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[Objective] Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., [Design and Methods] Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., [Results] Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., [Conclusions] We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.

[Background] Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy., [Methods] In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693., [Findings] 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71)., [Interpretation] This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Reprogrammed metabolism encompasses the capacity of cells to respond or adapt their metabolic signalling to support and enable cell survival in unfavourable or hostile conditions. This ability is enhanced in cancer cells to improve their adaptive phenotype and maintain both viability and uncontrolled proliferation. Metabolic flexibility is therefore one of the key hallmarks of cancer, although pathways involved in the metabolic plasticity of each cancer type remain to be elucidated. Metabolites are the final products of this adaptation, reflecting the aberrant changes in the genomic, transcriptomic and proteomic variability of tumors, and therefore provide useful biological and clinical information on cancer biology. This, together with the fact that metabolomics can be easily performed in readily accessible biological samples (i.e. plasma, urine), makes metabolic profiling of cancer patients a promising tool to characterize the tumor phenotype and identify novel biomarkers of potential clinical use...

Reprogrammed metabolism encompasses the capacity of cells to respond or adapt their metabolic signalling to support and enable cell survival in unfavourable or hostile conditions. This ability is enhanced in cancer cells to improve their adaptive phenotype and maintain both viability and uncontrolled proliferation. Metabolic flexibility is therefore one of the key hallmarks of cancer, although pathways involved in the metabolic plasticity of each cancer type remain to be elucidated. Metabolites are the final products of this adaptation, reflecting the aberrant changes in the genomic, transcriptomic and proteomic variability of tumors, and therefore provide useful biological and clinical information on cancer biology. This, together with the fact that metabolomics can be easily performed in readily accessible biological samples (i.e. plasma, urine), makes metabolic profiling of cancer patients a promising tool to characterize the tumor phenotype and identify novel biomarkers of potential clinical use..., La reprogramación del metabolismo permite a las células para responder o adaptar su regulación metabólica para permitir la supervivencia celular en condiciones desfavorables u hostiles. Esta capacidad aumenta en las células cancerosas para mejorar su fenotipo adaptativo y mantener tanto la viabilidad como la proliferación incontrolada. Así, la flexibilidad metabólica es una de las características distintivas del cáncer, aunque todavía quedan por dilucidar las vías implicadas en la plasticidad metabólica de cada tipo de tumor. Los metabolitos son los productos finales de esta adaptación, que en último término reflejan los cambios aberrantes que sufren los tumores reflejando la variabilidad genómica, transcriptómica y proteómica de los mismos y, por lo tanto, proporcionando información relevante sobre la biología del cáncer. Además, el estudio de los perfiles de metabolitos (metabolómica) puede realizarse fácilmente en muestras biológicas de fácil acceso (plasma, orina), constituyendo así una herramienta prometedora para caracterizar el fenotipo tumoral e identificar nuevos biomarcadores de potencial utilidad clínica...

[Introduction] Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs., [Methods] We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs., [Results] The dataset contained 535 patients with a median age of 62 years (range: 26–89). The median Ki-67% was 4 (range: 0–20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1–32.0) for octreotide versus 30.1 months (95% CI: 23.1–38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71–1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively., [Conclusion] Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients., Fac. de Medicina, TRUE, pub

This work was partially funded by Pfizer, Project G1808 from the Spanish National Taskforce on Neuroendocrine Tumors (GETNE), Ministry of Science, Innovation and Universities of Spain (MICINN) and FEDER funding (Ref. RTI2018-095166-B-I00) and Autonomous Community of Madrid (NOVELREN-CM. Ref: B2017/BMD3751). B.S. is funded by AECC (POSTDO46SOLD, Spain). A.L.-L. thanks CEU-International Doctoral School (CEINDO) for her fellowship. A.L.-P. is funded by CAM (PEJD-2019-PRE/BMD-17058, Progama de Empleo Juvenil (YEI), co-funded by European Union (ERDF/ESF, “Investing in your future”). C.C.-P. was partially funded by CAM (PEJD-2016-PRE/BMD-2666). B.R.-C. was partially funded by CAM (PEJD-2017-PRE/BMD-4981). ALS is funded by Instituto de Salud Carlos III (Contrato Rio Hortega). M.R.-M. is funded by AECC (CLSEN19003RIES)., Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research., Unión Europea, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE), Asociación Española Contra el Cáncer (AECC), Instituto de Salud Carlos III, Pfizer, Depto. de Medicina, Fac. de Medicina, TRUE, pub

Squamous cell carcinoma is the most frequent histologic type of anal carcinoma. The standard of care since the 1970s has been a combination of 5-fluorouracil, mitomycin C, and radiotherapy. This treatment is very effective in T1/T2 tumors (achieving complete regression in 80-90% of tumors). However, in T3/T4 tumors, the 3-year relapse free survival rate is only 50%. The VITAL trial aimed to assess the efficacy and safety of panitumumab in combination with this standard treatment. In this study, 27 paraffin-embedded samples from the VITAL trial and 18 samples from patients from daily clinical practice were analyzed by whole-exome sequencing and the influence of the presence of genetic variants in the response to panitumumab was studied. Having a moderate- or high-impact genetic variant in PIK3CA seemed to be related to the response to panitumumab. Furthermore, copy number variants in FGFR3, GRB2 and JAK1 were also related to the response to panitumumab. These genetic alterations have also been studied in the cohort of patients from daily clinical practice (not treated with panitumumab) and they did not have a predictive value. Therefore, in this study, a collection of genetic alterations related to the response with panitumumab was described. These results could be useful for patient stratification in new anti-EGFR clinical trials

Las neoplasias neuroendocrinas (NNEs) son una familia de tumores de una gran heterogeneidad biológica. Globalmente son neoplasias con un índice mutacional bajo y no se han identificado mutaciones genéticas conductoras o driver sobre las que se pueda actuar desde el punto de vista terapéutico. Sin embargo, los mecanismos epigenéticos juegan un papel determinante en la biología e historia natural de estos tumores. La expresión de los miRNAs está desregulada en cáncer a través de distintos mecanismos, incluidos la amplificación o delección de los genes que los codifican, alteraciones en la regulación de su transcripción, modificaciones epigenéticas y alteraciones en la maquinaria de su biogénesis, y pueden funcionar como oncogenes o como genes supresores de tumores dependiendo de los genes diana sobre los que actúen. Múltiples estudios han demostrado su utilidad como biomarcadores diagnósticos, pronósticos y terapéuticos en otras neoplasias, pero la evidencia en NNEs es escasa. La hipótesis que fundamenta este trabajo es que las NNEs presentan un perfil de expresión de miRNAs característico y que la identificación de estos miRNAs desregulados puede tener una utilidad clínica diagnóstica, pronóstica, y potencialmente terapéutica. En base a ello, el objetivo global fue caracterizar el perfil de expresión de miRNAs en NNEs de origen GEP y pulmonar, y evaluar su utilidad como potenciales biomarcadores en la clínica. Con este fin hemos analizado retrospectivamente en una cohorte de 128 pacientes con NNEs la expresión de un panel de 84 miRNAs relacionados con cáncer mediante PCR-arrays en muestras pareadas tumorales y no tumorales, con los siguientes objetivos específicos: 1) identificar el perfil de expresión diferencial de miRNAs en tejido tumoral respecto al tejido sano; 2) identificar el perfil de expresión de miRNAs en función de distintas variables clínicas y patológicas de interés, 3) evaluar su valor pronóstico añadido respecto a las variables pronósticas clínicas ya, Neuroendocrine neoplasms (NENs) are a family of tumors of great biological heterogeneity. Overall, they are neoplasms with a low mutational burden and no driver mutations have been identified that may be adequate targets for therapy. However, epigenetic mechanisms play a determining role in the biology and natural history of these tumors. The expression of miRNAs is deregulated in cancer through different mechanisms, including the amplification or deletion of the genes that encode them, alterations in the regulation of their transcription, epigenetic modifications and alterations in the machinery of their biogenesis. MiRNAs may function as oncogenes or as tumor suppressor genes depending on the target genes they regulate. Multiple studies have demonstrated their utility as diagnostic, prognostic, and therapeutic biomarkers in other malignancies, but the evidence in NENs is scarce. The hypothesis underlying this work is that NENs present a characteristic miRNA expression profile and that the identification of these deregulated miRNAs can be of potential diagnostic, prognostic or therapeutic utility. Based on this, the overall objective of this study was to characterize the expression profile of miRNAs in NENs of gastroentero-pancreatic (GEP) and pulmonary origin, and to evaluate their utility as potential biomarkers in the clinic. To this end, we have retrospectively analyzed in a cohort of 128 NENs patients the expression of a panel of 84 cancer-related miRNAs using PCR-arrays in paired tumor and non-tumor samples, with the following specific objectives: 1) to identify the differential miRNAs expression profile in tumor versus non-tumor tissue; 2) to identify the differential miRNA expression profile based on different clinical and pathological variables of interest, 3) to evaluate their added prognostic value with respect to the already known clinical prognostic variables, and 4) to explore the genes regulated by these miRNAs in order to identify the molecular path

[Background] Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs)., [Methods] Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1., [Results] From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6–18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations., [Conclusion] SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062), [Implications for Practice] Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.