A phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors

Desmoid fibromatosis (DF) are mesenchymal neoplasms, with potential aggressive course and relevant clinical impact. New systemic therapy modalities are needed in this symptomatic/progressive population. In this multicenter, phase II trial (NCT03275818), patients with symptomatic/progressing DF received three cycles of weekly nab-paclitaxel. Brief pain inventory short form (BPI-SF) was collected at baseline and in every visit. MRI was performed every 3 months. Primary composite endpoint was RECIST 1.1 overall response rate (ORR) and/or clinical response (improvement ≥ 2 points in BPI-SF). If 40% of patients achieved clinical/radiological response, further investigation would be warranted. Toxicity, progression-free survival (PFS), pattern of response and its correlation with clinical best response and BPI, variation of physical function, and analgesic consumption were secondary endpoints. The translational research reported was not a pre-specified secondary outcome. Forty eligible patients started therapy, being 35 radiologically and clinically evaluable. The study achieved its primary endpoint, as 7(20%) patients obtained RECIST partial response, whereas 31(89%) experienced pain reduction of ≥2 points in BPI-SF worst pain. Therapy was well tolerated. With a median follow-up of 30(14-44) months, median 12 and 24-months PFS rates were 91%(CI 95%, 82-100) and 84%(CI 95%, 71-97). For clinical progression, 12 and 24-months PFS rates were 85% (CI 95%, 73-97) and 74% (CI 95%, 58-90) respectively. Short course of nab-paclitaxel is active, safe and achieves quick and durable responses in progressing/symptomatic DF patients.

Desmoid tumors of the breast are rare, comprising 0.2% of all breast tumors. They may be locally invasive but do not metastasize. The etiology is multifactorial including surgical trauma in the setting of prior cosmetic augmentation breast implants. We submit a case of a large desmoid tumor in the breast following silicone implant placement three years prior to patient presentation. The patient was treated with wide local excision to negative margins and implant exchange. A follow up breast magnetic resonance imaging at 3 and 6 months did not detect a recurrence thus far.

Mutation in the CTNNB1 gene, leading to a deregulation of the WTN/β-catenin pathway, is a common feature of desmoid tumors (DTs). Many β-catenin inhibitors have recently been tested in clinical studies; however, BC2059 (also referred as Tegavivint), a selective inhibitor of nuclear β-catenin that works through binding TBL-1, is the only one being evaluated in a clinical study, specifically for treatment of desmoid tumor patients. Preclinical studies on BC2059 have shown activity in multiple myeloma, acute myeloid leukemia and osteosarcoma. Our preclinical studies provide data on the efficacy of BC2059 in desmoid cell lines, which could help provide insight regarding antitumor activity of this therapy in desmoid tumor patients. In vitro activity of BC2059 was evaluated using desmoid tumor cell lines. Ex vivo activity of BC2059 was assessed using an explant tissue culture model. Pharmacological inhibition of the nuclear β-catenin activity using BC2059 markedly inhibited cell viability, migration and invasion of mutated DT cells, but with lower effect on wild-type DTs. The decrease in cell viability of mutated DT cells caused by BC2059 was due to apoptosis. Treatment with BC2059 led to a reduction of β-catenin-associated TBL1 in all mutated DT cells, resulting in a reduction of nuclear β-catenin. mRNA and protein levels of AXIN2, a β-catenin target gene, were also found to be downregulated after BC2059 treatment. Taken together, our results demonstrate that nuclear β-catenin inhibition using BC2059 may be a novel therapeutic strategy for desmoid tumor treatment, especially in patients with CTNNB1 mutation.

Multiple primary cancers are defined as primary malignant tumors of different histological origins in one person. Desmoid-type fibromatosis (DF) is an extremely rare, locally aggressive, connective tissue malignancy that can be rooted anywhere in the body with the most common sites being thoracic wall and extremities. In contrast, granular cell tumors are rare neoplasms derived from Schwann cells commonly found in the oral cavity, skin and gastrointestinal tract. Moreover, diagnosing a patient with two primary cell tumors has become more common and the challenge of treatment becomes the focus in clinical situations. However, findings of a mass containing DF encapsulated by a granular cell tumor. Currently, there are no established guidelines for this rare condition. This case report serves to raise awareness of these two uncommon primary tumors emerging in an idiosyncratic nature.

Background: The treatment of choice for desmoid-type fibromatosis (DF) has been changed to active surveillance (AS). However, few studies have reported clinical outcomes of AS modality in Asian countries. This study aimed to clarify the significance of AS as a DF treatment modality. Methods: A total of 168 lesions from 162 patients with extra-abdominal DF were included. The mean age at diagnosis was 39 years (1-88 years), and the median maximum tumor diameter at the first visit was 64.1 mm (13.2-255.8 mm). The clinical outcomes of AS and the risk factors requiring active treatment (AT) (defined as an event) from AS modality were investigated. Results: Of the 168 lesions, 94 (56%) were able to continue AS, with a 5-year event-free survival of 54.8%. Of the 68 lesions with PD, 21 (30.9%) lesions were able to continue AS. Neck location (p = 0.043) and CTNNB1 S45F mutation (p = 0.003) were significantly associated with the transition to AT, and S45F mutation was a significant factor associated with the transition to AT by multivariate analysis (hazard ratio: 1.96, p = 0.048). AT outcomes after AS were evaluable in 65 lesions, and 49 (75%) lesions did not require a transition to a second AT. Conclusions: AS was revealed as an effective treatment modality. The transition to AT needs to be considered for neck location and CTNNB1 S45F mutation DF. Good results can be obtained by selecting a treatment method that considers the tumor location even in cases that require intervention.

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