How have gamma-secretase inhibitors changed the treatment landscape for desmoid tumors?

Summary

In the early 2010s, a paradigm shift in the management of DTs emerged, with a ‘wait-and-see’ strategy becoming the preferred initial approach for the majority of the patients. Prospective data have since shown that up to 30% experience spontaneous disease regression, and approximately two-thirds remain treatment-free at five years. As a result, surgery is now reserved as an upfront option only for selected cases, while most individuals who are symptomatic, have life-threatening disease, or show clear radiological or clinical progression are primarily managed with systemic therapies. Before 2023, no medical therapy had been approved for DTs, although agents such as multitargeted tyrosine kinase inhibitors, including sorafenib and pazopanib, and conventional chemotherapy, were used in clinical practice. In this context, gamma-secretase inhibitors (GSIs) have recently emerged as one of the most compelling pharmacotherapeutic approaches investigated in DTs, supported by a biologically sound rationale and the most robust clinical evidence to date in this disease.