145 KRAS mutation may be one of the chemo-resistant phenotype of ovarian clear cell carcinoma

Objectives Ovarian clear cell carcinoma (OCCC) is more prevalent in Japan than western countries, and exhibits chemo-resistant phenotype and poor survival. In this study, we characterized the patient-derived xenograft (PDX) model of OCCC, and to correlate the clinical features of OCCC with KRAS mutation. Methods We transplanted 19 primary or metastatic tumors derived from ovarian cancer patients directly into NOG mice. The comprehensive gene expression and mutation profiles as well as histologic characteristics were compared between parental tumors and PDX ones. Response to cytotoxic agents was analyzed using PDX model, and correlated with clinical outcome. In 61 consecutive OCCC patients, the genomic DNAs were extracted from FFPE, and analyzed KRAS mutations. Results Total of 6/19 (31.6%) PDX models were established, and 2 were found to be OCCC in histological assessment. One of the OCCC PDXs had KRAS mutation, which exhibited resistance for platinum- and taxane-drugs and the patient had poor clinical outcome. The other PDX tumor without KRAS mutation was sensitive to cytotoxic agents and the patient showed good clinical outcome. Then we correlated KRAS mutations with their clinical features in OCCC. From 13 samples, we detected KRAS mutations (21%). Except for one patient, KRAS mutated OCCC had stage I diseases. Two patients experienced recurrences, and both of them had no response to conventional chemotherapy. They showed significantly worse overall survival than other recurrent OCCC patients without KRAS mutation. Conclusions KRAS mutation may be one of the chemo-resistant phenotypes in OCCC.