Predictive biomarkers of systemic treatment in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis of randomized controlled trials.

Abstract

770 Background: Pancreatic ductal adenocarcinoma (PDAC) is typically treated with unselected therapy. Biomarkers for response prediction are needed to improve therapeutic outcomes. Herein we evaluate predictive biomarkers for fluoropyrimidine- and gemcitabine-based regimens in PDAC, from randomized controlled trials (RCTs). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science databases were searched for RCTs comparing fluoropyrimidine and gemcitabine-based regimens in patients with PDAC, evaluating the association between biomarker and overall survival (OS). Hazard ratios (HR) compare treatment arms in biomarker low and high subgroups, whereas the ratio of HR (RHR) compares the effect between low and high subgroups to identify strong predictive biomarkers. Results: A total of 1,271 studies were screened; final analysis included 16 studies with 23 biomarkers. The majority were tissue based (n=22); one transcriptomic signature (GemPred) and 22 proteins. hENT1 was evaluated in 6 studies, DCK, DPD and RRM1 in 2 and the remainder assessed in a single study. No biomarker demonstrated correlation with favorable OS for gemcitabine-based regimens, yet several were predictive for OS in patients receiving fluoropyrimidine-based therapy. Benefit from fluoropyrimidine-based regimens was observed for GemPred(-) (Table, HR [95% CI], 0.53 [0.38-0.73]), DPD-low in one study (0.67 [0.49-0.90]), hENT1-low in 3 of 6 studies (0.47 [0.28-0.80], 0.62 [0.47-0.83], 0.55 [0.40-0.77]), and HuR-high (0.71 [0.50-0.99]). The pooled effect for all low expression subgroups trended toward advantage (0.88 [0.77-1.00]), yet not statistically significant likely due to heterogeneity (I² = 66.6%). The pooled effect for biomarker high subgroups did not demonstrate significance (1.04 [0.95-1.15]). GemPred showed the strongest predictive effect for fluoropyrimidine-based regimens in GemPred(-) tumors (RHR 3.11, [1.57-6.16]). Conclusions: Several biomarkers (GemPred, hENT1, DPD, HuR) were predictive of superior OS with fluoropyrimidine-based as compared to gemcitabine-based therapy for patients with PDAC in a meta-analysis of RCTs comparing these regimens. Further validation is needed. Results for select biomarkers. Displayed as (HR [95% CI]). Biomarker Low Biomarker High Ratio of HR CDA 1.07 [0.77, 1.50] 1.06 [0.68, 1.66] 0.99 [0.57, 1.72] DCTD 0.81 [0.52, 1.26] 1.09 [0.68, 1.75] 1.35 [0.70, 2.57] DPD 0.67 [0.49, 0.90] 0.63 [0.33, 1.13] 0.91 [0.46, 1.81] GemPred 0.53 [0.38, 0.73] 1.65 [0.91, 2.99] 3.11 [1.57, 6.16] hENT1 (10D7G2) 0.47 [0.28, 0.80] 1.01 [0.23, 4.35] 2.15 [0.45, 10.30] hENT1 (SP120) 0.62 [0.47, 0.83] 1.02 [0.42, 2.46] 1.65 [0.65, 4.17] hENT1 0.55 [0.40, 0.77] 0.92 [0.57, 1.46] 1.67 [0.94, 2.97] HuR 1.02 [0.85, 1.22] 0.71 [0.50, 0.99] 0.70 [0.47, 1.03] RRM2 0.98 [0.75, 1.28] 1.02 [0.49, 2.14] 1.04 [0.48, 2.27]