Capecitabine plus cisplatin (XP) is a standard treatment for metastatic gastric cancer (mGC). Capecitabine activation requires the enzymes uridine-cytidine kinase 2 (UCK2) and orotate phosphoribosyl transferase (OPRT). We previously used mass spectrometry to quantitate UCK2 in tumor samples from 5-FU-treated patients with stage II/III colorectal cancer; UCK2 protein expression > 319 amol/ug of tumor protein was associated with improved survival. Here, we assessed whether these biomarkers would predict survival among mGC patients treated with XP.
Archived tumor samples from patients with mGC were microdissected and solubilized for mass spectrometric quantitation of 16 protein biomarkers. Kaplan-Meier survival curves were compared using a log-rank test. Multivariate Cox models of survival included clinical covariates and protein biomarkers.
mGC tumor samples from 116 XP-treated patients were analyzed (males: 64%; median age: 55 years). All samples expressed OPRT protein (range: 202 – 1719 amol/ug), and 114 of 116 expressed UCK2 (range: 119 – 933 amol/ug). Patients with UCK2 expression above the pre-defined cutoff of 319 amol/μg (n = 30) had longer time to progression (TTP) (HR: 0.60; p = 0.020) than patients below the cutoff. Results for overall survival (OS) were similar (HR: 0.59; p = 0.015). OPRT protein expression > 790 amol/ug (n = 24) was associated with longer TTP (HR: 0.58; p = 0.019) and longer OS (HR: 0.60; p = 0.029). In multivariate analysis, UCK2 and OPRT remained independent predictors of survival after adjustment for age, gender, ECOG performance status, metastatic sites, and other clinical covariates.
We validated a pre-defined UCK2 expression cutoff and discovered an OPRT cutoff in an XP-treated mGC patient cohort. Patients with tumor expression of UCK2 and OPRT proteins above quantified thresholds survived longer than patients with lower expression. Mass spectrometric quantitation of these common tumor proteins at diagnosis may improve patient selection for XP. Studies to validate these and other chemopredictive biomarkers are ongoing.
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D. Yan, E. An, Y. Tian, F. Cecchi, T. Hembrough: Employment: NantOmics. All other authors have declared no conflicts of interest.