Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer

SIMPLE SUMMARY: Ovarian cancer remains a clinical challenge with considerable mortality. Circulating tumor DNA (ctDNA) has been suggested as a prognostic biomarker and enables the longitudinal evaluation of a patient’s disease and response to treatment. However, the role of ctDNA in treatment monitoring and for guiding treatment decisions in ovarian cancer remains unclear. We aimed to examine a gene methylation biomarker in the plasma of patients suffering a relapse of ovarian cancer in order to investigate prognostic potential and identify patients most likely to benefit from treatment, measured by overall survival. In the study, the methylated gene HOXA9 was found to be significantly related to poor survival, with the potential to observe the progression of the disease at an early stage and spare patients from ineffective treatment. Monitoring ctDNA during treatment is clinically feasible, further efforts are, however, required for standardization and for demonstrating improvement in treatment management. ABSTRACT: Methylated Homeobox A9 circulating tumor DNA (meth-HOXA9) has been suggested as a blood-based biomarker in epithelial ovarian cancer (EOC), although its prognostic significance remains unproven. The aim of the present study was to investigate the prognostic impact of meth-HOXA9 in patients with recurrent EOC. DNA was purified from 4 mL plasma and, following bilsulfite conversion, meth-HOXA9 was analyzed using a methylation-specific droplet digital PCR. Detection of meth-HOXA9 was reported as a percentage of total DNA and as a binary variable (detectable and undetectable). Meth-HOXA9 status and its dynamics during palliative treatment were correlated with overall survival (OS) as the primary endpoint. At baseline, meth-HOXA9 was detected in 65.9% (83/126) of the patients. The median OS was 8.9 and 17.9 months in patients with detectable and undetectable meth-HOXA9 at baseline (hazard ratio: 2.04, p = 0.002), which remained significant in the multivariate analysis. Median OS in patients with an increase in meth-HOXA9 after one treatment cycle was 5.3 months compared to 33 months in patients with undetectable meth-HOXA9 (p < 0.001). Meth-HOXA9 was significantly related to poor survival and may serve as a prognostic marker in patients with recurrent EOC. The longitudinal monitoring of meth-HOXA9 is clinically feasible with the perspective of aiding clinical decision making.