Special Issue Advancements and Challenges in Neuroendocrine Tumor Research

Dear Editor,

Neuroendocrine tumors (NETs) are a rare and heterogeneous group of malignancies that still present significant clinical and research challenges. NETs can develop in almost any part of the body and lead to diversified symptoms that ultimately result in delayed diagnosis. In the last decades, several advancements have been made to better understand the pathophysiology of these neoplasms and the mechanisms by which these slow-growing tumors undergo tumorigenesis. However, the rarity of the samples and the heterogeneity of the site of occurrence have translated into substantial gaps in knowledge about NETs. This editorial highlights the most recent contributions to NET research, focusing on gender differences, biomarkers with prognostic and therapy monitoring intent, novel treatments, and survival outcomes.

Gender disparities are a hot topic in different diseases and everyday life. They belong to the bigger picture of progress toward personalized medicine in disease presentation, progression, and response to treatment across many cancer types, and NETs are no exception. While the absence of gender differences in NET patients bearing MEN-1 syndrome proposes similar screening and follow-up for both genders [1], the study on gender differences in lung NETs provides valuable insights into the distinct clinical trajectories and outcomes between male and female patients [2] as demonstrated by Modica et al. [1] and Liccardi et al. [2], respectively. The observed variations in frequency, presentation, and survival of NETs according to gender underscore the need for more detailed research into how sex hormones, genetic factors, and environmental factors influence the malignancy process in NETs. This line of research could ultimately pave the way for more personalized approaches to diagnosis and treatment that take gender-specific factors into account to maximize the benefit of different treatments for both sexes.

The identification of germline mutations in NETs is also a topic of active research which can lead to the discovery of novel and unpredicted targets for some patient subgroups. In this frame, the study by Tsoy and colleagues [3] exploited targeted gene panels in next-generation sequencing from 93 NET patients to assess the association between specific gene mutations and NET histotype. Although the number of patients was limited, mutations of interesting genes such as APC, ABCC8, and HABP2, already involved in the tumorigenesis of other malignancies and metabolic conditions, were identified. These observations suggest that some patients may benefit from alternative or combined treatments developed for other indications, shedding light on novel pathogenetic mechanisms in NET patients and prompting further research to evaluate the significance of those associations in larger NET cohorts.

Identifying biomarkers for diagnosis, prognosis, or to guide treatment decisions is still core to improving patient outcomes and advancing personalized medicine. The Ki-67 proliferation index is a well-established marker for tumor cell growth, and its role in predicting survival outcomes in NETs is becoming increasingly important. In this collection, the work by Daskalakis and colleagues [4] gives a new look at Ki-67 indices in small-intestinal NETs that could significantly impact prognosis and follow-up strategies, particularly when considering more aggressive therapeutic interventions in patients with high-risk profiles. Adding to the list of NET biomarkers, one promising new candidate described in the research by Mancini et al. [5] is indoleamine 2,3-deoxygenase (IDO), an enzyme implicated in immune modulation and tumor progression that has been reported to mediate immune evasion mechanisms. Likewise, Ki-67, measuring its activity, could allow clinicians to gain insights into tumor behavior, potentially identifying patients at higher risk and with poorer outcomes, who would benefit from more aggressive treatment or immune-based therapies as earlier lines of medical intervention.

As the list of biomarkers increases, so does the promise of ctDNA mirroring the tumor burden in NETs. Liquid biopsy is reshaping diagnostic and monitoring strategies for several cancers. This progress is not only a technical achievement but also a window into the future of more accessible, real-time diagnostics. The findings by Gagliardi et al. [6] highlight the potential of liquid biopsy in capturing the mutational landscape of NETs, emphasizing the promise of integrating liquid biopsy into comprehensive genomic profiling for these tumors. However, limitations in patient numbers and genomic breadth remind us of the broader challenge in NET research: the need for robust, scalable approaches that can overcome heterogeneity.

Biomarker discovery drives therapeutic innovations by identifying targets and stratifying patients for more effective treatments like peptide receptor radionuclide therapy (PRRT). PRRT has emerged as an effective second- or third-line of treatment for (SSTR)-positive advanced, non-operable NETs that are not eligible for other first-line therapies. Several protocol regimens of ¹⁷⁷Lu-DOTATATE have been proposed. In this special issue, following up on the meaning of innovation and, hopefully, stimulating important debate, we showcase the preliminary results of a randomized phase II trial of patients with gastroenteropancreatic and pulmonary NET treated with ¹⁷⁷Lu-DOTATATE by Grassi et al. [7]. Patients were randomly assigned a personalized treatment schedule based on their clinical history and the presence of comorbidities. The toxicity reported was very low and PRRT was well tolerated, indicating that by monitoring adverse effects and identifying patient subgroups at higher risk of toxicity, clinicians can better manage treatment regimens and optimize therapeutic outcomes. These findings will contribute to a better stratification and identification of NET patients benefitting from PRRT, broadening the usage of this treatment in clinical practice.

Continuing in the realm of somatostatin analogs, several SSTR agonists exist to endeavor somatostatin receptor activation, mainly SSTR2 and SSTR5, to control symptomatology and cell proliferation. Bistika et al. [8] report a novel pan-SSTR ligand with a high affinity for SSTR3 as a useful alternative to pasireotide for the medical treatment of pancreatic NETs and other tumors with elevated SSTR3 expression.

This special collection also features a revision of the literature by Vitale and colleagues from the Neuroendocrine Tumors, Innovation in Knowledge and Education (NIKE) group [9] on the use of cabozantinib, a multi-kinase inhibitor, for the treatment of NETs. The review explores insights into cabozantinib’s impact on NET treatment, and it summarizes important results, particularly in patients with advanced disease or those who have not responded to conventional therapies. As this and other targeted agents are tested in clinical trials, there is hope that cabozantinib will constitute a new option for NET patients, improving survival and their quality of life.

The research presented in the special issue “Advancements and Challenges in Neuroendocrine Tumor Research” showcases significant achievements in understanding the complex landscape of NETs. Core areas of focus include gender differences, the search for prognostic and therapy response biomarkers, emerging treatments, and the need for better management of drug toxicities and survival outcomes. As our knowledge of NETs expands, integrating these findings into clinical practice will be essential for advancing personalized medicine and improving patient outcomes.