CA125 over-release behavior following a 75-g oral glucose test as a predictive biomarker of multidrug resistance in patients with ovarian cancer

Abstract

Multidrug resistance is a major cause of death in patients with ovarian cancer. To improve patient survival, we developed a novel, noninvasive and convenient tool, the 75-gram oral glucose (75gOG)-stimulated CA125 test, to monitor cancer chemoresistance in real time. Our in vitro proof-of-principal experiments revealed that post-75gOG glucose and insulin peaks can synergistically increase cancer-derived CA125 levels, and the increase in CA125 secretion (ΔCA125) is correlated with the overactivation of the insulin receptor (IR)-PI3K-Akt axis and increases (ΔIC50s) in cisplatin/taxol IC50s. Correspondingly, among the 93 patients enrolled, post-75gOG CA125 over-release (i.e., enhanced ΔCA125) behavior was associated with overexpression of the IR-PI3K-Akt pathway and its downstream components, namely, IR, pAkt, pS6 and GLUT4, in cancer specimens. Furthermore, both pre- and postsurgical 75gOG CA125 tests demonstrated that CA125 over-release showed excellent prediction efficacy on the chemoresistance potential of ovarian cancer; notably, the former indicated the need for an optimal debulking surgery, and the latter suggested the use of IR-PI3K-Akt inhibitors. Both test results possess independent prognostic significance for the 2-year progression-free survival (PFS) and overall survival (OS) of patients. The odds ratios and corresponding 95% confidence intervals (95% CIs) were 2.680 (95% CI: 1.393–5.156) for patients with CA125 over-release behavior evidenced by a presurgical 75gOG CA125 test or 3.822 (95% CI: 1.942–7.522) for that evidenced by a postsurgical test in PFS; and 3.320 (95% CI: 1.508–7.309) for patients with CA125 over-release behavior evidenced by a presurgical test or 5.212 (95% CI: 2.241–12.121) for that evidenced by a postsurgical test in OS.