Clinical validation of a DNA methylation biomarker to predict overall survival of relapsed ovarian cancer patients

Abstract

Background: About 70% of ovarian cancer (OC) patients relapse after initial chemotherapy, making it crucial to predict survival before second-line treatment. Our previous work discovered a blood-based DNA methylation prognostic signature (PLAT-M8) that uses 8 CpG sites related to chemoresistance. We aim to validate this biomarker and its correlation with clinicopathological features and treatment profiles in additional cohorts. Methods: Extracted DNA from whole blood was provided from the BriTROC-1 (n=47) and OV04 cohorts (n=57) upon the first relapse. Additional samples from Hammersmith Hospital (n=100) were collected during first-line chemotherapy (cycles 3-4 and 6). Bisulphite pyrosequencing was used to quantify DNA methylation at the previously identified 8 CpG sites. The methylation data obtained were combined with previous data from ScoTROC-1D and 1V (n=141) and OCTIPS (n=46). Cox regression was used to assess overall survival (OS) after relapse concerning clinicopathological characteristics. The DNA methylation Class (Class 1 vs 2) was determined by consensus clustering. Findings: Blood DNA methylation at relapse predicts better clinical outcomes. Methylation Class shows no association with outcome during first-line chemotherapy treatment. Methylation Class 1 is associated with shorter survival, as indicated by a meta-analysis of five cohorts (OS: HR 2.54, 1.67-3.85). Class 2 patients on carboplatin monotherapy have the best prognosis, while Class 1 patients on the same treatment have the poorest prognosis (OS: aHR 9.69, 2.38-39.47). Class 1 is linked to older patients (>75 years) with advanced-stage, platinum-resistant cases, correlating with residual disease, and shorter progression-free survival. In contrast, Class 2 of PLAT-M8 is linked to platinum-sensitive patients, and higher complete response rates by RECIST criteria, but shows no correlation with CA-125. These findings emphasise the potential of PLAT-M8 in guiding second-line chemotherapy decisions. Interpretation: PLAT-M8 methylation biomarker is associated with survival in OC patients with relapse and hypothetically may predict platinum treatment response at second-line chemotherapy.