High expression of the ADC target Claudin-6 associates with aggressive endometrial cancer and remains high in metastatic lesions

BACKGROUND: Patients with advanced or recurrent endometrial cancer (EC) have limited treatment options. The development of antibody-drug conjugates (ADCs) offers new treatment strategies by targeted delivery of cytotoxic payloads, including conventional chemotherapy, to cancer cells. An ADC targeting Claudin-6 is currently in clinical testing however expression patterns of Claudin-6 has not been thoroughly explored in EC. METHODS: Membrane expression of Claudin-6 was evaluated by immunohistochemistry in a large, prospectively collected EC cohort with 1106 primary tumours and 187 metastatic lesions. Claudin-6 expression was scored according to the Gastric criteria and correlated with clinicopathological characteristics and follow-up data. RESULTS: Claudin-6 expression was detected in 18% of ECs and was highly expressed in 10% of all samples. High expression was observed in 49% of serous tumours and 22% of carcinosarcomas. High Claudin-6 independently predicted poor disease-specific survival in multivariate analysis (HR: 1.7, CI: 1.2-2.4, p = 0.002). In the paired primary-metastasis cohort, Claudin-6 was highly expressed in 19% of primary tumours and, of these, 77% maintained high expression in at least one corresponding metastatic lesion. CONCLUSIONS: Our study identified Claudin-6 as an independent prognostic marker in EC and as a potential target for ADCs, particularly in serous and carcinosarcoma subtypes.