/PGL diagnosis was 100%. PHEO/PGL scores were 70 ± 3 vs 8.5 ± 1 in controls (P < 0.0001), and ROC analysis was 0.99 ± 0.004 (P < 0.0001). Diagnostic metrics were 94% accurate, 100% sensitive, and 92% specific. Imaging correlation with 68Ga-PET-SSA was 100%. NETest levels in PHEOs (n = 26) were significantly (P < 0.0001) elevated (83 ± 4) vs 66 ± 4 in PGLs (n = 40) and mixed PHEOs/PGLs (n = 5: 37 ± 3). Adrenal-derived tumors (n = 30) exhibited higher scores (76 ± 5) than extra-adrenal-derived tumors (66 ± 4, P < 0.05). Cluster 2 tumors exhibited significantly (P = 0.034) elevated NETest levels (n = 4: 92 ± 2) vs cluster 1 tumors (n = 35: 69 ± 4). Regulatory pathway analysis identified elevated RAS-RAF, metastatic, pluripotential, neural and secretory gene cluster levels (P < 0.05) in PHEOs compared to PGLs. Cluster 2 PPGLs exhibited elevated (P = 0.046) levels of growth factor signaling genes compared to cluster 1. The PHEOs/PGLs in the pediatric cohort (n = 10) were all NETest-positive (81 ± 8) and exhibited a gene expression profile spectrum analogous to adults. Circulating NET transcript analysis identifies PHEOs/PGLs with 100% efficacy and is likely to have clinical utility in the diagnosis and management of PHEO/PGL patients.