Rechallenge in GIST progressing to imatinib, sunitinib and regorafenib: An Italian survey

Abstract

Background: We retrospectively collected data from metastatic Italian GIST patients treated with imatinib or sunitinib reintroduction after progression to conventional three or four lines of therapy. Material and methods: 104 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected in the present analysis from 6 cancer centres. All patients received all three standard kinase inhibitors. Imatinib dose increase as active second line or 800 mg upfront in exon 9 mutant GIST were allowed. Specific mutations were recorded if available (deletion versus others) and correlated with survival and response according to RECIST 1.1 or CHOI criteria. Results: Seventy-one patients were evaluable. 63 received Imatinib 400 mg as rechal-lenge, while 8 patients were treated with sunitinib at personalised dose and schedule according to the physician's choice. Mutational status was available in all patients and in 68 patients details about type of mutation were achievable. The median follow-up was 13 months (range 1-42 months). The median time to progression (TTP) in patients receiving a rechallenge therapy was 5.4 months (95% CI 1.9-13.5) and Overall Survival (OS) was 10.6 months (95% CI 2.8-26.9). Apparently, in this setting a correlation between mutational status and response rate, TTP or OS was not found. On the contrary , considering only exon 11 mutated patients and comparing patients with deletion vs non deleted ones a significant difference was identified both in terms of TTP and OS (respectively, P ¼ 0.04 and P ¼ 0.02). Conclusions: Our retrospective data confirm that the rechallenge of imatinib or suniti-nib is a reasonable option in advanced GIST patients after failure of previous treatments. As expected, imatinib is the most frequently prescribed option in the Italian real-life setting, demonstrating a TTP and OS longer than those observed in previous studies. Also the prognostic value of the specific type of exon 11 KIT mutations has been confirmed in our series. F2 Molecular characterization and pharmacological profile of myxofibrosarcoma primary cultures Background: Myxofibrosarcoma (MFS) is one of the most common sarcoma of the extremities in adult patients and is characterized by a high propensity for multiple local recurrences. Morphologically, it is a myxoid variant belonging to the heterogeneous group of malignant fibrous histiocytomas (MFH). Distinctive histologic features of MFS may include: myxoid stroma, prominent curvilinear blood vessels and pleomor-phic areas. Given its relatively recent recognition as a distinct pathologic entity, the clinical behavior and outcomes for patients with MFS are uncertain, and the efficacy of chemotherapy is still not well documented, no randomized trials to guide treatment protocols. Although MFH molecular and cellular biology has been widely investigated, and a large number of human MFH cell lines are available, only a few number of MFS cell lines have been established. In an effort to improve the current understanding of the molecular biology and treatment outcomes of high grade MFS, we have conducted an analysis on a series of MFS patient-derived primary cultures. Material and methods: Three primary or recurrence MFS were harvested intraopera-tively from patients undergoing resection and the cells were brought into cell culture. The diagnostic impact of CD109 expression was evaluated and we also investigate TGF-ß as a marker of chemoresistance. Moreove the efficacy of different drugs which are currently used, including ifosfamide, epirubicin, ifosfamide in combination with epirubi-cin or trabectedin for the treatment of soft tissue sarcoma (STS) was assessed. Results: The results showed an overexpression of CD109 gene in all samples compared to the matched healthy tissues highlighting that CD109 could represent a promising marker for MFS diagnosis and a potential therapeutic target. Furthermore, our findings indicated that TGF-ß could be involved in MFS chemoresistance. Finally, pharmacological analysis confirmed the sensitivity of the cultures to the chemotherapy. In particular the most active regimes were represented by epirubicin alone and in combination