Correlation of CTNNB1 Mutation Status with Progression Arrest Rate in RECIST Progressive Desmoid-Type Fibromatosis Treated with Imatinib: Translational Research Results from a Phase 2 Study of the German Interdisciplinary Sarcoma Group (GISG-01)

Kasper, Bernd; Gruenwald, Viktor; Reichardt, Peter; Bauer, Sebastian; Hohenberger, Peter; Haller, Florian

doi:10.1245/s10434-016-5132-4

Cited by 53 publications

(33 citation statements)

References 22 publications

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“…Knowing the mutational status of patients at diagnosis could enable clinicians to decide between a low dose of sorafenib alone (T41A and wild‐type DTs) versus a low dose of sorafenib in combination with an autophagy inhibitor (S45F DTs), which could obviate some of the undesirable adverse effects observed in the higher doses of sorafenib. In contrast to our results, Kasper et al observed a positive correlation between S45F‐mutated patients and imatinib progression arrest rate. However, this study had an overrepresentation of S45F mutations and a remarkably lower percentage of wild‐type DTs.…”

Section: Discussioncontrasting

confidence: 99%

Autophagy inhibition overcomes sorafenib resistance in S45F‐mutated desmoid tumors

Braggio

Koller

Jin

et al. 2019

Cancer

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Background Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. Methods Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism. Results We found distinctive groups of higher‐ and lower‐responder cells. Clustering the lower‐responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild‐type and T41A‐mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F‐mutated DTs. The investigation of autophagy showed the dependency of S45F‐mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored. Conclusions Our findings suggest that the response to sorafenib differs when comparing S45F‐mutated DTs and T41A‐mutated or wild‐type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F‐mutated DT cells, suggesting that profiling β‐catenin status could guide clinical management of desmoid patients who are considering sorafenib treatment.

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Section: Discussioncontrasting

confidence: 99%

Autophagy inhibition overcomes sorafenib resistance in S45F‐mutated desmoid tumors

Braggio

Koller

Jin

et al. 2019

Cancer

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“…Immunohistochemically, the fibroblasts show nuclear and cytoplasmic positivity for β-catenin. CTNNB1 mutations have been detected in up to 85.0% of sporadic DTF cases [8], resulting in the stabilization and translocation of β-catenin into the nucleus where it acts as a transcription factor. It was also demonstrated that the 5-year recurrence-free survival rate of DTF patients with these mutations is significantly worse than that of patients with wild-type CTNNB1 [9].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical and Molecular Analyses Focusing on Mesenchymal Cells in Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis

et al. 2018

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Objective: This study was designed to evaluate the prevalence of CTNNB1 (β-catenin) mutations in cases of papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) expressing aberrant nuclear and cytoplasmic immunoreactivity for β-catenin. Methods: Eight cases of PTC-DTF were available for this study. Immunohistochemistry for β-catenin and BRAF^V600E was performed. CTNNB1 and BRAFV600E mutations were also evaluated by direct sequencing. Results: For β-catenin, although we could demonstrate aberrant nuclear and cytoplasmic immunoreactivity in DTF components in all cases, suggesting activated Wnt signaling, direct sequencing revealed a missense mutation, c.121A>G (p.T41A), in exon 3 in only one case, and no mutations in exons 3, 4, and 5 in the other cases. In the BRAF^V600E analyses, immunohistochemistry revealed positive staining in the carcinoma cells but not DTF components of all cases. These findings were subsequently validated by direct sequencing. Conclusion: This study suggests the significance of the BRAFV600E mutation and activation of Wnt signaling pathway in the carcinoma cells and DTF components, respectively. We believe that the CTNNB1 mutations are not the major factor behind β-catenin translocation indicating Wnt pathway activation. Further study is required to evaluate whether molecular abnormalities other than the CTNNB1 mutation cause activation of Wnt signaling in DTF components of PTC-DTF.

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“…Currently, there is no reliable tool for choosing the best systemic treatment in progressive desmoid tumor. However, some studies suggest that desmoid tumors harboring CTTNB1 mutations are more sensitive to imatinib than desmoid tumors without CTTNB1 mutations [44], and the CTTNB1 S45F mutation is associated with resistance to NSAIDs (meloxicam) compared to other mutations or the absence of mutations (4/4 vs. 9/29) [48]. Further clinical trials are urgently needed to identify predictive factors and properly assess the activity of the treatment using randomized trials and trials using quality of life data.…”

Section: Management Of Desmoid Tumormentioning

confidence: 99%

Adult desmoid tumors: biology, management and ongoing trials

Penel

Chibon

Salas

2017

Current Opinion in Oncology

117

102

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Purpose of reviewTo summarize the current knowledge about the biology and clinical management of adult desmoid tumors.Recent findingsIn the past decade, we have learned that desmoid tumors are driven by alterations of the Wnt/APC/β-catenin pathway, sporadic desmoid tumors are associated with somatic mutations of CTNNB1, and germline mutations of APC and somatic mutations of CTNNB1 are probably mutually exclusive. One-third of desmoid tumors are misdiagnosed; a second pathological opinion is therefore of major importance for desmoid tumor. Surgery is no longer regarded as the cornerstone of desmoid tumors; several retrospective studies have demonstrated the safety of a ‘wait and see’ policy in sporadic abdominal wall desmoid tumor. Desmoid tumors is no longer regarded as an absolute contraindication for pregnancy. At least two new investigational drugs targeting the Wnt/APC/β-catenin pathway are currently being developed.SummaryThe management of desmoid tumors requires multidisciplinary expertise by an experienced team. We must fully understand the physiopathology of the disease (factors influencing the natural history of the disease) and learn how to avoid desmoid tumors occurrence in patients with APC germline mutations, identify reliable prognostic/predictive factors and better assess the efficacy of systemic treatment.

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Correlation of CTNNB1 Mutation Status with Progression Arrest Rate in RECIST Progressive Desmoid-Type Fibromatosis Treated with Imatinib: Translational Research Results from a Phase 2 Study of the German Interdisciplinary Sarcoma Group (GISG-01)

Cited by 53 publications

References 22 publications

Autophagy inhibition overcomes sorafenib resistance in S45F‐mutated desmoid tumors

Autophagy inhibition overcomes sorafenib resistance in S45F‐mutated desmoid tumors

Immunohistochemical and Molecular Analyses Focusing on Mesenchymal Cells in Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis

Adult desmoid tumors: biology, management and ongoing trials

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