A Novel Four-Gene Score to Predict Pathologically Complete (R0) Resection and Survival in Pancreatic Cancer

Simple Summary A biomarker to predict survival is a critical need in pancreatic cancer treatment. We hypothesized that a four-gene score, which was previously reported to reflect cell proliferation, can be used as a predictive biomarker for pancreatic cancer. A total of 954 patients were analyzed for both discovery and validation of the four-gene score from publicly available datasets for pancreatic cancer, in order to investigate the relationship between the score and clinical features of pancreatic cancer, such as metastasis, cancer aggressiveness, immune cell infiltration, patient survival, and resectability. We found that the score correlated with clinical aggressiveness in pancreatic cancer, and did so to a higher degree compared to breast cancer cohorts. We found that the four-gene score identified poor survival in pancreatic cancer, and has potential as a predictive biomarker of treatment response in metastatic pancreatic cancer, as well completion of a pathologically complete (R0) resection. Appropriately utilized, the four-gene score could be a valuable prognostic and predictive tool for pancreatic cancer in the future. Pathologically complete (R0) resection is essential for prolonged survival in pancreatic cancer. Survival depends not only on surgical technique, but also on cancer biology. A biomarker to predict survival is a critical need in pancreatic treatment. We hypothesized that this 4-gene score, which was reported to reflect cell proliferation, is a translatable predictive biomarker for pancreatic cancer. A total of 954 pancreatic cancer patients from multiple cohorts were analyzed and validated. Pancreatic cancer had the 10th highest median score of 32 cancers in The Cancer Genome Atlas (TCGA) cohort. The four-gene score significantly correlated with pathological grade and MKI67 expression. The high four-gene score enriched cell proliferation-related and cancer aggressiveness-related gene sets. The high score was associated with activation of KRAS, p53, transforming growth factor (TGF)-beta, and E2F pathways, and with high alteration rate of KRAS and CDKN2A genes. The high score was also significantly associated with reduced CD8(+) T cell infiltration of tumors, but with high levels of interferon-gamma and cytolytic activity in tumors. The four-gene score correlated with the area under the curve of irinotecan and sorafenib in primary pancreatic cancer, and with paclitaxel and doxorubicin in metastatic pancreatic cancer. The high four-gene score was associated with significantly fewer R0 resections and worse survival. The novelty of the study is in the application of the four-gene score to pancreatic cancer, rather than the bioinformatics technique itself. Future analyses of inoperable lesions are expected to clarify the utility of our score as a predictive biomarker of systemic treatments.