Systemic Therapies for Desmoid Tumors: A Review of Past, Present, and Future Treatments

Summary

Desmoid tumors (DTs) are rare, fibroblastic neoplasms characterized by locally aggressive behavior, unpredictable clinical trajectories, and a substantial impact on patient quality of life despite minimal metastatic potential. Although the underlying biology of DTs remains incompletely defined, associations with prior trauma, hormonal exposure, and aberrant Wnt/β-catenin signaling-including somatic CTNNB1 mutations and germline APC alterations seen in Familial Adenomatous Polyposis-have informed both historical and contemporary therapeutic approaches. Management strategies have evolved from surgery-dominant paradigms toward individualized, multimodal treatment algorithms emphasizing systemic medical therapy, as reflected in current NCCN and Desmoid Tumor Working Group recommendations. This review focuses on the medical management of DTs, tracing the evolution from earlier noncytotoxic therapies, including antiestrogen agents such as tamoxifen, to modern systemic options supported by prospective and randomized data. We summarize available evidence for four principal classes of medical therapy: nonsteroidal anti-inflammatory drugs, cytotoxic chemotherapy (with particular emphasis on anthracycline-based regimens), tyrosine kinase inhibitors-most notably sorafenib-and the emerging class of γ-secretase inhibitors. Recent phase III data supporting the efficacy of nirogacestat highlight a shift toward mechanism-based, targeted treatment with demonstrable benefits in progression-free survival, symptom control, and patient-reported outcomes. Collectively, these advances underscore a maturing therapeutic landscape in which systemic therapy plays a central role in disease control, symptom palliation, and preservation of function for patients with advanced desmoid tumors.