1. Introduction
Desmoid tumors (DT) are rare fibroblastic neoplasms arising from connective tissue that can develop throughout the body and exhibit variable clinical behavior. While our understanding of the etiology of these tumors remains incomplete, there is an association of these tumors with a history of trauma and suggestion of a potential hormonal role in their development. Somatic mutations in β-catenin (CTNNB1), adenomatous polyposis coli (APC) gene mutations and germline APC mutations in Familial Adenomatous Polyposis (FAP) syndrome are also associated with DTs [ 1 , 2 , 3 ].
Incidence is documented at approximately 2–4 persons per million per year, and can manifest with a significant clinical burden and negatively impact quality of life [ 1 ]. Although metastatic potential is minimal and mortality is low, patients can suffer the morbidity of locally aggressive tumors including: acute on chronic pain, swelling, and subsequent mass effect, which, based on location, can result in decreased range of motion, bowel obstruction, compromise of visceral organs, and more. The natural history of the disease evolution and progression is variable, and the National Comprehensive Cancer Network (NCCN) clinical practice guidelines and the Desmoid Tumor Working Group (DTWG) have proposed management guidelines that are nuanced and structured around multidisciplinary care [ 4 , 5 , 6 ]. Given the potential for prolonged stability, or even spontaneous regression, current guidelines support active surveillance as the first step in management for many patients with DT. However, for the significant portion of patients who progress or develop symptoms, multiple therapeutic options exist. Interventions include surgery, radiotherapy, other locoregional therapy (cryoablation, high-intensity-focused ultrasound, radiofrequency ablation), and notably, systemic medical therapies. This review will discuss the medical therapies for desmoid tumor, highlighting more historic treatments including tamoxifen with less of a presence in the current DT treatment landscape, and an overview of currently employed therapies supported by the most recent data.
2. Methods/Literature Search Strategy
A narrative review with a structured literature search was performed. The review was designed to provide a comprehensive, clinically oriented overview of the evolution of systemic therapies for desmoid tumors. The search strategy was designed to be broad and reproducible, and evidence synthesis was guided by multidisciplinary clinical expertise to provide a balanced overview of the field. This narrative review was prepared with attention to the SANRA framework for narrative reviews, with emphasis on a clearly defined clinical aim, transparent description of the literature search, appropriate referencing, and balanced synthesis of the available evidence. To reduce the risk of undue selection bias, the review used a broad, predefined multi-database search strategy supplemented by reference cross-checking, and evidence was incorporated on the basis of clinical relevance, historical importance, and practice-changing impact.
The literature search was conducted using PubMed/MEDLINE, EMBASE, and ClinicalTrials.gov from inception through January 2026. Search terms included “desmoid tumor,” “desmoid fibromatosis,” “aggressive fibromatosis,” “CTNNB1,” “systemic therapy,” “chemotherapy,” “tyrosine kinase inhibitor,” “gamma-secretase inhibitor,” “nirogacestat,” “sorafenib,” “doxorubicin,” “methotrexate,” “tamoxifen,” and “NSAID,” used in various Boolean combinations. Inclusion criteria were: (1) clinical studies, trials, or reviews reporting systemic medical therapies for desmoid tumors in adult or pediatric populations; and (2) studies reporting at least one of the following outcomes: overall response rate, progression-free survival, overall survival, or toxicity profile. Case reports and studies with fewer than five patients were excluded. Reference lists of selected articles were manually reviewed to identify additional relevant studies. Articles were selected for relevance to systemic medical treatment of desmoid tumors, with emphasis on prospective trials, influential retrospective series, clinical practice-informing studies, and key historical reports that shaped treatment development. Outcomes of interest included response, disease control, progression-free survival, toxicity, symptom burden, and patient-reported benefit where available.
3. Body and Discussion
In the history of desmoid tumor treatment, patterns in prevalence have revealed possible risk factors, and guided early interventions and therapies. For example, patterns of prevalence and incidence revealed a possible relationship between DTs and hormone exposure. Epidemiologic studies have consistently noted a female preponderance and disproportionate number of childbearing age women afflicted with desmoid tumors [ 7 , 8 , 9 ]. For example, a representative study in Denmark in 2022 of 179 patients with desmoid tumors demonstrated 76% were female with a median patient age of 38 [ 3 ]. Furthermore, DT incidence increases during pregnancy, with oral contraceptive use, and in the setting of recent pregnancy [ 1 , 2 , 7 , 10 ]. In addition, spontaneous regression of tumor burden has been observed during menopause, or after tamoxifen treatment [ 9 ]. As such, an observational theory was developed regarding tumor development: estrogen may influence tumor growth and spontaneous regression.
In the setting of this observation and proposed tumor progression mechanism, desmoid tumor has previously been treated with the selective estrogen receptor modulating (SERM) therapy, tamoxifen. However, an overview of the most recent data does not demonstrate a discrete cause–effect relationship between tamoxifen, or tamoxifen and sulindac, on disease control or tumor regression [ Table 1 ]. Pertinent studies in this space include a systematic review from 2011, which identified 41 studies over approximately 30 years, including 168 patients with DT treated with antiestrogen agents, alone or in combination with nonsteroidal anti-inflammatory drugs. The overall response rate was reported as 51% [ 10 ]. Importantly, response was not found to correlate with estrogen receptor status of the tumor. In the setting of a tumor with a natural regressing and remitting phenotype, these data were not consistent with a durable and causative relationship between estrogen exposure/chemically induced absence, and tumor regression [ 10 ].
Clinical trials have attempted to investigate if the relationship between hormone fluctuations and DT incidence or progression can be targeted with medical therapy. Specifically, clinical trials evaluating tamoxifen with and without a NSAID have demonstrated safety and an acceptable profile of adverse effects; however, there is insufficient data to conclude rates of regression are reliably above the spontaneous regression rate for DTs. A Children’s Oncology Group phase II trial from 2013 enrolled 59 patients to evaluate safety and efficacy of tamoxifen and sulindac for DT. While serious side effects were limited, with ovarian cysts being the most common, the two year progression-free survival rate was not found to be significantly decreased from the natural history of untreated disease (approximately 36%) [ 13 ]. These data are consistent with the consensus in the literature; as such, this noncytotoxic medical therapy regimen is no longer standard of care at sarcoma centers of excellence.
Today, studies and clinical trials have focused efforts on promising new medical therapies that can be organized into four key classes: First, there remains a role for nonsteroidal anti-inflammatory drugs (NSAIDs), which was previously dominated by sulindac and has been expanded to include indomethacin and celecoxib. Second, a cornerstone of modern treatment, cytotoxic agents notably of the anthracycline class, currently best exemplified by Doxil (liposomal doxorubicin). Third, within the category of targeted therapies: tyrosine kinase inhibitors (TKIs), most notably, sorafenib. Fourth and lastly, a newer class of specific and targeted therapies, γ-secretase inhibitors, with representative medications nirogacestat and varegacestat (AL102).
3.1. NSAIDs
NSAIDs were explored early in the management of desmoid tumors as relatively well-tolerated noncytotoxic agents; later observations of COX-2 overexpression in desmoid tumors provided a biologic rationale supporting their continued study in this disease [ 14 , 15 ]. In the setting of known, well-tolerated, FDA-approved COX-1 and COX-2 blockers, studies were conducted to investigate whether various NSAIDs could influence desmoid tumor regression and recurrence [ Table 2 ]. However, interpretation of these, and subsequently described, medication response rates requires consideration of the underlying natural history of desmoid tumors. Desmoid tumor natural history is recognized to be highly variable and commonly includes prolonged stability, spontaneous regression, and delayed regression after an initial period of progression [ 16 , 17 , 18 ]. In a contemporary prospective, multicenter, observational study, amongst a cohort of 108 patients under active surveillance, 39% demonstrated RECIST progression at a median follow-up of 32.3 months, while spontaneous regression was observed initially in 25% and after dimensional progression in an additional 31%, highlighting that meaningful tumor regression may occur in the absence of systemic intervention [ 19 ].
Against this background, although NSAIDs in isolation or in combination with other treatments have consistently demonstrated tolerability and a low adverse-effect profile, the reported response rates of agents such as sulindac and meloxicam have not been clearly shown to exceed the baseline rates of spontaneous stabilization or regression expected in the natural course of disease [ 12 , 13 ]. As such, current NCCN guidelines include the use of NSAIDs, for example sulindac, primarily in the role of pain management or as an adjunct to a primary medical therapy [ 4 ].
3.2. Anti-Metabolites/Cytotoxic Therapies
Methotrexate (MTX), an anti-folate anti-metabolite, is a frequently used chemotherapeutic choice for multiple cancers, and it is also FDA-approved for autoimmune conditions including rheumatoid arthritis. Multiple clinical trials have demonstrated efficacy of a methotrexate-containing regimen to treat recurrent DTs or disease not amenable to local therapies [ Table 3 ]. A phase II trial of 26 patients from 2007 demonstrated measurable response in 8 patients (31%) and 10 patients with stable disease following weekly injection with methotrexate and vinblastine [ 23 ]. As with other cytotoxic choices, the efficacy of methotrexate is achieved at the cost of higher rates of adverse effects. In patients treated with MTX for DT, the most common grade 3 and higher adverse effects are neutropenia and transaminitis [ 14 ]. More recently, MTX regimens have been replaced by alternative cytotoxic agents. In the systematic review by Tsukamoto et al., a methotrexate containing regimen disease control rate was 71–100%, compared to more currently popular agents such as Doxil (liposomal doxorubicin) with 90–100% [ 24 ].
Regarding systemic therapies for desmoid tumor, anthracycline containing regimens have consistently demonstrated efficacy in the last twenty years of published literature and clinical trials [ Table 3 ]. Specifically, Doxil is a pegylated liposomal doxorubicin, and it is a formulation that has overtaken MTX as a primary cytotoxic therapy for the desmoid tumor patient population. Doxorubicin is an anthracycline with multifaceted cytotoxic activity, predominantly linked to topoisomerase II-associated DNA damage, but also mediated through DNA intercalation. More recent data suggest that, during DNA replication, doxorubicin may additionally impair fork progression through a topoisomerase II–independent intercalative mechanism [ 30 ]. It has been utilized in the treatment of multiple cancers including: breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers. Of note, one of the major side effects of doxorubicin is cardiotoxicity, which limits its utilization by patients with poor heart function and can limit tolerable doses and impact desired efficacy. Ultimately, when compared to other drug classes, or other cytotoxic/chemotherapy agents, Doxil demonstrates favorable progression-free survival (PFS) in DT relative to systemic options available at the time of respective publications [ 26 , 27 , 29 ].
In a 2010 study by Pires de Camargo et al., Doxil demonstrated superior PFS when compared to other notable cytotoxic therapy agents on the market, as well as alternative therapies such as hormonal agents and TKIs [ 31 ]. Regarding adverse effects, the study reports two patients, of the 35 who received anthracyclines, who developed cardiotoxicity [ 31 ]. Although both patients had improvement in their symptoms with medical management, cardiotoxicity remains one of the key limiting variables in prescribing doxorubicin. Evaluating these data in the context of medical management of DT, recognizing cross-era comparisons with newer targeted agents should be interpreted cautiously; many major cancer centers and sarcoma centers of excellence utilize Doxil as a first-line therapy for patients with progressing DT.
3.3. Tyrosine Kinase Inhibitors
TKIs including pazopanib, imatinib and sorafenib have all been employed in desmoid tumors [ Table 4 ]. While pazopanib in some studies has demonstrated lower toxicity than imatinib, among the drug class, sorafenib has the most extensive efficacy data and thus is the preferred agent at present [ 32 , 33 , 34 ]. Specifically, a 2023 systematic review by Tsukamoto et al. reviewed medical treatment options for progressive desmoid tumors and found that tyrosine kinase inhibitors as a class demonstrated meaningful clinical activity, although cross-study comparisons between individual agents are limited by differences in study design, patient selection, and reported endpoints [ 24 ]. More recent real-world comparative data from Noujaim et al. further support the clinical activity of specifically sorafenib and pazopanib in routine practice, while underscoring that TKI selection should be individualized on the basis of efficacy, toxicity profile, and patient-specific considerations [ 32 ].
Sorafenib, an oral multitargeted receptor tyrosine kinase inhibitor, has taken a leading role as the primary TKI utilized as a first-line agent for desmoid tumor [ 24 , 33 ]. A leading argument for the mechanism of this medication class in influencing desmoid tumor regression is theorized to be inhibition of PDGFRB kinase activity [ 35 ]. In addition to an established and clinically familiar safety profile, sorafenib is distinguished from other TKIs by the strength of its supporting evidence base, particularly the landmark randomized phase III trial by Gounder et al. [ 34 ]. With a median follow-up of 27.2 months, the investigators demonstrated a 2-year progression-free survival rate of 81% in the sorafenib group versus 36% in the placebo group [ 34 ]. The most commonly reported adverse events were grade 1 and grade 2 events (53% sorafenib v 69% placebo), although 47% of patients developed grade 3 or 4 adverse events compared to 25% in the placebo group. The grade 3 and 4 adverse events were most commonly cutaneous or gastrointestinal, and led to a significantly higher rate of discontinuation of the trial regimen in the sorafenib group than in the placebo group. This landmark study has played a key role in establishing sorafenib as the representative TKI in desmoid tumor management.
3.4. γ-Secretase Inhibitors
Finally, a promising new therapy for desmoid tumor, nirogacestat, falls within the final medication class: γ-secretase inhibitors [ Table 4 ]. Just as NSAIDs have been used to target the COX-2 expression pattern of DTs, γ-secretase inhibitors became a therapy of interest after evidence that desmoids highly express Notch1. The Notch signaling pathway has been identified to influentially impact desmoid proliferation, and the γ-secretase enzyme is an integral protein in the signaling pathway, cleaving the Notch intracellular domain and facilitating its nuclear translocation to promote gene transcription [ 43 , 44 ]. γ-secretase inhibitors block Notch signaling and, as such, were theorized to restrain DT growth. In phase I and phase II trials, nirogacestat showed antitumor activity and pain palliation. A 2023 phase III randomized, placebo-controlled trial enrolled patients with progressing desmoids to explore this new medication class. Nirogacestat had a significant progression-free survival benefit over placebo (HR 0.29, p < 0.001), and the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo [ 41 ]. The documented adverse events were most commonly (95%) grade 1 or grade 2, although, among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction. Overall, the study robustly demonstrated the medication’s impact on progression-free survival, objective response, pain, disease-specific symptom burden, physical functioning, role functioning, and health-related quality of life, and, subsequently, in November of 2023, the FDA-approved nirogacestat (OGSIVEO) for adult patients with progressing desmoid tumors who require systemic treatment [ 41 ]. Further trials are ongoing exploring safety and efficacy of novel γ-secretase inhibitors including the RINGSIDE trial, a phase II/III trial utilizing the agent AL102 in a patient population of adults with progressive desmoid tumor [ Table 4 ].
4. Conclusions
In the setting of a rare, heterogeneous soft tissue neoplasm with an often indolent yet potentially morbid clinical course, the medical management of desmoid tumors has undergone a meaningful evolution over the last several decades. Early observational and epidemiologic studies provided foundational insight into potential biologic drivers of disease, including hormonal exposure and aberrant Wnt/β-catenin signaling, which in turn guided the development of initial noncytotoxic therapeutic strategies. However, as prospective data have matured and randomized trials have become feasible in this disease space, the limitations of earlier empiric approaches, particularly antiestrogen-based regimens, have become increasingly apparent.
Contemporary management paradigms now emphasize active surveillance for select patients, followed by a stepwise introduction of systemic therapy when disease progression, symptom burden, or functional compromise necessitate intervention. Within this framework, systemic medical therapy has emerged as a cornerstone of treatment for patients with progressive or symptomatic disease not amenable to local control. Tyrosine kinase inhibitors, most notably sorafenib, have demonstrated durable disease stabilization with a favorable toxicity profile and now represent a commonly employed first-line systemic option at many centers. Further, cytotoxic chemotherapy, particularly anthracycline-based regimens such as pegylated liposomal doxorubicin, remains among the most consistently effective options for disease control, though its use must be balanced against cumulative toxicity and patient-specific comorbidities. Concerns for the potential of cardiotoxicity is typically addressed through baseline cardiac assessment and risk-adapted interval monitoring during treatment, particularly in patients with higher cumulative exposure or underlying cardiovascular risk. During the treatment course, monitoring and surveillance allow for dose adjustment or discontinuation if clinically meaningful cardiac dysfunction emerges.
Perhaps most notably, the development and successful phase III evaluation of γ-secretase inhibition with nirogacestat marks a pivotal advance in the field and the first FDA-approved therapy for management of progressing desmoid tumors. For the first time, a targeted therapy grounded in a defined biologic pathway has demonstrated robust improvements not only in progression-free survival, but also in patient-reported outcomes including pain, physical functioning, and overall quality of life. At the same time, ovarian dysfunction should be recognized as a major treatment-related toxicity of nirogacestat, particularly given the predominance of desmoid tumors in young women. Although ovarian dysfunction may improve after treatment discontinuation in many patients, the degree and timing of recovery may not yet be predictable at the individual-patient level. Accordingly, for patients of reproductive age, this risk warrants explicit pre-treatment counseling regarding menstrual and reproductive effects, consideration of fertility preservation when future childbearing is desired, and early involvement of gynecology or reproductive endocrinology when appropriate. During treatment, monitoring for menstrual irregularity and other symptoms of ovarian dysfunction is warranted, and these risks should be incorporated into shared decision-making alongside the demonstrated benefits of nirogacestat in disease control, symptom burden, and quality of life. These data underscore an important shift toward mechanism-based treatment strategies and highlight the feasibility of conducting high-quality randomized trials in desmoid tumor populations.
5. Future Directions
Looking forward, several key areas warrant continued investigation. Regarding targeted therapies, In addition to γ-secretase inhibition, other mechanism-based strategies are emerging, including β-catenin-directed therapies such as tegavivint (BC2059), which disrupts the β-catenin/TBL1-TBLR1 interaction and has shown preclinical activity in desmoid tumor models with early clinical evaluation ongoing [ 45 , 46 ]. Additionally, improved molecular stratification, particularly with respect to CTNNB1 mutation subtype, may refine treatment selection and sequencing, as emerging data suggest differential responses to select medical therapies. Because CTNNB1 encodes β-catenin, a central mediator of the dysregulated Wnt/β-catenin signaling pathway that underlies desmoid tumor biology, mutational subtype of this and related proteins may carry mechanistic as well as clinical relevance. For example, Hamada et al. reported that the CTNNB1 S45F mutation was associated with poor response to meloxicam, and all S45F-mutant tumors in their prospective cohort demonstrated progressive disease [ 22 ]. This finding supported the possibility that mutation subtype may have predictive as well as prognostic value in conservative and systemic treatment selection. More broadly, these findings suggest that biologically informed molecular stratification may help guide future personalization of therapy in desmoid tumors, particularly as pathway-directed agents continue to enter clinical practice. In addition, further study is needed to define the optimal timing, duration, and sequencing of systemic agents, especially as newer targeted therapies are integrated into clinical practice. Finally, given the chronic nature of disease for many patients, long-term toxicity, fertility preservation, and survivorship considerations must remain central to therapeutic decision-making.
As the treatment landscape continues to expand, multidisciplinary care anchored in shared decision-making remains essential. Ongoing collaboration between sarcoma centers, cooperative groups, and patient advocacy organizations will be critical to advancing both clinical outcomes and quality of life for patients with desmoid tumors.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Conceptualization, S.L.N. and A.M.D.; methodology, S.L.N. and A.M.D.; software, S.L.N. and A.M.D.; validation, S.L.N. and A.M.D.; data curation, S.L.N. and A.M.D.; writing—original draft preparation, S.L.N.; writing—review and editing, S.L.N. and A.M.D. All authors have read and agreed to the published version of the manuscript.
Data Availability Statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Bektas M. Bell T. Khan S. Tumminello B. Fernandez M.M. Heyes C. Oton A.B. Desmoid tumors: A comprehensive review Adv. Ther. 2023 40 3697 3722 10.1007/s12325-023-02592-0 37436594 PMC10427533
2. Devata S. Chugh R. Desmoid tumors: A comprehensive review of the evolving biology, unpredictable behavior, and myriad of management options Hematol. Oncol. Clin. N. Am. 2013 27 989 1005 10.1016/j.hoc.2013.07.008 24093172
3. Anneberg M. Svane H.M.L. Fryzek J. Nicholson G. White J.B. Edris B. Smith L.M. Hooda N. Petersen M.M. Baad-Hansen T. The epidemiology of desmoid tumors in Denmark Cancer Epidemiol. 2022 77 102114 10.1016/j.canep.2022.102114 35121405
4. von Mehren M. Kane J.M. Agulnik M. Bui M.M. Carr-Ascher J. Choy E. Connelly M. Dry S. Ganjoo K.N. Gonzalez R.J. Soft tissue sarcoma, version 2.2022, nccn clinical practice guidelines in oncology J. Natl. Compr. Cancer Netw. 2022 20 815 833 10.6004/jnccn.2022.0035 PMC10186762 35830886
5. The Desmoid Tumor Working Group The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients Eur. J. Cancer 2020 127 96 107 10.1016/j.ejca.2019.11.013 32004793
6. Kasper B. Baldini E.H. Bonvalot S. Callegaro D. Cardona K. Colombo C. Corradini N. Crago A.M. Dei Tos A.P. Dileo P. Current management of desmoid tumors: A review JAMA Oncol. 2024 10 1121 1128 10.1001/jamaoncol.2024.1805 38900421
7. Debaudringhien M. Blay J.Y. Bimbai A.M. Bonvalot S. Italiano A. Rousset-Jablonski C. Corradini N. Piperno-Neumann S. Chevreau C. Kurtz J.E. Association between recent pregnancy or hormonal contraceptive exposure and outcome of desmoid-type fibromatosis ESMO Open 2022 7 100578 10.1016/j.esmoop.2022.100578 36116422 PMC9588892
8. Reitamo J.J. Scheinin T.M. Hayry P. The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor Am. J. Surg. 1986 151 230 237 10.1016/0002-9610(86)90076-0 3946757
9. Deyrup A.T. Tretiakova M. Montag A.G. Estrogen receptor-beta expression in extraabdominal fibromatoses: An analysis of 40 cases Cancer 2006 106 208 213 10.1002/cncr.21553 16333857
10. Bocale D. Rotelli M.T. Cavallini A. Altomare D.F. Anti-oestrogen therapy in the treatment of desmoid tumours: A systematic review Colorectal Dis. 2011 13 e388 e395 10.1111/j.1463-1318.2011.02758.x 21831172
11. Hansmann A. Adolph C. Vogel T. Unger A. Moeslein G. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors Cancer 2004 100 612 620 10.1002/cncr.11937 14745880
12. Quast D.R. Schneider R. Burdzik E. Hoppe S. Moslein G. Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective estrogen receptor modulators and sulindac: A single-center long-term observational study in 134 patients Fam. Cancer 2016 15 31 40 10.1007/s10689-015-9830-z 26275868
13. Skapek S.X. Anderson J.R. Hill D.A. Henry D. Spunt S.L. Meyer W. Kao S. Hoffer F.A. Grier H.E. Hawkins D.S. Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: Results of a children’s oncology group (cog) phase ii study Pediatr. Blood Cancer 2013 60 1108 1112 10.1002/pbc.24457 23281268 PMC4646066
14. Riedel R.F. Agulnik M. Evolving strategies for management of desmoid tumor Cancer 2022 128 3027 3040 10.1002/cncr.34332 35670122 PMC9546183
15. Mignemi N.A. Itani D.M. Fasig J.H. Keedy V.L. Hande K.R. Whited B.W. Homlar K.C. Correa H. Coffin C.M. Black J.O. Signal transduction pathway analysis in desmoid-type fibromatosis: Transforming growth factor-beta, COX2 and sex steroid receptors Cancer Sci. 2012 103 2173 2180 10.1111/cas.12037 23035734 PMC4278584
16. Schut A.W. Timbergen M.J.M. van Broekhoven D.L.M. van Dalen T. van Houdt W.J. Bonenkamp J.J. Sleijfer S. Grunhagen D.J. Verhoef C. A nationwide prospective clinical trial on active surveillance in patients with non-intraabdominal desmoid-type fibromatosis: The grafiti trial Ann. Surg. 2023 277 689 696 10.1097/SLA.0000000000005415 35166264 PMC9994811
17. Colombo C. Hakkesteegt S. Le Cesne A. Barretta F. Blay J.Y. Grunhagen D.J. Penel N. Lam L. Fiore M. Palassini E. Active surveillance in patients with extra-abdominal desmoid-type fibromatosis: A pooled analysis of three prospective observational studies Clin. Cancer Res. 2025 31 603 610 10.1158/1078-0432.CCR-24-2340 39620931 PMC11788647
18. Timbergen M.J.M. Schut A.W. Grunhagen D.J. Sleijfer S. Verhoef C. Active surveillance in desmoid-type fibromatosis: A systematic literature review Eur. J. Cancer 2020 137 18 29 10.1016/j.ejca.2020.06.022 32738571
19. Colombo C. Fiore M. Grignani G. Tolomeo F. Merlini A. Palassini E. Collini P. Stacchiotti S. Casali P.G. Perrone F. A prospective observational study of active surveillance in primary desmoid fibromatosis Clin. Cancer Res. 2022 28 4027 4032 10.1158/1078-0432.CCR-21-4205 35247923
20. Tsukada K. Church J.M. Jagelman D.G. Fazio V.W. McGannon E. George C.R. Schroeder T. Lavery I. Oakley J. Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis Dis. Colon. Rectum 1992 35 29 33 10.1007/BF02053335 1310270
21. Nishida Y. Tsukushi S. Shido Y. Wasa J. Ishiguro N. Yamada Y. Successful treatment with meloxicam, a cyclooxygenase-2 inhibitor, of patients with extra-abdominal desmoid tumors: A pilot study J. Clin. Oncol. 2010 28 e107 e109 10.1200/JCO.2009.25.5950 20026797
22. Hamada S. Futamura N. Ikuta K. Urakawa H. Kozawa E. Ishiguro N. Nishida Y. CTNNB1 S45F mutation predicts poor efficacy of meloxicam treatment for desmoid tumors: A pilot study PLoS ONE 2014 9 e96391 10.1371/journal.pone.0096391 24788118 PMC4006838
23. Skapek S.X. Ferguson W.S. Granowetter L. Devidas M. Perez-Atayde A.R. Dehner L.P. Hoffer F.A. Speights R. Gebhardt M.C. Dahl G.V. Vinblastine and methotrexate for desmoid fibromatosis in children: Results of a Pediatric Oncology Group Phase II Trial J. Clin. Oncol. 2007 25 501 506 10.1200/JCO.2006.08.2966 17290057
24. Tsukamoto S. Takahama T. Mavrogenis A.F. Tanaka Y. Tanaka Y. Errani C. Clinical outcomes of medical treatments for progressive desmoid tumors following active surveillance: A systematic review Musculoskelet. Surg. 2023 107 7 18 10.1007/s12306-022-00738-x 35150408
25. Patel S.R. Evans H.L. Benjamin R.S. Combination chemotherapy in adult desmoid tumors Cancer 1993 72 3244 3247 10.1002/1097-0142(19931201)72:11<3244::AID-CNCR2820721118>3.0.CO;2-D 8242548
26. Gega M. Yanagi H. Yoshikawa R. Noda M. Ikeuchi H. Tsukamoto K. Oshima T. Fujiwara Y. Gondo N. Tamura K. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis J. Clin. Oncol. 2006 24 102 105 10.1200/JCO.2005.02.1923 16382119
27. Constantinidou A. Jones R.L. Scurr M. Al-Muderis O. Judson I. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis Eur. J. Cancer 2009 45 2930 2934 10.1016/j.ejca.2009.08.016 19767198
28. Azzarelli A. Gronchi A. Bertulli R. Tesoro J.D. Baratti D. Pennacchioli E. Dileo P. Rasponi A. Ferrari A. Pilotti S. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis Cancer 2001 92 1259 1264 10.1002/1097-0142(20010901)92:5<1259::AID-CNCR1446>3.0.CO;2-Y 11571741
29. Garbay D. Le Cesne A. Penel N. Chevreau C. Marec-Berard P. Blay J.Y. Debled M. Isambert N. Thyss A. Bompas E. Chemotherapy in patients with desmoid tumors: A study from the French Sarcoma Group (FSG) Ann. Oncol. 2012 23 182 186 10.1093/annonc/mdr051 21444357
30. Van Ravenstein S.X. Mehta K.P. Kavlashvili T. Byl J.A.W. Zhao R. Osheroff N. Cortez D. Dewar J.M. Topoisomerase II poisons inhibit vertebrate DNA replication through distinct mechanisms EMBO J. 2022 41 e110632 10.15252/embj.2022110632 35578785 PMC9194788
31. de Camargo V.P. Keohan M.L. D’Adamo D.R. Antonescu C.R. Brennan M.F. Singer S. Ahn L.S. Maki R.G. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor) Cancer 2010 116 2258 2265 10.1002/cncr.25089 20187095 PMC2925106
32. Noujaim J. Gupta A.A. Holloway C.L. Saleh R. Srikanthan A. Lemieux C. Soroka H.P. Tibout P. Turcotte R. Feng X. Real-word experience of pazopanib and sorafenib in patients with desmoid tumors: A CanSaRCC multi-center study Eur. J. Cancer 2024 205 114119 10.1016/j.ejca.2024.114119 38759389
33. Gounder M.M. Lefkowitz R.A. Keohan M.L. D’Adamo D.R. Hameed M. Antonescu C.R. Singer S. Stout K. Ahn L. Maki R.G. Activity of Sorafenib against desmoid tumor/deep fibromatosis Clin. Cancer Res. 2011 17 4082 4090 10.1158/1078-0432.CCR-10-3322 21447727 PMC3152981
34. Gounder M.M. Mahoney M.R. Van Tine B.A. Ravi V. Attia S. Deshpande H.A. Gupta A.A. Milhem M.M. Conry R.M. Movva S. Sorafenib for advanced and refractory desmoid tumors N. Engl. J. Med. 2018 379 2417 2428 10.1056/NEJMoa1805052 30575484 PMC6447029
35. Heinrich M.C. McArthur G.A. Demetri G.D. Joensuu H. Bono P. Herrmann R. Hirte H. Cresta S. Koslin D.B. Corless C.L. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor) J. Clin. Oncol. 2006 24 1195 1203 10.1200/JCO.2005.04.0717 16505440
36. Chugh R. Wathen J.K. Patel S.R. Maki R.G. Meyers P.A. Schuetze S.M. Priebat D.A. Thomas D.G. Jacobson J.A. Samuels B.L. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial Clin. Cancer Res. 2010 16 4884 4891 10.1158/1078-0432.CCR-10-1177 20724445
37. Penel N. Le Cesne A. Bui B.N. Perol D. Brain E.G. Ray-Coquard I. Guillemet C. Chevreau C. Cupissol D. Chabaud S. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): An FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up Ann. Oncol. 2011 22 452 457 10.1093/annonc/mdq341 20622000
38. Jo J.C. Hong Y.S. Kim K.P. Lee J.L. Lee J. Park Y.S. Kim S.Y. Ryu J.S. Lee J.S. Kim T.W. A prospective multicenter phase II study of sunitinib in patients with advanced aggressive fibromatosis Invest. New Drugs 2014 32 369 376 10.1007/s10637-013-0059-0 24425345
39. Kasper B. Gruenwald V. Reichardt P. Bauer S. Rauch G. Limprecht R. Sommer M. Dimitrakopoulou-Strauss A. Pilz L. Haller F. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG) Eur. J. Cancer 2017 76 60 67 10.1016/j.ejca.2017.02.001 28282612
40. Toulmonde M. Pulido M. Ray-Coquard I. Andre T. Isambert N. Chevreau C. Penel N. Bompas E. Saada E. Bertucci F. Pazopanib or methotrexate-vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): A non-comparative, randomised, open-label, multicentre, phase 2 study Lancet Oncol. 2019 20 1263 1272 10.1016/S1470-2045(19)30276-1 31331699
41. Gounder M. Ratan R. Alcindor T. Schoffski P. van der Graaf W.T. Wilky B.A. Riedel R.F. Lim A. Smith L.M. Moody S. Nirogacestat, a gamma-secretase inhibitor for desmoid tumors N. Engl. J. Med. 2023 388 898 912 10.1056/NEJMoa2210140 36884323 PMC11225596
42. Kasper B. Gounder M. Chugh R. Singh A. Van Tine B.A. Andelkovic V. Choy E. Lewin J. Ratan R. Yovell J. 1766P Updated results of the RINGSIDE phase II trial and open-label extension of AL102 for treatment of desmoid tumors Ann. Oncol. 2024 35 S1051 S1052 10.1016/j.annonc.2024.08.1857
43. Shang H. Braggio D. Lee Y.J. Al Sannaa G.A. Creighton C.J. Bolshakov S. Lazar A.J. Lev D. Pollock R.E. Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors Cancer 2015 121 4088 4096 10.1002/cncr.29564 26349011 PMC4635059
44. Gounder M.M. Notch inhibition in desmoids: “Sure it works in practice, but does it work in theory?” Cancer 2015 121 3933 3937 10.1002/cncr.29562 26348868
45. Braggio D.A. Costas C.d.F.F. Koller D. Jin F. Zewdu A. Lopez G. Batte K. Casadei L. Welliver M. Horrigan S.K. Preclinical efficacy of the Wnt/beta-catenin pathway inhibitor BC2059 for the treatment of desmoid tumors PLoS ONE 2022 17 e0276047 10.1371/journal.pone.0276047 36240209 PMC9565452
46. Cranmer L.D. Razak A.R.A. Ratan R. Choy E. George S. Liebner D.A. Stenehjem D.D. Gounder M.M. Results of a phase I dose escalation and expansion study of tegavivint (BC2059), a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumor J. Clin. Oncol. 2022 40 11523 10.1200/JCO.2022.40.16_suppl.11523