Advances in the Treatment of Gastroenteropancreatic Neuroendocrine Carcinomas: Are we Moving Forward?

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small cell lung cancer, a far more common G3 neuroendocrine neoplasm, although emerging molecular and clinical data increasingly question this approach. In this article, we will briefly summarize epidemiology and prognosis of gastroenteropancreatic neuroendocrine carcinomas to emphasize the very low incidence, aggressive nature, and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background compared with small cell lung cancer, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors), and additional treatment strategies targeting other tumor vulnerabilities (ie, Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient's care and prognosis.

Oxidized lipids in the metabolic profiling of neuroendocrine tumors - Analytical challenges and biological implications.

Untargeted metabolomics can be a great tool for exploring new scientific areas; however, wrong metabolite annotation questions the credibility and puts the success of the entire research at risk. Therefore, an effort should be made to improve the quality and robustness of the annotation despite of the challenges, especially when final identification with standards is not possible. Through non-targeted analysis of human plasma samples, from a large cancer cohort study using RP-LC-ESI-QTOF-MS/MS, we have resolved MS/MS annotation through spectral matching, directed to hydroxyeicosatetraenoic acids (HETEs) and, MS/MS structural elucidation for newly annotated oxidized lyso-phosphatidylcholines (oxLPCs). The annotation of unknowns is supported with structural information from fragmentation spectra as well as the fragmentation mechanisms involved, necessarily including data from both polarity modes and different collision energies. In this work, we present evidences that various oxidation products show significant differences between cancer patients and control individuals and we establish a workflow to help identify such modifications. We report here the upregulation of HETEs and oxLPCs in patients with neuroendocrine tumors (NETs). To our knowledge, this is the first attempt to determine HETEs in NETs and one of very few studies where oxLPCs are annotated. The obtained results provide an important insight regarding lipid oxidation in NETs, although their physiological functions still have to be established and require further research.