Neuroendocrinology | 2021
NETest: a systematic review focusing on the prognostic and predictive role.
Abstract
The NETest is a standardized and reproducible liquid biopsy for neuroendocrine tumors (NETs). It evaluates the expression of 51 NET genes by real-time polymerase chain reaction, providing an accurate molecular profile of the neoplasm. Diagnostic utility of NETest has been widely demonstrated, while its role in predicting prognosis and treatment response is less studied. This systematic review aims to collect and discuss the available evidence on the prognostic and predictive role of NETest, trying to answer 3 questions, frequently raised in clinical practice. Is NETest able to differentiate stable from progressive disease? Increased NETest levels (at least >40%) correlate with disease progression. Is NETest able to predict tumor progression and tumor response to treatment? Some studies demonstrated that the baseline NETest score >33–40% could predict tumor progression. Moreover, NETest performed after treatment (as peptide receptor radionuclide therapy) could predict treatment response also before radiological findings, since the decrease or stability of NETest score predicts tumor response to treatment. Is NETest able to evaluate tumor recurrence risk after surgery? NETest can predict surgical treatment outcome detecting minimal residual disease after radical surgery, which is characterized by a lower but positive NETest score (20–40%), while a higher score (>33–40%) is associated with nonradical surgery. In conclusion, in addition to its demonstrated diagnostic role, this systematic review highlights the efficacy of NETest to assess disease status at the moment of the NETest execution and to predict tumor recurrence after surgery. The efficacy for other applications should be proven by additional studies. © 2021 S. Karger AG, Basel Introduction Neuroendocrine neoplasms (NENs) are heterogeneous in terms of primary sites, neuroendocrine differentiation, clinical behavior, and response to treatments. In this field, the possibility to relay on easy to execute markers for estimating the prognosis and for predicting rePuliani et al. Neuroendocrinology 2 DOI: 10.1159/000518873 sponse to treatment could be essential for improving the clinical management of these patients [1]. Nowadays in patients affected by neuroendocrine tumors (NETs), the strongest predictors of overall survival (OS) are tumor grade and stage [2]. Circulating biomarkers have been studied for diagnosis and follow-up of patients affected by NENs. While in functional NENs it is possible to analyze secretory products or their metabolites in blood and/or in urinary sample, in nonfunctioning tumors only the so-called general tumor markers can be used [3]. Chromogranin A (CgA) is the most used general tumor marker, with both diagnostic and predictive value [4]. The prognostic role of this marker has been advocated since the demonstration of the correlation with OS [5], poorer outcome [6], and tumor burden [7]. However, there are multiple limitations of CgA use. A false-positive value can be observed in nononcological diseases, such as atrophic gastritis, hypergastrinemia, heterophile antibodies, impaired kidney function, or use of antisecretory medications, especially proton pump inhibitors [3, 8, 9]. False-negative results can happen in case of less differentiated disease, since CgA is a secretory product of the neuroendocrine cells [10]. Neuron-specific enolase (NSE) is physiologically present in neurons and neuroendocrine cells and its circulating form is a biomarker for OS in gastroenteropancreatic (GEP) NEN patients [11, 12]. However, serum NSE is increased only in 30–50% of these patients [13]. A significant association of NSE levels with survival was also demonstrated in patients affected by small cell lung cancer [14]. As a prognostic marker of NETs, NSE is minimally correlated with tumor size but associated with grading. In fact, its levels result higher in patients with poorly differentiated neuroendocrine carcinoma (NEC) [15]. Preliminary data of the use of serum neutrophil-lymphocyte ratio (NLR) are available in patients affected by lung NECs. In these patients, an increasing preoperative NLR is associated with higher stage and inversely correlates with post-resection OS and relapse-free survival [16, 17]. The predictive value of worse survival of the pre-operative NLR was also demonstrated in patients with gastric NENs undergoing surgery [18] and in intestinal and pancreatic NETs (Ki-67 <10%) treated with lanreotide [19]. Recently, NETest has been developed and proposed mostly for the diagnosis of NENs, demonstrating in a recent meta-analysis on 10 studies a diagnostic accuracy of 95–96% [20]. The aim of this systematic review is to collect and discuss the available evidence on the role of NETest in predicting prognosis and treatment response, including both systemic treatments, used in metastatic patients, and surgical and ablative strategies, used in localized disease, in patients affected by NENs, trying to answer the following questions: (1) Is NETest able to differentiate stable from progressive disease? (2) Is NETest able to predict tumor progression and response to therapy? (3) Is NETest able to predict tumor recurrence after surgery? Materials and Methods We performed this study according to the Cochrane Collaboration and PRISMA statement [21]. Data Sources and Searches From June to November 2020, we searched for English-language articles in MEDLINE. No date restriction has been applied. Search terms used were: “NETest”; “predictive biomarker” AND “neuroendocrine”; “prognostic biomarker” AND “neuroendocrine”; “liquid biopsy” AND “neuroendocrine.” Additionally, we searched in EMBASE, Cochrane Library, and SCOPUS using “NETest” as a search term. Eligibility criteria for study selection included studies on humans with any of the following designs: randomized clinical trials, prospective non-randomized trials, retrospective studies, and case series. We selected: (1) articles on NETest; (2) data on prognostic value or treatment response prediction or treatment response assessment of NETest; and (3) patients affected by any subtypes of NENs. Exclusion criteria were: (1) non-original articles or case reports; and (2) articles reporting only data on the diagnostic value of NETest. A final update of the search was conducted in May 2021 and one additional study was included. Article Selection Each study was screened by abstract and title and potentially eligible studies were further assessed in detail by retrieving fulllength articles. Each full-length article was independently reviewed by two separate authors (G.P. and V.D.V.) following inclusion criteria. Two authors independently extracted data from the articles that met the inclusion criteria. A standardized form was used to extract the following information: year of publication, type of study, number of included patients, age at diagnosis, sex, histopathological examination, staging and outcomes, treatment strategy (surgery, medical treatment, and radiotherapy), time of execution and values of NETest, correlation of NETest with disease status, prognosis, and treatment response. Quality of studies has been assessed by MINORS score [22]. Results From the original number of 244 articles, 26 have been selected by title and abstract. After full-text evaluation, a total of 20 articles were included in the systematic review (Fig. 1).