Actionable biomarker co-expression in advanced ovarian cancer: folate receptor alpha expression and related markers

Folate receptor-α is an established therapeutic target in ovarian cancer and identifies candidates for mirvetuximab soravtansine. However, co-expression patterns between folate receptor-α and other actionable biomarkers, and their therapeutic implications, remain incompletely characterized.

We conducted a single-institution cohort study of 110 patients with platinum-resistant ovarian cancer treated with mirvetuximab soravtansine (2019-2025). Tumor biomarkers were assessed using immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. Co-expression among 10 biomarkers, including folate receptor-alpha, estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2, BRCA, homologous recombination/loss of heterozygosity, programmed death-ligand 1, claudin-6, and tumor mutational burden, were evaluated using Jaccard similarity indices, Cohen's kappa statistics, and correlation analyses. Exploratory progression-free survival and overall survival analyses were performed by folate receptor-α and estrogen receptor sub-groups.

Folate receptor-α expression was high in 80% of tumors and intermediate/low in 20%. Co-expression analyses demonstrated largely independent biomarker patterns, reflecting biological heterogeneity. A hormone receptor-associated cluster emerged, including strong co-expression between folate receptor-α and estrogen receptor (Jaccard = 0.76), and moderate overlap between estrogen receptor and claudin-6 (0.62), programmed death-ligand-1 and estrogen receptor (0.56), and programmed death-ligand-1 and folate receptor-α (0.50). Survival outcomes were comparable between folate receptor-α-high and folate receptor-α-intermediate/low tumors. Among folate receptor-α-high tumors, estrogen receptor expression (≥10%) did not meaningfully stratify progression-free or overall survival outcomes.

Biomarker co-expression in advanced ovarian cancer demonstrates substantial heterogeneity, with patterns that may inform future biomarker-guided treatment combinations and sequencing strategies. Prospective validation is needed to refine multi-marker frameworks and determine whether biologically driven treatment approaches based on co-expression biomarker patterns may have clinical utility. Exploratory analyses support further investigation of folate receptor-α as a potentially graded rather than strictly binary biomarker; however, these findings are hypothesis-generating.