Low-dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors: relationship to CTNNB1 mutation status

Nishida, Yoshihiro; Tsukushi, Satoshi; Urakawa, Hiroshi; Hamada, Shunsuke; Kozawa, Eiji; Ikuta, Kazunari; Ando, Yumiko; Ishiguro, Naoki

doi:10.1007/s10147-015-0829-0

Cited by 19 publications

(25 citation statements)

References 35 publications

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“…However, this evidence was not confirmed by other groups who reported a statistically not significant trend of poorer outcome in patients harboring the S45F mutation or no correlation between the specific CTNNB1 mutation and RFS (Mullen et al, 2013;Romero et al, 2012). Regarding the impact of mutations on response to medical treatment, Nishida et al did not find a correlation between the efficacy of methotrexate or vinblastine and specific CTNNB1 mutations (Nishida et al, 2015). On the other hand, only the S45F mutation was significantly associated with a poor response to meloxicam (Hamada et al, 2016) and with a progression arrest rate after imatinib treatment (Kasper et al, 2016).…”

Section: Introductionmentioning

confidence: 82%

“…Regarding the impact of mutations on response to medical treatment, Nishida et al . did not find a correlation between the efficacy of methotrexate or vinblastine and specific CTNNB1 mutations (Nishida et al ., ). On the other hand, only the S45F mutation was significantly associated with a poor response to meloxicam (Hamada et al ., ) and with a progression arrest rate after imatinib treatment (Kasper et al ., ).…”

Section: Introductionmentioning

confidence: 97%

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β‐Catenin in desmoid‐type fibromatosis: deep insights into the role of T41A and S45F mutations on protein structure and gene expression

et al. 2017

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Desmoid‐type fibromatosis (DF) is a rare mesenchymal lesion with high risk of local recurrence. Specific β‐catenin mutations (S45F) appeared to be related to this higher risk compared to T41A‐mutated or wild‐type (WT). We explored the influence of both mutations and WT on structure stability and affinity of β‐catenin for α‐catenin and the pattern of gene expression that may influence DF behavior. Using 33 surgically resected primary DFs harboring T41A (n = 14), S45F (n = 10), or WT (n = 9), we performed a comparative molecular analysis by protein/protein interaction modeling, gene expression by DASL microarrays, human inflammation gene panel, and assessment of immune system‐based biomarkers by immunohistochemistry. Mutated proteins were more stable than WT and formed a weaker complex with α‐catenin. Consensus unsupervised gene clustering revealed the presence of two DF group‐mutated (T41A + S45F) and WT (P = 0.0047). The gene sets ‘Inflammatory‐Defense‐Humoral Immune Response’ and ‘Antigen Binding’ were significantly enriched in T41A. The deregulation of 16 inflammation‐related genes was confirmed. Low numbers of T cells and tumor‐associated macrophages (TAM) infiltrating the tumors and low/absent PD‐1/PD‐L1 expression were also identified. We demonstrated that mutated DFs (T41A or S45F) and WT are two distinct molecular subgroups with regard to β‐catenin stability, α‐catenin affinity, and gene expression profiling. A different inflammation signature characterized the two mutated groups, suggesting mediation either by T41A or by S45F. Finally, all mutated cases showed a low number of TIL and TAM cells and a low or absent expression of PD‐1 and PD‐L1 consistent with β‐catenin activation insensitive to checkpoint blockade.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 97%

β‐Catenin in desmoid‐type fibromatosis: deep insights into the role of T41A and S45F mutations on protein structure and gene expression

et al. 2017

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“…Considering these enigmatic behaviors, the therapeutic approach for extra-peritoneal DF has been shifting from surgery with a wide surgical margin to conservative therapy [7, 8]. Recently, several therapeutic modalities for DF were reported including ‘wait & see’ only [9], COX-2 inhibitor therapy [10], hormonal therapy [11], low-dose chemotherapy [12], and tyrosine kinase inhibitors [13, 14], while few studies have investigated the prognosticators of these conservative therapies thus far.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical staining with non-phospho β-catenin as a diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with extra-peritoneal desmoid-type fibromatosis

et al. 2017

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BackgroundImmunohistochemical staining with conventional anti-β-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatosis (DF). This study aimed to evaluate the diagnostic and prognostic value of immunohistochemical staining with anti-non-phospho β-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-β-catenin antibody.MethodsBetween 2003 and 2015, 40 patients with extra-peritoneal sporadic DF were prospectively treated with meloxicam or celecoxib, a COX-2 inhibitor, therapy. The efficacy of this treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Immunohistochemical staining was performed on formalin-fixed material to evaluate the expression of β-catenin and non-phospho β-catenin, and the positivity was grouped as negative, weak, moderate, and strong. DNA was isolated from frozen tissue or formalin-fixed materials, and the CTNNB1 mutation status was determined by direct sequencing.ResultsOf the 40 patients receiving COX-2 inhibitor treatment, there was one with complete remission, 12 with partial remission, 7 with stable disease, and 20 with progressive disease. The mutation sites in CTNNB1 were detected in 22 (55%) of the 40 cases: T41A (17 cases), S45F (3 cases), and T41I and S45P (1 each). The positive nuclear expression of non-phospho β-catenin showed a significant correlation with positive CTNNB1 mutation status detected by Sanger method (p = 0.025), and poor outcome in COX-2 inhibitor therapy (p = 0.022). In contrast, nuclear expression of β-catenin did not show a significant correlation with either CTNNB1 mutation status (p = 0.43) or outcome of COX-2 inhibitor therapy (p = 0.38).ConclusionsNuclear expression of non-phospho β-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho β-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.

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“…Recent studies have suggested that desmoid tumors with different CTNNB1 mutations have diverse tumorigenic potency against various treatment modalities. Desmoid tumors with S45F mutation had higher rates of local recurrence after surgery [10,12,13], and greater resistance to meloxicam treatment [14], whereas the efficacy of low-dose chemotherapy was not associated with the mutation status of CTNNB1 [15]. Taking these findings into consideration, the mutation status of CTNNB1 in desmoid tumors would appear to alter not only tumorigenicity, but also the responsiveness to surgical and conservative treatment.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of cultured desmoid cells with different CTNNB1 mutation status

et al. 2015

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Desmoid tumors are benign mesenchymal neoplasms with a locally aggressive nature. The mutational status of β‐catenin gene (CTNNB1) is presumed to affect the tumorous activity of the cells. In this study, we isolated three kinds of desmoid cell with different CTNNB1 status, and compared their characteristics. Cells were isolated from three patients with abdominal wall desmoid during surgery, all of which were resistant to meloxicam treatment. The mutational status of the CTNNB1 exon 3 was determined for both parental tumor tissues and isolated cultured cells. β‐catenin expression was determined with immunohistochemistry. Responsiveness to meloxicam was investigated with MTS assay together with COX‐2 immunostaining. mRNA expressions of downstream molecules of Wnt/β‐catenin pathway were determined with real‐time RT‐PCR. Three kinds of cell isolated from desmoid tumors harboring different CTNNB1 mutation status (wild type, T41A, and S45F), all exhibited a spindle shape. These isolated cells could be cultured until the 20th passage with unchanged proliferative activity. Nuclear accumulation of β‐catenin was observed in all cultured cells, particularly in those with S45F. Proliferating activity was significantly suppressed by meloxicam (25 μmol/L, P < 0.007) in all three cell cultures, of which parental desmoid was resistant to meloxicam clinically. The mRNA expressions of Axin2, c‐Myc, and Cyclin D1 differently increased in the three cultured cell types as compared with those in human skin fibroblast cells (HDF). Inhibitors of Wnt/β‐catenin pathway downregulated Axin2, c‐Myc, and Cyclin D1 significantly. Isolated and cultured desmoid tumor cells harboring any one of the CTNNB1 mutation status had unique characteristics, and could be useful to investigate desmoid tumors with different mutation status of CTNNB1.

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Low-dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors: relationship to CTNNB1 mutation status

Abstract: MTX and VBL treatment every other week is well tolerated and achieved a favorable response in patients resistant to meloxicam treatment, regardless of CTNNB1 mutation status.

Cited by 19 publications

References 35 publications

β‐Catenin in desmoid‐type fibromatosis: deep insights into the role of T41A and S45F mutations on protein structure and gene expression

β‐Catenin in desmoid‐type fibromatosis: deep insights into the role of T41A and S45F mutations on protein structure and gene expression

Immunohistochemical staining with non-phospho β-catenin as a diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with extra-peritoneal desmoid-type fibromatosis

Characteristics of cultured desmoid cells with different CTNNB1 mutation status

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