Clinical validation of a DNA methylation biomarker associated with overall survival of relapsed ovarian cancer patients

Abstract

Approximately 70% of ovarian cancer (OC) patients relapse after chemotherapy, underscoring the need to assess survival before second‐line treatment. We previously identified PLAT‐M8, an 8‐CpG blood‐based methylation signature linked to chemoresistance. This study validates its correlation with clinicopathological features and treatment profiles in additional cohorts. 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 OS after relapse concerning clinicopathological characteristics. The DNA methylation Class (Class 1 vs. 2) was determined by consensus clustering. As for results, blood DNA methylation at relapse correlates with clinical outcomes, but it has no impact during first‐line treatment. Class 1 is linked to shorter survival (summary OS: HR 2.50, 1.64–3.79) and poorer prognosis on carboplatin monotherapy (OS: aHR 9.69, 95% CI: 2.38–39.47). It is associated with older (>75 years), advanced‐stage, platinum‐resistant patients, residual disease, and shorter PFS. In contrast, Class 2 is linked to platinum sensitivity, higher complete response rates (RECIST), and better prognosis but shows no correlation with CA‐125. These findings highlight PLAT‐M8's potential in guiding second‐line chemotherapy decisions. The PLAT‐M8 methylation biomarker is associated with survival in relapsed OC patients and may potentially predict their response to second‐line platinum treatment.