Metabolomic profile of neuroendocrine tumors identifies methionine, porphyrin, and tryptophan metabolisms as key dysregulated pathways associated with patient survival.

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.

MicroRNA signature and integrative omics analyses define prognostic clusters and key pathways driving prognosis in patients with neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are mutationally quiet (low number of mutations/Mb), and epigenetic mechanisms drive their development and progression. We aimed at comprehensively characterising the microRNA (miRNA) profile of NENs, and exploring downstream targets and their epigenetic modulation. In total, 84 cancer-related miRNAs were analysed in 85 NEN samples from lung and gastroenteropancreatic (GEP) origin, and their prognostic value was evaluated by univariate and multivariate models. Transcriptomics (N = 63) and methylomics (N = 30) were performed to predict miRNA target genes, signalling pathways and regulatory CpG sites. Findings were validated in The Cancer Genome Atlas cohorts and in NEN cell lines. We identified a signature of eight miRNAs that stratified patients in three prognostic groups (5-year survival of 80%, 66% and 36%). Expression of the eight-miRNA gene signature correlated with 71 target genes involved in PI3K-Akt and TNFα-NF-kB signalling. Of these, 28 were associated with survival and validated in silico and in vitro. Finally, we identified five CpG sites involved in the epigenetic regulation of these eight miRNAs. In brief, we identified an 8-miRNA signature able to predict survival of patients with GEP and lung NENs, and identified genes and regulatory mechanisms driving prognosis in NEN patients.

Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer: Lessons Learned and Future Perspectives.

OPINION STATEMENT: Colorectal cancer (CRC) is a major public health problem and the 2nd leading-cause of cancer-related death worldwide. Around 30% of patients present with metastatic disease and 50% of those with early disease will eventually relapse. The metastatic spread occurs mainly to the liver, which is the exclusive site in 30-40% of the cases. Surgery is the main curative option for liver recurrence, but only one out of five patients are eligible for resection. Moreover, even if surgery is feasible, recurrence rate is high, occurring in up to 75% of patients. Therefore, additional treatment to improve these disappointing outcomes has been sought. Adjuvant and perioperative chemotherapy aim to eradicate early micrometastatic disease, decreasing recurrence rates, and improving survival outcomes. Different chemotherapy regimens, mainly extrapolated from the adjuvant experience, have showed conflicting results, with improvements in disease free but not in overall survival. The addition of targeted therapies to chemotherapy has improved response rates and resectability when administered preoperatively, but did not have an impact on survival in the adjuvant setting. There is a need to critically synthetize the available evidence on perioperative and conversion therapy from the past years, and appraise areas of current research and potential future directions.

Diagnosis in Neuroendocrine Neoplasms: From Molecular Biology to Molecular Imaging.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel imaging techniques leads to an accurate diagnosis and a better treatment approach. To determine the functionality of the tumour, somatostatin receptor expression, differentiation, and primary tumour origin are the main determining tumour-dependent factors to guide treatment, both in local and metastatic stages. Until recently, little was known about the biological behaviour of these tumours. However, in recent years, many advances have been achieved in the molecular characterization and diagnosis of NENs. The incorporation of novel radiotracer-based imaging techniques, such as 68Gallium-DOTATATE PET-CT, has significantly increased diagnostic sensitivity, while introducing the theragnosis concept, offering new treatment strategies. Here, we will review current knowledge and novelties in the diagnosis of NENs, including molecular biology, pathology, and new radiotracers.

Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance.

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.

Chemotherapy in NEN: still has a role?

Neuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behavior. Primary tumor site, extent of disease, tumor differentiation and expression of so matostatin receptors, proliferation and growth rates are the major prognostic factors that determine the therapeutic strategy. Treatment options for advanced disease have considerably expanded in recent years, particularly for well differentiated tumors (NETs). Novel drugs approved over the past decade in this context include somatostatin analogues and 177Lu-oxodotreotide for somatostatin-receptor-positive gastroenteropancreatic (GEP) NETs, sunitinib for pancreatic NETs (P-NETs), and everolimus for P-NETs and non-functioning lung or gastrointestinal NETs. Nevertheless, chemotherapy remains an essential component of the treatment armamentarium of patients with NENs, particularly of patients with P-NETs or those with bulky, symptomatic or rapidly progressive tumors (generally G3 or high-G2 NENs). In this manuscript we will comprehensively review available evidence related to the use of chemotherapy in lung and GEP NENs and will critically discuss its role in the treatment algorithm of this family of neoplasms.

Targeted Cancer Therapy: What's New in the Field of Neuroendocrine Neoplasms?

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.

Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials.

Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel-Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59-2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71-0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3-4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.