Serum insulin-like growth factor binding protein 3 as a promising diagnostic and prognostic biomarker in esophagogastric junction adenocarcinoma

Abstract

Background: Esophagogastric junction adenocarcinoma (EJA) lacks serum biomarkers to assist in diagnosis and prognosis. Here, we aimed to evaluate the diagnostic and prognostic value of serum insulin-like growth factor binding protein 3 (IGFBP3) in EJA patients.

Methods: 320 participants were recruited from November 2016 to January 2020, who were randomly divided into a training cohort (112 normal controls and 102 EJA patients including 24 early-stage patients) and a validation cohort (56 normal controls and 50 EJA patients including 12 early-stage patients). We used receiver operating characteristics curve (ROC) to evaluate diagnostic value. The predictive performance of the nomogram was evaluated by the concordance index (C-index).

Results: Serum IGFBP3 levels were significantly lower in early-stage EJA or EJA patients than those in controls (P < 0.01). Measurement of serum IGFBP3 demonstrated an area under curve of 0.819, specificity 90.18% and sensitivity 43.14% in training cohort. Similar results were observed in validation cohort (0.804, 87.50%, 42.00%). Importantly, serum IGFBP3 had a satisfactory diagnostic value for early-stage EJA (0.822, 90.18%, 45.83% and 0.811, 84.48%, 50.00% in training and validation cohorts, respectively). Furthermore, survival analysis demonstrated that lower serum IGFBP3 level was related to poor prognosis (P < 0.05). Cox multivariate analysis revealed that serum IGFBP3 was an independent prognostic factor (HR = 0.468, P = 0.005). Compared with TNM stage, a nomogram based on serum IGFBP3, tumor size and TNM stage indicated an improved C-index in prognostic prediction (0.625 vs. 0.735, P = 0.001).

Conclusions: We found that serum IGFBP3 was a potential diagnostic and prognostic marker of EJA. Meanwhile, the nomogram might predict the prognosis of EJA more accurately and efficiently.

Keywords: Diagnosis; Esophagogastric junction adenocarcinoma; IGFBP3; Nomogram; Prognosis.

Fig. 1

The study flowchart of serum IGFBP3 in EJA, showing steps involved in diagnosis and prognosis assessment for serum IGFBP3. EJA esophagogastric junction adenocarcinoma

Fig. 2

Level and ROC curve analysis of serum IGFBP3 for EJA. Serum IGFBP3 levels in normal controls, EJA and early-stage EJA patients in training cohort (A) and validation cohort (B) are shown in scatter plot and box plot. The lines in the box are means. The ROC curves of serum IGFBP3 to distinguish EJA and early-stage EJA patients and normal controls in training cohort (C) and validation cohort (D). The “EJA” curve (blue line) shows healthy subjects vs. all EJA subjects (early + late-stage), and the “early-stage EJA” curve (green line) shows healthy subjects vs. only the early-stage EJA subjects. EJA esophagogastric junction adenocarcinoma, ROC receiver-operating characteristics curve

Fig. 3

Kaplan–Meier curves for serum IGFBP3 with EJA patients. Patients with low serum IGFBP3 level had short survival. EJA esophagogastric junction adenocarcinoma

Fig. 4

Construction and performance evaluation of the nomogram. Nomogram based on serum IGFBP3, tumor size and TNM stage to predict the 1-, 3- and 5-years OS for EJA patients. The nomogram used by adding the points determined on the point scale of each variable, the total points projected on the bottom scales match the probability of 1-, 3-, and 5-year OS of EJA patient (A). Time-dependent C-index of nomogram based on serum IGFBP3, tumor size and TNM stage for OS of EJA patient (B) and internally validated with using a bootstrap resampling method (C). Calibration plots showed good agreement for the survival probability at 1-, 3- and 5-year between the nomogram prediction and actual observed results (D–F). Decision curve analysis of serum IGFBP3, tumor size and TNM stage and nomogram. The straight black line represents the assumption that all patients die, and the horizontal line represents the assumption that no deaths happen (G). Clinical impact curve of nomogram. The red curve (number of high-risk individuals) indicated the number of people who were classifed as positive (high risk) by the nomogram at each threshold probability; the blue dotted curve (number of high-risk individuals with event) was the number of true positives at each threshold probability (H). EJA esophagogastric junction adenocarcinoma, OS overall survival

Fig. 5

Survival curve of risk stratification for OS based on prediction of nomogram. Patients in high-risk group had short survival. Low risk: total points ≤ 100. High risk: total points > 100. OS overall survival