Prognostic and predictive value of a five-molecule panel in resected pancreatic ductal adenocarcinoma: A multicentre study

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has a devastating prognosis. The performance of clinicopathologic parameters and molecules as prognostic factors remains limited and inconsistent. The present study aimed to construct a multi-molecule biomarker panel to more accurately predict post-resectional prognosis of PDAC patients.

Methods: Firstly, a novel computational strategy integrating prognostic evidence from omics and literature on the basis of bioinformatics prediction (CIPHER) to generate the network, was designed to systematically identify potential high-confidence PDAC-related prognostic candidates. After specimens from 605 resected PDAC patients were retrospectively collected, 23 candidates were detected immunohistochemically in tissue-microarrays for the development cohort to construct a multi-molecule panel. Lastly, the panel was validated in two independent cohorts.

Findings: According to the constructed five-molecule panel, disease-specific survival (DSS) was significantly poorer in high-risk patients than in low-risk ones in development cohort (HR 2.15, 95%CI 1.51-3.05, P<0.0001; AUC 0.67). In two validation cohorts, similar significant differences between the two groups were also observed (HR 3.18 and 3.31, 95%CI 1.89-5.37 and 1.78-6.16, All P<0.0001; AUC 0.72 and 0.73). In multivariate analyses, this panel was the sole prognosticator that was significant in each cohort. Furthermore, its predictive power for long-term survival, higher than its individual constituents, could be largely enhanced by combination with traditional clinicopathological variables. Finally, adjuvant chemotherapy (ACT) correlated with better DSS only in high-risk patients, uni- and multi-variately, in all the cohorts.

Interpretation: The novel prognostic panel developed by a systematically network-based strategy presents strong ability in prediction of post-resectional survival of PDAC patients. Furthermore, panel-defined high-risk patients might benefit more from ACT.

Keywords: Adjuvant chemotherapy; Pancreatic ductal adenocarcinoma; Prognosis; Prognostic panel; Radical resection.

Fig. 1

The flow chart of this study.

Fig. 2

Construction of the five-molecule prognostic panel. (a) Bioinformatics-based identification of PDAC-related prognostic candidates. The candidates labelled bold are those pathway-representative ones to be detected immunohistochemically in PUMCH cohort. (b) Construction of the five-molecule panel using the LASSO Cox PH model. (c) Immunohistochemical expression of the proteins included in the five-molecule panel in tumour and non-tumour tissues.

Fig. 3

Kaplan-Meier survival curves, time-dependant ROC curves and risk score by the five-molecule panel in development and validation cohorts of PDAC. (a) Survival curves of high- and low-risk groups (left panel); ROC curves for survival at 1 and 2 years (intermediate panel); survival status at 2 years after surgery in high- and low-risk groups (right panel) in the development cohort. (b) Survival curves of high- and low-risk groups (left panel); ROC curves for survival at 1 and 2 years (intermediate panel); survival status at 2 years after surgery in high- and low-risk groups (right panel) in the validation cohort 1. (c) Survival curves of high- and low-risk groups (left panel); ROC curves for survival at 1 and 2 years (intermediate panel); survival status at 2 years after surgery in high- and low-risk groups (right panel) in the validation cohort 2.

Fig. 4

Prognostic value of the five-molecule panel in some subgroups of PDAC for all the 500 patients. (a) The five-molecule panel for T1/2 or T3 patients. (b) The five-molecule panel for patients without or with nodal involvement. (c) The five-molecule panel for patients with well/moderately or poorly differentiated tumours. (d) The five-molecule panel for patients with or without adjuvant chemotherapy.

Fig. 4

Prognostic value of the five-molecule panel in some subgroups of PDAC for all the 500 patients. (a) The five-molecule panel for T1/2 or T3 patients. (b) The five-molecule panel for patients without or with nodal involvement. (c) The five-molecule panel for patients with well/moderately or poorly differentiated tumours. (d) The five-molecule panel for patients with or without adjuvant chemotherapy.

Fig. 5

Comparison of prognostic efficiencies between the five-molecule panel and its individual constituents, as well as clinicopathologic variables. (a) and (b) The 2 year-dependant ROC curves (a) and forest plot (b) of the five-molecule panel (risk score) and single markers in the development cohort. (c) and (d) The 2 year-dependant ROC curves of the five-molecule panel (classifier), and its combination with overall (c) or individual clinicopathological variables (d). P value with asterisk denotes the extent to which the predictive power of single component or clinicopathological variable, was lower than that of the five-molecule, and determined based on the bootstrap strategy using R package ‘pROC’. HR, hazard ratio.

Fig. 6

The value of the five-molecule panel in distinguishing patients who benefit from adjuvant chemotherapy in PDAC. (a) All patients. (b) T3 patients. (c) N1/2 patients. (d) G3 patients. (e) High-risk patients. (f) Low-risk patients.