How Desmoid Tumor Treatment Has Changed–And What's Next

Mark Agulnik, MD, of the Keck School of Medicine of USC, reflects on 2 decades of evolution in sarcoma care, detailing how the management of desmoid tumors has fundamentally shifted from surgical interventions toward patient-centered systemic strategies. Historically, clinical practice relied heavily on upfront surgical resection and traditional chemotherapy. However, modern management has largely moved away from primary surgery, reserving surgical intervention for rare, select cases. Similarly, the reliance on cytotoxic chemotherapy has diminished significantly as safer, highly effective targeted options have emerged.

Today's treatment paradigm prioritizes active surveillance alongside oral targeted therapeutics, including tyrosine kinase inhibitors like sorafenib (Nexavar) and novel gamma-secretase inhibitors such as nirogacestat (Ogsiveo). As varegacestat, another gamma-secretase inhibitor, progresses through clinical development toward potential regulatory approval, oncologists will soon face nuanced decisions regarding first-line therapy selection. When evaluating multiple agents within the same class side by side, clinicians and patients will need to carefully balance comparative efficacy outcomes against specific adverse event profiles to determine the optimal individualized approach.

Looking to the future, Agulnik emphasizes that defining the optimal sequencing of systemic therapies remains a critical unmet need. A primary clinical objective is to minimize treatment duration, aiming to deliver maximum therapeutic benefit while limiting unnecessary drug exposure. Mitigating long-term toxicities is particularly vital with gamma-secretase inhibitors, which carry known risks regarding ovarian function and fertility. Although clinical evidence indicates that ovarian function typically recovers after treatment cessation, potential long-term reproductive impacts remain a key concern. Over time, integrating predictive biomarkers into routine practice could further refine drug selection. Ultimately, the expanding repertoire of oral therapies and ongoing research mark an exciting era in sarcoma oncology, offering tailored, effective options that prioritize long-term patient health.