Bernd Kasper1, Viktor Gruenwald2, Peter Reichardt3, Sebastian Bauer4, Peter Hohenberger5, Florian Haller6. 1. Sarcoma Unit, Interdisciplinary Tumor Center, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany. bernd.kasper@umm.de. 2. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. 3. Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Berlin, Germany. 4. Sarcoma Center, West German Cancer Center, Essen, Germany. 5. Sarcoma Unit, Interdisciplinary Tumor Center, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany. 6. Institute of Pathology, Friedrich Alexander University, Erlangen-Nürnberg, Erlangen, Germany.
Abstract
BACKGROUND: CTNNB1 gene mutations are the molecular key events in the majority of sporadic desmoid-type fibromatosis (DF). The specific S45F mutation has been reported to be associated with a more aggressive clinical course in DF. For the current study, the CTNNB1 mutation status was analyzed in DF samples from the prospective German Interdisciplinary Sarcoma Group (GISG) phase 2 study evaluating imatinib to induce progression arrest in DF Response Evaluation Criteria In Solid Tumors (RECIST) progressive patients. METHODS: Thirty-seven patients were treated with a planned dose of imatinib 800 mg daily over 2 years (NCT01137916). The progression arrest rate (PAR) after 6 months of treatment was the primary endpoint of the study. CTNNB1 exon 3 mutation status was analyzed using Sanger sequencing. RESULTS: Thirty-three (97 %) of 34 patients reaching the primary endpoint were evaluable for CTNNB1 mutation exon 3 status. T41A mutations accounted for 30.3 % of the study samples and S45 mutations for 48.5 %, whereas CTNNB1 wild-type status was found in 21.2 %. The respective PAR at 6 months was 70, 81, and 43 %. Patients harboring CTNNB1 mutations demonstrated a higher PAR compared to wild-type DF. There was a statistically significant difference comparing patients with S45F mutations (85 % PAR) versus wild-type status (p = 0.05). CONCLUSIONS: Mutations at position S45 were overrepresented in the GISG-01 trial recruiting RECIST progressive patients only. The positive correlation of CTNNB1 mutation status with the progression arrest rate after imatinib therapy supports the idea of a potential predictive impact of the mutation status on DF treatment decision making.
BACKGROUND:CTNNB1 gene mutations are the molecular key events in the majority of sporadic desmoid-type fibromatosis (DF). The specific S45F mutation has been reported to be associated with a more aggressive clinical course in DF. For the current study, the CTNNB1 mutation status was analyzed in DF samples from the prospective German Interdisciplinary Sarcoma Group (GISG) phase 2 study evaluating imatinib to induce progression arrest in DF Response Evaluation Criteria In Solid Tumors (RECIST) progressive patients. METHODS: Thirty-seven patients were treated with a planned dose of imatinib 800 mg daily over 2 years (NCT01137916). The progression arrest rate (PAR) after 6 months of treatment was the primary endpoint of the study. CTNNB1 exon 3 mutation status was analyzed using Sanger sequencing. RESULTS: Thirty-three (97 %) of 34 patients reaching the primary endpoint were evaluable for CTNNB1 mutation exon 3 status. T41A mutations accounted for 30.3 % of the study samples and S45 mutations for 48.5 %, whereas CTNNB1 wild-type status was found in 21.2 %. The respective PAR at 6 months was 70, 81, and 43 %. Patients harboring CTNNB1 mutations demonstrated a higher PAR compared to wild-type DF. There was a statistically significant difference comparing patients with S45F mutations (85 % PAR) versus wild-type status (p = 0.05). CONCLUSIONS: Mutations at position S45 were overrepresented in the GISG-01 trial recruiting RECIST progressive patients only. The positive correlation of CTNNB1 mutation status with the progression arrest rate after imatinib therapy supports the idea of a potential predictive impact of the mutation status on DF treatment decision making.
Authors: Joanna Robles; Vahakn S Keskinyan; Matthew Thompson; Joseph T Davis; David Van Mater Journal: Pediatr Hematol Oncol Date: 2020-03-04 Impact factor: 1.969
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Authors: B Kasper; C Baumgarten; J Garcia; S Bonvalot; R Haas; F Haller; P Hohenberger; N Penel; C Messiou; W T van der Graaf; A Gronchi Journal: Ann Oncol Date: 2017-10-01 Impact factor: 32.976