Serum Biomarker Status with a Distinctive Pattern in Prognosis of Gastroenteropancreatic Neuroendocrine Carcinoma

Abstract

Objective: Gastroenteropancreatic neuroendocrine carcinoma (GEPNEC) is a major research focus, but the application of biomarkers to guide its prognostication and management is unsatisfying. Clinical values of conventional serum biomarkers, neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA199) warrant scrutiny.

Methods: Patients diagnosed with GEPNEC with baseline NSE, CEA, and CA199 levels provided in Peking University Cancer Hospital were retrospectively studied. Relationships between biomarkers and prognosis were investigated by the χ2 test, Kaplan-Meier analysis, and univariate and multivariate Cox regression analyses.

Results: A total of 640 GEPNEC patients were enrolled. NSE, CEA, and CA199 were elevated in 59.5%, 28.5%, and 21.3% of the population, respectively. Higher NSE had worse median overall survival (OS) (17.0 months vs. not reached, hazard ratio = 2.77 [2.06, 3.73], p < 0.001), and so did patients with higher CEA and CA199. Multivariable analysis confirmed that NSE and CA199 correlated with OS independently. Baseline NSE level and NSE remission predicted OS and the response of patients with first-line etoposide plus cisplatin (EP) treatment. Furthermore, we combined NSE/CEA/CA199 to segregate GEPNEC into novel subgroups, namely, adenocarcinoma-like NEC (ALN), neuroendocrine-like NEC (NLN), and triple-normal NEC (TNN). The groups shared distinctive clinicopathologic features and prognosis (21.0 months vs. 17.1 months vs. not reached, p < 0.001). The EP regimen remained the priority treatment option in NLN/TNN, while ALN was predisposed to "adenocarcinoma-like chemotherapy."

Conclusions: Elevation of NSE, CEA, or CA199 was common and independently indicates poor prognosis in GEPNEC patients. Serum biomarker-based subtypes suggest meaningful clinical implications and appropriate therapeutic approaches, illuminating promising ways to characterize the prognosis of GEPNEC.

Keywords: Biomarkers; Carbohydrate antigen 19-9; Carcinoembryonic antigen; Gastroenteropancreatic neuroendocrine carcinoma; Neuron-specific enolase; Overall survival; Subtype.

Fig. 1

OS regarding the biomarkers elevation in NEC: pure NEC with NSE (a), CEA (b), CA199 (c) and MiNEC with NSE (d), CEA (e), CA199 (f). MiNEC, mixed neuroendocrine non-neuroendocrine carcinoma; OS, overall survival; NSE, neuron-specific enolase; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 19-9.

Fig. 2

Predicative values of biomarkers remission in the advanced NEC with first-line EP regimens: NSE (a), CEA (b), CA199 (c). NSE, neuron-specific enolase; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 19-9; EP, etoposide plus cisplatin; ULN, upper limit of normal value.

Fig. 3

OS regarding the serum-based subtypes of the NEC. There are 2 patients without enough information (normal NSE level with lack of both CEA and CA199 information). NLN, neuroendocrine-like NEC; ALN, adenocarcinoma-like NEC; TNN, triple-normal NEC; OS, overall survival; NSE, neuron-specific enolase; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 19-9.