ABSTRACT
BACKGROUND: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. METHODS: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. RESULTS: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. CONCLUSION: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). GOV IDENTIFIER: NCT01584297.
Subject(s)
Ovarian Neoplasms , Female , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ketoconazole/therapeutic use , Steroid 17-alpha-Hydroxylase/genetics , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Enzyme Inhibitors , Granulosa Cells/metabolism , Granulosa Cells/pathologyABSTRACT
OBJECTIVE: Recent studies defend a possible prognostic and therapeutic value of the identification of microsatellite instability (MSI) in colorectal cancer. This work tries to assess the impact that the identification of MSI tumours can have in clinical practice. MATERIAL AND METHODS: We recovered tumour samples from 92 of the 143 patients operated on for colorectal cancer in our institution between 1995 and 2000. Five MSI markers (BAT 25, BAT 26, D2S123, D5S346 and D17S250) were studied on them. The rate and clinicopathologic characteristics of MSI tumours were investigated along with their impact on the global and disease-free survival as compared with microsatellite stable (MSS) tumours. RESULTS: All 5 microsatellite markers' status were established in 73 patients (79.3% of the samples). Among them, 7 tumours showed instability in just one marker (low microsatellite instability [MSI-L]) whereas 5 tumours had mutations in 2 or more markers (high microsatellite instability [MSI-H]), for a total 15.4% rate of MSI tumours. All MSI-H tumours were located in the right colon. We could not fi nd any impact from MSI detection on global or disease-free survival. CONCLUSIONS: MSI determination did not identify groups of patients with a different prognosis. Moreover, with such low incidence its determination can only be justified in those cases that fulfill Bethesda's criteria to identify families with Lynch's syndrome.