Biomarkers and receptor expression in neuroendocrine tumours

Neuroendocrine tumours (NETs) are uncommon tumours which have a diverse biology. The aims of this thesis were to identify potential new biomarkers and further develop understanding of tumour biology in NETs. The following were assessed i) somatostatin receptor (SSTR) and dopamine-2 receptor (D2R) expression in NETs, ii)HER expression and their associated prognosis, iii) Angiopoietin expression in NETs and their prognostic significance, iv) proteomic analysis of serum and NET cell lines to identify novel markers and finally v) the role of 68Ga-DOTATATE PET in imaging of NETs. Immunohistochemical studies were performed to determine whether SSTR and D2R are co-expressed in NETs. D2R was co-expressed with SSTR-2 and -5 in 93% of low grade tumours, with lower co-expression in higher grade tumours. HER family of receptors are involved in oncogenesis; the expressions of these receptors were assessed. Immunohistochemical analysis of these receptors was performed in 82 cases. EGFR was expressed in 86%, HER-2 0%, HER-3 8.5% and HER-4 91.5%. The expression of EGFR was not associated with poor prognosis. Angiopoietins (Ang) are involved in tumourogenesis. Serum Ang-1 and Ang-2 were measured in patients and healthy controls. Ang-2 was significantly higher in patients compared to controls. Patients with Ang-2 levels >4756pg/ml had a shorter time to progression. Proteomic analysis using gel electrophoresis and LC/MS/MS of plasma from NET patients and established NET cell lines was performed to identify biomarkers. Proteomic cell line analysis identified 17 proteins in all cell lines including Mac-2 binding protein. We validated Mac-2 binding protein and it appears to be a potential marker for NETs. Finally, we performed a study to ascertain whether 68Ga-DOTATATE PET identifies more lesions in NET patients in whom 111In-DTPA-Octreotide showed faint/negative lesion uptake. 111In-DTPA-Octreotide scintigraphy identified 27 lesions compared to 168 lesions identified with Ga-68-DOTATATE PET. 68Ga-DOTATATE PET is a sensitive imaging modality for identifying NETs

A Multimodal Approach to the Management of Neuroendocrine Tumour Liver Metastases

Neuroendocrine tumours (NETs) are often indolent malignancies that commonly present with metastatic disease in the liver. Surgical, locoregional, and systemic treatment modalities are reviewed. A multidisciplinary approach to patient care is suggested to ensure all therapeutic options explored

The role of serotonin inhibition within the treatment of carcinoid syndrome

Carcinoid syndrome is the most frequent hormonal complication associated with neuroendocrine neoplasms. It was first reported in 1954, and the classical symptoms are diarrhoea, flushing and abdominal pain. It is caused by the secr etion of several vasoactive substances, the most prominent being serotonin, which play a pathophysiological role in the clinical symptoms which characterise carcinoid syndrome. Therefore, the focus of carcinoid syndrome treatment is to reduce serotonin production and hence improve the patient’s quality of life. There are a variety of managemen t options for carcinoid syndrome including medical, surgical and loco-regional interventional radiological procedures. The most widely used are somatostatin analogues with three clinically approved drugs: lanreotide and octreotide (first-generation) and pasireotide (second-generation). Both everolimus and interferon used in combination with octreotide have shown significant reduction in urinary 5-hydroxyindoleacetic acid compared to octreotide alone. Telotristat ethyl has been increasingly utilised for patients with symptoms despite taking somatostatin analogues. It has also been shown to have a significant improvement in bowel movement frequency which was associated with a significant improvement in quality of life. Peptide receptor radionuclide therapy has proven symptomatic improvement in patients with uncontrolled symptoms. Chemotherapy is primarily reserved for patients with high proliferation tumours, with limited research on the efficacy in reducing symptoms. Surgical resection remains the optimal treatment due to being the only one that can achieve a cure. Liver-directed t herapies are considered in patients where curative resection is not possible. There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome

Liver cirrhosis in England--an observational study: are we measuring its burden occurrence correctly?

Objectives: Mortality due to liver disease (of which cirrhosis is the end‐stage) is increasing more than any other chronic condition in the UK. This study aims to demonstrate that (i) exclusive reliance on mortality rates may not reveal the true burden of liver cirrhosis, and (ii) diverse use of diagnostic coding may produce misleading estimates. Design: Observational study Setting: The Office for National Statistics death registry was interrogated to investigate liver cirrhosis mortality trends in England and Wales, from 1968 to 2011. Main outcome: Standardised mortality trends according to three different definitions of liver cirrhosis based on the specificity of diagnostic codes were calculated: 1(chronic liver diseases), 2 (alcoholic and unspecified cirrhosis only) and 3 (cirrhosis as end‐stage liver disease). The mortality trends were compared to incidence rates established in a previous population‐based study (based on definition 3), from 1998 to 2009, to investigate discrepancies between these two measures. Results: Over the study period, the overall standardised liver cirrhosis mortality rates were 8·8, 5∙1 and 5∙4 per 100,000 person‐years for definitions 1, 2 and 3 of respectively. The mortality rates for definition 3 in 1998 and 2009 were 6∙2 and 5∙9 per 100,000 person‐years respectively; whilst the equivalent incidence rates were at least three‐ and six‐fold higher: 23∙4 and 35∙9 per 100,000 person-years respectively. This discrepancy between incidence and mortality rates was also at least three‐fold in men and women separately, and across age‐groups. Conclusion: Mortality rates underestimated the incidence of liver cirrhosis by at least three‐fold between 1998 and 2009 and varied with differing definitions of disease. Mortality data should not be used exclusively as an indicator for the occurrence of liver cirrhosis in the population. Routinely collected healthcare data are available to measure occurrence of this disease. Careful consideration should be taken when selecting diagnostic codes for cirrhosis

Sex Differences in Survival from Neuroendocrine Neoplasia in England 2012–2018:A Retrospective, Population-Based Study

Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England’s National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73–5.90) to 10.26 (6.6–14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p &lt; 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor.</p

Evaluating cost-effectiveness in the management of neuroendocrine neoplasms

The rapid evolution of novel, costly therapies for neuroendocrine neoplasia (NEN) warrants formal high-quality cost-effectiveness evaluation. Costs of individual investigations and therapies are high; and examples are presented. We aimed to review the last ten years of standalone health economic evaluations in NEN. Comparing to published standards, EMBASE, Cochrane library, Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database and the Health Technology Assessment (HTA) Database were searched for health economic evaluations (HEEs) in NEN published between 2010 and October 2019. Of 12 economic evaluations, 11 considered exclusively pharmacological treatment (3 studies of SSAs, 7 studies of sunitinib, everolimus and/or 177Lu-DOTATATE and 1 study of telotristat ethyl) and 1 compared surgery with intraarterial therapy. 7 studies of pharmacological treatment had placebo or best supportive care as the only comparator. There remains a paucity of economic evaluations in NEN with the majority industry funded. Most HEEs reviewed did not meet published health economic criteria used to assess quality. Lack of cost data collected from patient populations remains a significant factor in HEEs where clinical expert opinion is still often substituted. Further research utilizing high-quality effectiveness data and rigorous applied health economic analysis is needed

1331ptumour growth rate tgr when using lanreotide autogel lan before during and after peptide receptor radionuclide therapy prrt in advanced neuroendocrine tumours nets

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Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Elevated Peripheral Blood Plasma Concentrations of Tie-2 and Angiopoietin 2 in Patients with Neuroendocrine Tumors

Background: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. Methods: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. Results: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. Conclusions: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges–Lehmann estimators of median treatment differences from placebo of −54.0% (95% confidence limits, −85.0%, −25.1%, P < 0.001) and −89.7% (95% confidence limits, −113.1%, −63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659)