Oncologists Perceive Shift Away from Surgery in Progressive Desmoid Tumors

During a live event for oncologists in Minnesota, Brittany Siontis, MD, a sarcoma oncologist at Mayo Clinic, and participants explored the evidence that has repositioned systemic therapy and particularly the gamma-secretase inhibitor nirogacestat (Ogsiveo) as the preferred intervention for patients with progressive desmoid tumors, while surfacing the practical complexities of ovarian toxicity counseling and the persistent challenge of knowing when to stop treatment.

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CASE SUMMARY

• A 41-year-old woman presented to her gynecologist with a 6-month history of a discrete, tender, and enlarging mass in her right abdominal wall.
• No presenting symptoms
• The patient denies prior trauma to the site or gastrointestinal symptoms.
• She had 2 prior pregnancies including a caesarian section
• Denies chronic comorbidities and concomitant medications; normal menses; report of latest Pap smear is negative; no known family history of familial adenomatous polyposis (FAP) or colorectal cancer
• Focused physical examination: abdominopelvic: firm, well defined, immobile mass tender to palpation in the right upper quadrant
• Imaging studies: T2-weighted MRI reveals mildly hypertense mass measuring 4.5 × 3.7 cm along right rectus abdominis muscle with well-defined margins and vascular enhancement

Desmoid tumors are exceedingly rare; roughly 1000 to 1650 cases are diagnosed annually in the United States, accounting for approximately 10% of all sarcoma diagnoses.¹ The heterogeneity of their clinical behavior makes management decisions particularly difficult. Siontis noted that the majority of patients will experience stable disease or spontaneous regression, and 20% to 30% of tumors will shrink without any intervention. That unpredictability has shifted frontline recommendations toward active surveillance and away from immediate surgery, which historically carried recurrence rates of 24% to 77% regardless of surgical margins.

When the group was asked whether the case patient should undergo biopsy, 85% said yes. Siontis agreed, noting that imaging alone cannot confirm the diagnosis, and that pathologic review by a pathologist with expertise in soft tissue tumors is essential. She also flagged the importance of identifying patients who may harbor an underlying APC mutation: intra-abdominal location and multifocal disease should raise suspicion for FAP, and those patients should be referred for genetic testing and colorectal cancer screening.

CASE UPDATE

Initial treatment plan​

• Biopsy showed desmoid tumor, and her gynecologist decided to observe the patient for enlargement of her abdominal mass and symptoms onset.​
• Management consisted of OTC NSAIDs as directed.​

Four months later​

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• The patient returns to her gynecologist with complaints of visceral pain and bloating, nausea, and constipation​

Focused physical examination ​

• Abdominopelvic: Right upper quadrant mass now associated with muscular rigidity, localized edema and pain to palpation​
• Follow-Up T2 Weighted MRI: Mass has rapidly enlarged (15%), now measuring 4.2 x 5.7 with well-defined margins and vascular enhancement​

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Balkrishna N. Jahagirdar, MBBS, of HealthPartners in Edina, Minnesota, noted that next-generation sequencing (NGS) would not change his management at that moment; the presence or absence of a CTNNB1 mutation does not currently alter treatment decisions. Siontis acknowledged this could shift as more is learned about the prognostic value of specific mutations such as S45F.

Participants were then asked about their preferred first-line approach for a symptomatic or progressive desmoid. Responses were strikingly distributed: 39% selected cryotherapy, 31% active surveillance, and 15% each chose surgery and nirogacestat. “I think pretty much any of these answers could apply, depending on the patient you have sitting in front of you,” said Siontis. She emphasized that among systemic therapies, surgery has fallen considerably in priority given postresection recurrence risk, and that radiation, although occasionally useful, carries the risk of secondary malignancy in a predominantly young patient population.

The DeFi trial (NCT03785964) formed the evidentiary backbone of the systemic therapy discussion. The phase 3, double-blind, placebo-controlled study enrolled 142 patients with histologically confirmed, radiographically progressive desmoid tumors across 37 sites in North America and Europe. Patients were randomly assigned 1:1 to nirogacestat 150 mg twice daily or placebo until progression or unacceptable toxicity; treatment-naive patients amenable to therapy, as well as those with refractory or recurrent disease with a median of 2 prior lines, were eligible. Siontis emphasized the enrollment requirement for documented progression before study entry as critically important: because desmoid tumors can spontaneously stabilize or regress, requiring demonstrated growth prevents patients with naturally indolent disease from inflating the efficacy signal.

The primary end point results were striking. Median progression-free survival (PFS) was not reached in the nirogacestat arm vs 15.1 months with placebo (HR, 0.29; 95% CI, 0.15-0.55; P <.001), and the probability of being event free at 2 years was 76% with nirogacestat vs 44% with placebo.² The objective response rate was 41% with nirogacestat vs 8% with placebo, with a complete response rate of 7%, a result Nicole Jacobi, MD, of Minnesota Oncology in Edina, said she found astonishing for this tumor type. Median time to response was 5.6 months, notably faster than the roughly 9 to 10 months observed in the sorafenib trial. Disease control rate reached 91%.

Jahagirdar raised a point that shaped the subsequent comparison with sorafenib: the placebo arm of DeFi also showed a small number of objective responses, underscoring the spontaneous regression phenomenon and reinforcing why a placebo-controlled design was essential. He was a co-chair on an earlier sorafenib (Nexavar) trial that predated DeFi, and his perspective on the progress made was evident. Siontis noted that while the sorafenib hazard ratio of 0.13 in the A091195 trial (NCT02066181) appears numerically more impressive than nirogacestat's 0.29, the 2 studies enrolled populations with different definitions of progression at entry and different standard-of-care comparator structures, making direct comparison unreliable.^2,3

Long-term follow-up data from DeFi, published in the Journal of Clinical Oncology in 2025, confirmed that the responses seen in the randomized portion of the study are durable with continued treatment.⁴ Among the 70 patients originally assigned to nirogacestat, 15 (21%) remained on treatment at up to 4 years, and the ORR deepened to 45.7% over time, with complete responses in 11.4% of patients. The probability of being event free remained at 78.8% from year 2 through year 4, suggesting that progression events occur mostly in the first year. Importantly, no new or worsening toxicity signals emerged with extended therapy.

Ovarian toxicity dominated the safety discussion. Among the 36 female patients of reproductive potential in DeFi, 75% experienced ovarian dysfunction, defined broadly as amenorrhea, premature menopause, or ovarian failure, with a median time to first onset of 8.9 weeks and a median event duration of 19.1 weeks.⁵ Siontis was careful to contextualize the definition as investigator-reported without formal menstrual diaries, and noted that the gamma-secretase mechanism appears to impair follicle maturation rather than deplete the follicle reserve, which Jahagirdar suggested made “ovarian suppression” a more accurate term than “ovarian failure.”

Critically, 71% of patients who elected to continue nirogacestat despite the toxicity had resolution while still on therapy, and all 11 patients who discontinued for any reason had resolution of ovarian toxicity. Siontis said she has had young female patients decline nirogacestat because of these data, and Jahagirdar observed that fear of the toxicity may be driving refusal more than the actual symptom experience. He said he had one patient on therapy who has had no menopausal symptoms. Jacobi asked whether referring premenopausal patients to a reproductive endocrinologist before initiating treatment would be appropriate, a practice Siontis endorsed as part of counseling.

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_{DISCLOSURES: Siontis previously disclosed consulting from Deciphera and institutional support from Ratio Therapeutics.}

REFERENCES

1. Kasper B, Baldini EH, Bonvalot S, et al. Current Management of Desmoid Tumors: A Review. JAMA Oncol. 2024;10(8):1121-1128. doi:10.1001/jamaoncol.2024.1805

2. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140

3. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379(25):2417-2428. doi:10.1056/NEJMoa1805052

4. Ratan R, et al. Efficacy and safety of long-term continuous nirogacestat treatment in adults with desmoid tumors: results from the DeFi trial. J Clin Oncol. 2025;43(34):3646-3651. doi:10.1200/JCO-25-00582

5. Loggers ET, Chugh R, Federman N, et al. Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study. Cancer. 2024;130(16):2812-2821. doi:10.1002/cncr.35324