Ex Vivo Modelling of Therapy Efficacy for Rare Krukenberg Tumors – A Report of Two Cases

Abstract

Krukenberg tumor (KT) is a rare subtype of ovarian neoplasms that manifests as secondary ovarian cancer. Most frequently, KTs originate from a primary in the gastrointestinal tract and account for 30 to 40% of all secondary ovarian cancers. A key histologic characteristic finding used in the diagnosis of KT is the presence of mucin-laden signet-ring cells. Bilateral metastasis into both ovaries has been reported in more than 80% of KTs, and a significant fraction of these cases are reported to receive no survival benefit from chemotherapy. Despite clinical evaluation of several chemotherapeutic treatments for the management of KT, the general prognosis of the disease is poor and radical surgery remains the main treatment shown to improve the overall survival. As no targeted therapies have been reported for KT, we performed an ex vivo drug screen to assess the efficacy of targeted therapeutics with patient-derived Krukenberg tumor cells. Tumor cells isolated from a coarse needle biopsy and tumor-associated immune cells derived from malignant ascites effusion from two patients with a gastric cancer derived KT were used for the analysis of responses to 120 drugs. A comparison of the results showed that tumor cells from both patients showed systematic sensitivity toward topoisomerase inhibition, epigenetic modulators, statins and alkaloid tubulin inhibitors. Ascites-derived immune cells displayed selective sensitivity to a number of targeted agents, including VEGFR inhibitor sunitinib. Flow cytometry analysis identified the effect of sunitinib to be immunomodulatory and targeted on the immunosuppressive M2 type macrophages. The immunomodulatory effect of sunitinib was confirmed from analysis of the patient ascites following treatment and was accompanied by sustained clinical response. These results support the concept of harnessing the immunomodulatory effects of VEGFR-TKI for cancer therapy and suggest further analysis also in the context of Krukenberg tumors.