Predicting Response to Bevacizumab in Ovarian Cancer: A Panel of Potential Biomarkers Informing Treatment Selection

Abstract

Purpose: The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial.Experimental Design: ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial).Results: Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and a 1 -acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P ¼ 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm.Conclusions: This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts.

Mass Spectrometric/Bioinformatic Identification of a Protein Subset That Characterizes the Cellular Activity of Anticancer Peptides

“…The three proteins with isoforms that were both up-and down-regulated are depicted in blue. Three apparently highly connected clusters constituted by ribosomal proteins(1), ribonucleoproteins(2), and members of the proteasome complex(3), are highlighted. and the third (cluster 3) contains members of the proteasome complex (PSMB5, PSMC2, PSMC3, PSMD5, PSMD7).…”

Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin

“…This is probably also true for angiogenesis inhibitors where patients' tumors have shown differing profiles of responsiveness. The reason for the differences is far from clear and the predictive value of angiogenic markers informing of treatment response is debated [37][38][39].…”

Prediction of anti-angiogenesis escape

“…Collinson et al [33] demonstrated that a signature of four serum proteomic biomarkers (mesothelin, fms-like tyrosine kinase-4, α 1 -acid glycoprotein, and CA125) was able to predict benefit from bevacizumab in a cohort of patients from the ICON7 study. The predictive ability was less strong in a second cohort from the same study, but patient numbers were small and it is likely that the validation analysis was underpowered.…”