Abstract 1966: Cell proliferation-related pathway scores (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) as predictive and prognostic biomarkers in pancreatic cancer

Abstract

Abstract Background: Given the poor survival and severe side effects of treatments for pancreatic cancer, we need prognostic and predictive biomarkers to guide management. We hypothesized that the cell proliferation-related pathway is associated with drug response and survival in pancreatic cancer. Methods: We studied six hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis (GSVA) was evaluated in 3 independent cohorts, TCGA-PDAC (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69). Results: We found that although G2M and E2F correlated strongly with each other (spearman's r = 0.976), Mitotic and p53 pathway scores correlated highly with the other cell function gene sets. All pathways were significantly associated with high expression of MKI67 and with proliferation score (all p > 0.001), but none with pathologically complete resection (R0). Mitotic Spindle pathway alone associated with high cytolytic activity (p = 0.020). All pathways were significantly associated with high expression of KRAS and TP53 genes and with high rate of KRAS gene alteration except for MYC v1. The G2M, E2F, and p53 pathway were significantly associated with a high rate of TP53 gene alteration (p = 0.026, 0.011, and 0.07, respectively). Interestingly, different pathway correlated with AUC of different agents, such as Gemcitabine (Mitotic: r=0.706 [p = 0.01]), Paclitaxel (MYC v2: r = -0.636 [p < 0.05]), Apatinib (Mitotic: r = -0.556 [p = 0.03]), Palbociclib (E2F: r =0.675 [p < 0.01]), and Sorafenib (G2M: r = -0.593 [p = 0.03]), for pancreatic cancer. Among all six pathways, only G2M was significantly associated with worse patient survival consistently in all 3 cohorts. Conclusion: Each proliferation-related pathway was predictive of unique agent, and G2M score predicts survival of pancreatic cancer. Citation Format: Masanori Oshi, Lan Le, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Cell proliferation-related pathway scores (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) as predictive and prognostic biomarkers in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1966.