Purpose: About 80% of patients with pancreatic cancer (PC) succumb to the disease despite curative resection, many of whom recur within 6 months of surgery. This demonstrate that current staging is inadequate and that there is a clear need to better define prognostic phenotypes prior to significant intervention.
Method: We assessed the relationship of aberrant expression of two pro-metastatic calcium-binding proteins, S100A2 and S100A4 with survival in 4 independent cohorts of patients (total n=547) who underwent operative resection for PC. A preoperative nomogram was derived using preoperatively assessable variables.
Results: High S100A2 and S100A4 expressions were an independent poor prognostic factor in both the training (HR=2.00, 95% CI=1.15–3.49, P=0.0216 and HR=3.34, 95% CI=1.69–6.62, P=0.0005 respectively) and validation (HR=1.73, 95% CI=1.20–2.48, P=0.0030 and HR=1.65, 95% CI=1.23–2.22, P=0.0009 respectively) cohorts. These results were further validated in a prospective cohort and another retrospective population based cohort. Aberrant expression of S100A2/A4 protein stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram using only variables that could be measured preoperatively (age, tumour size, tumour location and molecular biomarkers), predicted survival better than nomograms derived using clinicopathological variables, which can only be determined after surgery. A proof-of-principle study demonstrated that biomarker expression can be reliably assessed in preoperative EUS-FNA samples.
Conclusion: S100A4 and S100A2 are one of the very few biomarkers that have been independently validated in multiple patient cohorts. Their aberrant expression stratifies PC into distinct prognostic groups and potentially enables more accurate preoperative prognostication through a nomogram. The development and application of such nomograms has the potential to improve patient selection for surgery and assist clinicians in making “tie-breaker” decisions that would ultimately improve the overall survival and quality of life for patients with PC.