Serum insulin-like growth factor binding protein-3 as a potential biomarker for diagnosis and prognosis of oesophageal squamous cell carcinoma

Abstract

Background: Insulin-like growth factor binding protein-3 (IGFBP3) has been reported to be related to the risk of some cancers. Here we focussed on serum IGFBP3 as a possible biomarker of diagnosis and prognosis for oesophageal squamous carcinoma (ESCC).

Methods: Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum IGFBP3 level in the training cohort including 136 ESCC patients and 119 normal controls and the validation cohort with 55 ESCC patients and 42 normal controls. The receiver operating characteristics curve (ROC) was used to assess the diagnosis value. Cox proportional hazards model was applied to select factors for survival nomogram construction.

Results: Serum IGFBP3 levels were significantly lower in early-stage ESCC or ESCC patients than those in normal controls (p < .05). The specificity and sensitivity of serum IGFBP3 for the diagnosis of ESCC were 95.80% and 50.00%, respectively, with the area under the ROC curve (AUC) of 0.788 in the training cohort. Similar results were observed in the validation cohort (88.10%, 38.18%, and 0.710). Importantly, serum IGFBP3 could also differentiate early-stage ESCC from controls (95.80%, 52.54%, 0.777 and 88.10%, 36.36%, 0.695 in training and validation cohorts, respectively). Furthermore, Cox multivariate analysis revealed that serum IGFBP3 was an independent prognostic risk factor (HR = 2.599, p = .002). Lower serum IGFBP3 level was correlated with reduced overall survival (p < .05). Nomogram based on serum IGFBP3, TNM stage, and tumour size improved the prognostic prediction of ESCC with a concordance index of 0.715.

Conclusion: We demonstrated that serum IGFBP3 was a potential biomarker of diagnosis and prognosis for ESCC. Meanwhile, the nomogram might help predict the prognosis of ESCC. Key MessageSerum IGFBP3 showed early diagnostic value in oesophageal squamous cell carcinoma with independent cohort validation. Moreover, serum IGFBP3 was identified as an independent prognostic risk factor, which was used to construct a nomogram with improved prognosis ability in oesophageal squamous cell carcinoma.

Keywords: ESCC serum biomarker; Serum insulin-like growth factor binding protein-3; diagnosis and prognosis; oesophageal squamous cell carcinoma.

Figure 1.

Study overview of serum IGFBP3 in oesophageal squamous cell carcinoma.

Figure 2.

Serum IGFBP3 level. Median and interquartile range of serum IGFBP3 level in early-stage ESCC, advanced-stage ESCC, ESCC patients and normal controls in two cohorts (A: training cohort; B: validation cohort). Unpaired t test was applied to evaluate the IGFBP3 difference of early-stage ESCC, advanced-stage ESCC or ESCC patients and normal control in two cohorts.

Figure 3.

ROC curve of IGFBP3 in ESCC diagnosis. ROC curves of serum IGFBP3 to distinguish ESCC patients and normal controls in two cohorts (A: training cohort; B: validation cohort), and diagnostic value of early-stage ESCC in two cohorts (C: training cohort; D: validation cohort).

Figure 4.

Kaplan–Meier curves for OS. (A) survival curve for serum IGFBP3 with ESCC patients, Log-rank test was used to evaluate the significant difference. (B) adjusted survival curves for serum IGFBP3 with ESCC patients. The number of people alive at each time point in the high and low IGFBP3 groups was showed in “number at risk.”

Figure 5.

Nomogram based on serum IGFBP3, size of tumour and TNM stage to predict the 1 year, 3 years and 5 years of OS of ESCC patients.

Figure 6.

C-index curve to evaluate the predicted ability of the nomogram, C-index curve under the time distribution of 3 years (A) and five years (C) and internal verification by Bootstrap algorithm of three years (B) and five years (D).

Figure 7.

Calibration curve of nomogram to predict the overall survival rate of 1, 3 and 5 years (A–C). X-axis was the probability of 1, 3 or 5 years of OS predicted by nomogram. Y-axis was the actual OS of the patient included in the study.

Figure 8.

Decision curve analysis of serum IGFBP3, size of tumour, TNM stage and nomogram, A-C shown the decision curve for 1 year, 3 years, and 5 years of OS.

Figure 9.

Survival curve of risk stratification for OS according to prediction of nomogram. The low risk: Total points ≤192.5 for OS, the high risk: Total points >192.5 for OS. Log-rank test was used to evaluate the significant difference.