CTNNB1 S45F Mutation Predicts Poor Efficacy of Meloxicam Treatment for Desmoid Tumors: A Pilot Study

Abstract

We hypothesized that patterns of CTNNB1 (β-catenin) mutations would affect the outcome of conservative therapy in patients with desmoid tumors. This study aimed to determine the significance of CTNNB1 (β-catenin) mutations in predicting the treatment outcome in patients with desmoid tumors treated with meloxicam, a cyclooxygenase-2 (COX-2) selective inhibitor. Between 2003 and 2012, consecutive thirty-three patients with extra-peritoneal sporadic desmoid tumors were prospectively treated with meloxicam as the initial systemic medical therapy. The efficacy of meloxicam was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). DNA was isolated from frozen tissue or formalin-fixed materials. CTNNB1 mutation analysis was performed by direct sequencing. Positivity of nuclear β-catenin staining by immunohistochemistry was compared with the status of CTNNB1 mutations. The correlation between the efficacy of meloxicam treatment and status of CTNNB1 mutations was analyzed. Of the 33 patients with meloxicam treatment, one showed complete remission (CR), 7 partial remission (PR), 12 stable disease (SD), and 13 progressive disease (PD). The following 3 point mutations were identified in 21 of the 33 cases (64%): T41A (16 cases), S45F (4 cases) and S45P (one case). The nuclear expression of β-catenin correlated significantly with CTNNB1 mutation status (p = 0.035); all four cases with S45F mutation exhibited strong nuclear expression of β-catenin. S45F mutation was significantly associated with a poor response (all cases; PD) (p = 0.017), whereas the other mutations had no impact on efficacy. The CTNNB1 mutation status was of significant prognostic value for meloxicam treatment in patients with sporadic desmoid tumors.

Mixed Adenoneuroendocrine Carcinomas of the Gastrointestinal Tract: Targeted Next-Generation Sequencing Suggests a Monoclonal Origin of the Two Components

“…2). This mutation has already been linked to the nuclear localization of the protein in desmoid tumors [22]. …”

Simple resection of truncal desmoid tumors: A case series

“…with or without radiotherapy) and different surgical margin statuses [microscopically negative (R0) or positive (R1) margins] (10)(11)(12). In previous studies by the present authors, patients with extraperitoneal desmoid tumors were prospectively and consecutively treated with meloxicam, a cyclooxygenase-2 (COX-2) inhibitor (13,14), and a significant predictive value of CTNNB1 for this conservative treatment was demonstrated (15).…”

“…In all patients enrolled in the present study since August 2008, desmoid tumors were histologically diagnosed using specimens obtained by incisional biopsy at the time of referral and treated at Nagoya University Hospital. Part of the obtained specimens were snap-frozen and stored at -80˚C for mutation analysis as previously described (15). Briefly, DNA was extracted from the frozen tissue or 5-µm-thick formalin-fixed, paraffin-embedded tissue using the High Pure PCR Template Preparation kit (Roche Diagnostics GmbH, Mannheim, Germany), according to the manufacturer's protocol.…”

“…Briefly, DNA was extracted from the frozen tissue or 5-µm-thick formalin-fixed, paraffin-embedded tissue using the High Pure PCR Template Preparation kit (Roche Diagnostics GmbH, Mannheim, Germany), according to the manufacturer's protocol. The extracted DNA was subjected to polymerase chain reaction (PCR) analysis in order to determine the existence of point mutations in codons 41 or 45 of CTNNB1 exon 3 using two pairs of primers spanning these mutation sites, as previously described (15). Amplified PCR products were subjected to direct sequencing.…”

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

“…Mutation status of CTNNB1 was determined using DNA extracted from frozen tissue or 5-μm-thick formalin-fixed, paraffinembedded tissue. The DNA was subjected to PCR amplification using specific primers for CTNNB1 exon 3, as reported previously [23]. Purified products were subjected to direct sequencing using the above primers (forward) along with Applied Biosystems (Foster City, CA, USA) Big Dye Terminator V3.1 and an Applied Biosystems 3730x DNA analyzer at FASMAC Co. Ltd. (Kanagawa, Japan).…”