Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects

Abstract

Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions. Tyrosine kinase and γ-secretase inhibitors are primarily used in the targeted therapy of DF. The use of these drugs, however, is mainly based on the recommendations of retrospective studies with small sample sizes. Previous studies that focused on the mechanism, efficacy, and safety of targeted therapy for DF were reviewed to provide references for clinical applications and research. The efficacy and safety of targeted therapy were compared with those of other systemic therapy options. Targeted therapy does not provide considerable advantages in efficacy and safety over other medical treatments and is usually applied after the failure of antihormonal therapies, nonsteroidal anti-inflammatory drugs, and chemotherapy. Further studies are required to explore the mechanism, indications, and appropriate drug dosage of the targeted therapy of DF.

Keywords

targeted therapy / desmoid-type fibromatosis / tyrosine kinase inhibitor / γ-secretase inhibitor

Introduction

Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions [¹,²]. Trauma, surgery, pregnancy, and oral contraceptives are high-risk factors of DF development [³,⁴]. Gene mutations, particularly β-catenin and APC gene mutations, play key roles in DF pathogenesis [⁴,⁵]. The Wnt (β-catenin) pathway has been verified to play an important role in DF pathogenesis [⁵–⁹]. Most cases of sporadic DF involve a mutation in the β-catenin gene [⁵,⁸,¹⁰,¹¹]. Similarly, most cases associated with familial adenomatous polyposis (FAP) involve mutations in APC, which regulates β-catenin degradation [⁶,¹²,¹³].

DF has a variable and unpredictable clinical course. Some tumors progress, whereas others will not grow and may even regress spontaneously [¹⁴]. The consensus on the treatment of DF has changed over the past decade, with most centers moving away from primary radical surgery toward a frontline “watchful waiting” policy [¹,²,¹⁵–¹⁸]. Medical therapy is an important strategy for the treatment of progressive DF, particularly cases with unresectable lesions that are adjacent to important organs. Drugs used in targeted therapy mainly include tyrosine kinase inhibitors (TKIs) and γ-secretase inhibitors [¹,¹⁹–²⁴].

Targeted therapy, however, is mainly applied on the basis of the results of retrospective studies with small sample sizes. Moreover, few works have compared the safety and efficacy of different drugs used for the targeted therapy of DF. Therefore, we summarize the mechanisms, current situation, and the future of targeted therapy for DF. Our review will provide a reference for the research and clinical application of targeted treatments for DF.

TKIs

TKIs block ligand-activated receptor phosphorylation and mitogen-activated kinase activation and proliferation; these effects ultimately inhibit cellular growth and proliferation [²⁵,²⁶]. TKIs that have been reported effective in DF therapy include imatinib, nilotinib, pazopanib, sorafenib, and sunitinib [¹,⁴].

Imatinib

Imatinib exerts an inhibitory effect on multiple class 3 receptor tyrosine kinases, including platelet-derived growth factor receptor ɑ (PDGFRɑ), PDGFRβ, and cKIT, which are associated with the Wnt pathway and may play important roles in DF development [⁴,²⁵,²⁷]. In 2002, Mace et al. characterized 9 DF cases through immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses and reported that all cases were positive for PDGFRɑ and PDGFRβ and 6 cases (66.7%) were positive for cKIT [²⁶]. Whether the inhibition of these imatinib targets resulted in imatinib-mediated clinical responses, however, remains unclear.

Heinrich et al. detected cKIT, PDGFRɑ, PDGFRβ, and β-catenin mutations in tumor specimens to determine the molecular basis for tumor responses to imatinib [²⁸]. They were unable to identify cKIT, PDGFRɑ, and PDGFRβ mutations and failed to find correlations between β-catenin and APC mutations and clinical responses to imatinib. In contrast to Mace et al. [²⁶], they did not detect PDGFRɑ expression or activation in the analyzed DF tumors, and they failed to detect phosphorylation despite the comparable levels of PDGFRβ expression in DF tumors and normal fibroblasts. The plasma levels of PDGFRɑ and PDGFRβ in patients with DF were elevated relative to those in normal patient controls. In addition, they found that the level of plasma PDGFRβ was inversely correlated with time to treatment failure. All their results provide evidence that the response of patients with DF to imatinib may be mediated through the inhibition of PDGFRβ kinase activity [²⁸].

Wcislo et al. [29] reported a case that achieved 3 years of sustained response with imatinib despite presenting negative results for PDGFRβ and c-kit (PDGFRɑ was not assessed). Chugh et al. [30] analyzed the expression of cKIT, PDGFRɑ, PDGFRβ, AKT, PTEN, FKHR, and β-catenin in specimens through IHC and the mutations of PDGFRɑ exon 18 and APC through allelic discrimination PCR. They reported that all the tested samples were positive for PDGFRɑ and PDGFRβ and that 1 of the 7 tested cases was positive for cKIT. None of the laboratory findings showed any statistically significant correlation with outcome or response. Therefore, further studies are required to confirm the hypothesis of Heinrich et al. [²⁸] and to identify biomarkers that can be used to predict patients who will respond to imatinib.

Mace et al. [²⁶] performed a study based on IHC and RT-PCR. In their study, 2 cases received imatinib therapy after the failure of chemotherapy, nonsteroidal anti-inflammatory drug (NSAID) therapy, and antiestrogen therapy. The cases received imatinib at the dose of 400 mg twice daily. Both cases responded to imatinib. The tumor masses of 1 case showed an overall size reduction of 50%. The other case showed tumor stability and ongoing reductions in tumor internal density and enhancement. Despite its small sample size, this study provided important information regarding the use of imatinib and other types of TKIs in DF treatment. Heinrich et al. reported the results of a phase II clinical study that was performed to further define the efficacy of imatinib in DF treatment [²⁸]. In this study, 19 patients received 400 mg of imatinib twice daily. Among the patients, 3 (15.7%) exhibited reductions of 50% in tumor volume, and 4 patients (21.1%) had stable disease for more than 1 year before treatment failure. Wcislo et al. [²⁹] reported a patient treated with 400 mg of imatinib once daily. The tumor dimensions of this patient showed sustained shrinkage from 65 mm×31 mm to 35 mm×20 mm during 3 years of follow-up. In a study by Chugh et al. [³⁰], imatinib was prescribed to 51 patients at the dosage of 100–300 mg twice daily on the basis of body surface area. The follow-up results showed progression-free survival (PFS) rates of 94%, 88%, 66%, and 58% at 2 months, 4 months, 1 year, and 3 years, respectively. Five patients (9.8%) remained progression-free after 4 years of treatment, and the tumor volumes of 3 patients (5.9%) reduced by more than 30%. The efficacy of imatinib in the treatment of progressive and recurrent DF was investigated in an FNCLCC/French Sarcoma Group phase II trial [²⁰]. All 40 patients received imatinib at the initial dose of 400 mg/day, which was later increased to 600 mg/day in 1 case (2%) and to 800 mg/day in 8 cases (20%) because of progression. The PFS of the patients at 3, 6, and 12 months were 91%, 80%, and 67%, respectively. The 2-year PFS and overall survival rates of the patients were 55% and 95%, respectively. A phase II study by the German Interdisciplinary Sarcoma Group involved 38 patients with DF who received 800 mg of imatinib per day [¹⁹]. The PFS at 9, 12, 15, 18, 21, and 24 months were 65%, 59%, 53%, 53%, 50%, and 45%, respectively, and the tumor volumes of 7 patients (19%) reduced by more than 30%. A review of 151 previously reported patients revealed overall response rates of 13% and PFS at 6, 12, and 24 months of 78%, 61%, and 51%, respectively. Moreover, the overall response rate of the high-dose group was better than that of the low-dose group (P = 0.039). Studies on the treatment of DF with imatinib are summarized in Table 1.

The toxic effects of imatinib in the treatment of gastrointestinal stromal tumors (GISTs) has been evaluated. Side effects occurred in almost all of cases, and grade 3–4 events occurred in approximately 41% of cases; however, 2/3 of the patients did not require a dose reduction [³¹]. Side effects occurred in almost all GIST cases in the 800 mg/day group. In addition, more instances of edema, anemia, rashes, lethargy, nausea, bleeding, diarrhea, and dyspnea were recorded in the 800 mg/day group than in the 400 mg/day group [³¹]. The majority of patients with DF who received 800 mg/day imatinib required dose reduction because of grade 3 or 4 toxicity [²⁸]. Grades 1, 2, 3, and 4 side effects occurred in 86.8%, 34.2%, 10.5%, and 2.6% of patients, respectively [¹⁹]. Among DF patients who received 400 mg/day imatinib, 45% experienced grade 3 side effects but none suffered grade 4 side effects. The safety and efficacy of imatinib at the initial dose levels of 400 and 800 mg/day for patients with GIST were assessed in EORTC 62005 and S0033/CALGB 150105 studies [³¹–³³]. Both studies showed equivalent response rates and overall survival for both dose levels. In both studies, more side effects were associated with high doses of imatinib than with low doses of imatinib. The results of the GIST studies provided important references for DF despite the absence of evidence indicating that high doses of imatinib cause severe side effects in patients with DF. Therefore, the suitable initial dose of imatinib in patients with DF that will exhibit low toxicity but equivalent efficacy as high doses of imatinib must be identified. The Italian Sarcoma Group, Heidelberg University, and Yonsei University are currently conducting the phase II trials NCT00928525, NCT01137916, and NCT02495519, respectively, to assess the safety and efficacy of imatinib in DF.

Nilotinib, pazopanib, sorafenib, and sunitinib

Nilotinib, an orally bioavailable selective second-generation TKI, is 30 times more potent than imatinib [³⁴]. It is used as second-line therapy for imatinib-resistant BCR-ABL positive CML [³⁵]. In addition to inhibiting BCR-ABL, nilotinib, similar to imatinib, has a potent effects against cKIT and PDGFR [³⁴,³⁶,³⁷]. Kasper et al. investigated the efficacy of nilotinib (800 mg/day) in patients with progressive disease or intolerance under imatinib treatment. In this study, 8 patients were treated with nilotinib for a median duration of 377 days (range: 88–751 days). A total of 88% of the patients showed PFS of 3 months. Nilotinib had mild side effects. Grades 1, 2, 3, and 4 side effects were observed in 75%, 0%, 13%, and 0% of the patients, respectively. No case required dose reduction because of toxicity. The mechanism underlying the therapeutic effect of nilotinib on DF remains unclear. Nevertheless, Kasper et al. presented encouraging results. The treatment mechanism, safety, and efficacy of nilotinib in the targeted therapy of DF need to be further studied.

Pazopanib is a multitargeted TKI of cKIT, PDGFRɑ, and PDGFRβ. The results of the PALETTE study, a randomized, double-blind, placebo-controlled phase III trial, demonstrated that pazopanib is a safe and effective treatment option for patients with metastatic nonadipocytic soft-tissue sarcoma after previous chemotherapy [³⁸]. Randomized controlled trials on the use of pazopanib in DF remain unavailable. Martin-Liberal et al. [³⁹] reported 2 cases that underwent therapy with pazopanib after the failure of surgery, chemotherapy, NSAIDS therapy, and antiestrogen therapy. The cases received an initial pazopanib dose of 800 mg/day. Both cases responded to pazopanib, and 1 of the cases maintained stable disease and had a sustained drop in T2 signal intensity for more than 1 year. The dose of pazopanib, however, was reduced from 800 mg/day to 200 mg/day because of side effects. The other case showed marked tumor shrinkage and reduced T2 signal intensity and suffered no toxicity. Szucs et al. [²²] reported that the tumors of 37.5% of 8 patients reduced by more than 30%, and the remaining patients maintained stable disease. Meanwhile, 75% of the patients derived clinical benefit from treatment in terms of improved function and/or pain reduction. Only 1 patient experienced grade 3 toxicity that resulted in early treatment discontinuation. In the PALETTE study, the most common adverse side effects were fatigue, diarrhea, nausea, weight loss, and hypertension; these side effects were mostly controllable through dose adjustments [³⁸]. The results of these studies are encouraging. Nevertheless, the efficacy and tolerability of pazopanib needs to be further confirmed because of the retrospective nature and the small sample size of these studies. The French Sarcoma Group is currently conducting a phase II trial (NCT01876082) that assesses the safety and efficacy of pazopanib in the treatment of DF [³⁹].

Sorafenib is another orally multitargeted TKI that has been reported useful in DF therapy. Gounder et al. [⁴⁰] studied 26 patients with DF who received sorafenib at the initial dose of 400 mg/day. The initial dose was adjusted in accordance with the severity of side effects. The tumors of 25% and 29% of the cases shrank by more than 30% and by 10%–29%, respectively. Meanwhile, 42% of the cases showed disease stability, whereas 4% showed progression. Notably, this study reported the rapid derivation of clinical benefit in 73% of the symptomatic cases. Clinical improvement was typically noted within 2 weeks of initiating sorafenib therapy. This period was shorter than that observed for imatinib. Side effects were controlled through dose adjustments and the inclusion of antidiarrheal and antihypertensive drugs. The National Cancer Institute is conducting a phase II trial (NCT02066181) to assess the safety and efficacy of sorafenib in DF [⁴].

Skubitz et al. [²⁴] reported a case of aggressive multicentric extra-abdominal DF that was responsive to sunitinib but resistant to imatinib. The spectrum of tyrosine kinases that is inhibited by sunitinib is broader than that is inhibited by imatinib and includes vascular endothelial growth factor receptors (VEGFRs). Direct evidence verifying the hypothesis that VEGFR inhibition accounts for the different responses to sunitinib and imatinib remains unavailable. Therefore, further studies are required to confirm this hypothesis and to identify biomarkers that can be used to identify patients who will respond to certain TKIs.

γ-secretase inhibitor

The Notch signaling pathway plays a key role in the differentiation of bone marrow cells, peripheral immune cells, and gastrointestinal cells [⁴¹–⁴³]. Abnormalities in the Notch pathway are associated with the poor prognosis of solid tumors and hematologic malignancies [⁴⁴–⁴⁷]. Remarkably, the Notch pathway cross-talks with the Wnt pathway, which plays a key role in DF development [⁴⁸,⁴⁹]. These observations provide evidence for the relationship between the Notch pathway and DF development. Kummar et al. reported that the response of DF to GSI is not associated with the status of β-catenin and the APC gene [²¹]. This finding suggests that DF can respond to GSI simply by inhibiting the Notch pathway instead of inhibiting the Wnt pathway synchronously. Given the limitation of the small sample sizes of previous studies on the relationship between Notch pathway and DF development, further studies are required to confirm this hypothesis.

γ-secretase cleaves the Notch intracellular domain, which then translocates to the nucleus where it modulates gene transcription [⁵⁰]. Therefore, γ-secretase inhibitors (GSIs) may inhibit DF by inhibiting the Notch pathway. The results of a study based on a preclinical cancer model showed that the combination of GSI with an inhibitor of the ERK pathway enhances gastric cancer cell death through the downregulation of Wnt/β-catenin pathways [⁵¹]. Arcaroli et al. reported that GSI may be beneficial for patients with elevated levels of components of the Wnt and Notch pathways [⁵²]. These results provide theoretical support for the effectiveness of GSI as a DF therapy.

A phase I study on the use of the GSI PF-903084014 in DF treatment showed that among 7 patients, 5 (71.4%) experienced partial response and 2 (28.6%) experienced stable disease [⁵³]. Treatment-related grades 3 and 4 side effects occurred in 35.9% and 1.6% of the patients, respectively. Meanwhile, the expression of the Notch pathway-related HES4 gene was inhibited in the peripheral blood samples of all evaluable patients. The results of a phase II study on the use of PF-903084014 in the treatment of adult DF showed that 5 patients (29%) achieved more than 30% tumor shrinkage after a median of 2 years of treatment [²¹]. Remarkably, 4 of these 5 patients had no response to imatinib and/or sorafenib before therapy with PF-903084014. During the follow-up time (median 25 (³–³⁰) months), 65% of patients showed sustained stable disease. All patients suffered grades 1 and 2 side effects, and 2 needed dose reduction. Grade 3 treatment-related side effects occurred in 47% of the patients. These results suggested that GSI is an option for the medical treatment of DF, especially when other treatments are ineffective. Meanwhile, the safety and efficacy of GSI must be confirmed in further studies.

Role of targeted therapy

The options for DF treatment include watchful waiting, surgery, radiation, and medical therapy. The results of previous studies have shown that targeted therapy is a completely novel option for DF treatment. Few researchers have discussed the role of targeted therapy in DF treatment. The role of targeted therapy in neoadjuvant and adjuvant therapy in combination with surgery must be assessed by further research. The role of targeted therapy in systemic therapy must be evaluated by comparing the therapeutic effects and adverse reactions of targeted therapy and commonly used chemotherapy protocols.

The rate of the spontaneous regression of DF is 20%–30% and can be observed at all sites of body, including extremities, abdominal wall, abdomen, etc. [¹⁴,⁵⁴]. Given the variable and unpredictable clinical course of DF, the consensus on treatment has changed from primary radical surgery to a front-line “watchful waiting” policy [¹,²,¹⁵–¹⁸]. A series of retrospective studies involving asymptomatic patients managed with a “watchful waiting” policy has shown PFS rates of 50% at 5 years [¹⁶–¹⁸,⁵⁵]. Therefore, similar to immediate surgery, targeted therapy should not be considered as the initial therapy for asymptomatic patients. Furthermore, the efficacy of targeted therapy should be assessed under the full consideration of the clinical course of DF because tumor shrinkage and disease stability in some cases are the clinical course rather than the effects of therapy.

The rate of local recurrence after operation falls in the range of 25%–60% at 5 years of follow-up [⁴,¹⁶,⁵⁶–⁶⁵]. Crago et al. [⁶⁶] reported that extremity location, young age, and large tumor size but not tumor margin are associated with recurrence. Surgery can cause postoperative complications and loss of function. Thus, the observation of Crago et al. [⁶⁶] led to the comprehensive reassessment of DF management and the prioritization of the preservation of function [¹]. Neoadjuvant therapy with targeted medicine may facilitate the regression of DF. This finding may be helpful in efforts to preserve function, reduce postoperative complications, and improve clinical outcomes. Multiple studies have shown that recurrent DF after surgery responds to targeted therapy [²⁶,²⁹]. These results provide further support for the use of targeted therapy for recurrent tumors after surgery. Nevertheless, the role of targeted therapy as a supplement to surgery in neoadjuvant and adjuvant therapy requires further study.

Medical therapy strategies for DF includes antihormonal therapy, NSAID therapy, chemotherapy, and targeted therapy. Previous studies on medical therapies for DF are summarized in Table 1, Fig. 1, and Fig. 2. Tamoxifen is the most commonly used antihormonal chemotherapeutic drug and may be used alone or in combination with NSAIDs [⁶⁷,⁶⁸]. The response rate of patients to hormone-based therapy varies from 33% to 50% (Table 1 and Fig. 1) [⁶⁹,⁷⁰]. The overall response rate of patients who received antihormone and/or NSAIDS therapy was significantly higher than that of patients who received imatinib (P<0.001) (Table 2, Fig. 3). Antiestrogens can increase the occurrence of thromboembolic events and can also increase the incidence of endometrial cancer and ovarian cysts [⁷¹,⁷²]. The rate of side effects of antiestrogens, however, is considerably lower than that of surgery, chemotherapy, and targeted therapy (Table 2, Fig. 3). Therefore, because of its low cost and limited toxicity, hormone-based therapy is used as the first-line medical treatment for DF.

Chemotherapy for DF treatment includes conventional dose chemotherapy and low-dose chemotherapy. Conventional dose chemotherapy is based on anthracycline-based regimens and is usually administered for 6 to 8 cycles [¹]. This regimen can achieve long-term PFS and even complete responses and is often used as second-line therapy after the failure of hormone-based regimens (Table 1) [⁷³,⁷⁴]. In our study, the overall response rate of anthracycline-based regimens is higher than that of imatinib and sorafenib regimens (Table 3, Fig. 3). Conventional dose chemotherapy is associated with high toxicity and can cause cardiac and hematological toxicities. Grade 3–4 toxicities occurred in approximately 31%–43% of patients [⁷³,⁷⁴]. However, we found that the rates of grade 3–4 side effects of imatinib and PF-903084014 were higher than those of anthracycline-based chemotherapy (Table 3, Fig. 3). Furthermore, pegylated liposomal doxorubicin is a better choice than conventional doxorubicin because of its low cardiac toxicity, which is an important consideration when treating young patients [⁷⁵]. Therefore, anthracycline-based chemotherapy should be selected before targeted therapy.

Low-dose chemotherapy is typically administered using methotrexate and vinblastine and has response rates of 15% to 60% (Table 1 and Fig. 1) [⁷³,⁷⁶]. The overall response rates of patients receiving chemotherapy is significantly higher than those of patients receiving imatinib (P<0.001) (Table 4, Fig. 3). Grade 3–4 side effects occurred in 13% to 20% cases undergoing methotrexate and vinblastine treatment [⁷⁷,⁷⁸]. The grade 3–4 side effect rates of methotrexate and vinblastine are significantly lower than those of imatinib and PF-903084014 (Table 4, Fig. 3). The most common side effect of vinblastine is neurotoxicity, which may be reduced by alternating vinblastine with vinorelbine [⁷⁷,⁷⁹]. Targeted therapy is mostly given after chemotherapy failure. Targeted therapy combined with chemotherapy has not been studied before, and studies should fully consider drug tolerability by patients.

Conclusions

Previous studies have shown the encouraging safety and efficacy of targeted therapy for DF. To the best of our knowledge, however, targeted therapy has not shown considerable advantages in efficacy and safety over other medical treatments. Furthermore, the application of targeted therapy, particularly in developing countries, is limited by its high costs. Therefore, targeted therapy is mainly used in cases after the failure of antihormonal therapies, NSAIDs, and chemotherapy. Future research on targeted therapy for DF should focus on the following aspects. First, the mechanisms and targets of targeted therapy should be further clarified through gene detection to help provide individualized treatment to patients. Second, the application of targeted therapy in preoperative neoadjuvant therapy and postoperative adjuvant therapy and in combination with other types of systemic therapies should be explored. Third, the appropriate dosage of various targeted drugs must be identified to improve the patient’s tolerance without reducing the therapeutic effect.

References

[1] Kasper B, Baumgarten C, Garcia J, Bonvalot S, Haas R, Haller F, Hohenberger P, Penel N, Messiou C, van der Graaf WT, Gronchi A; Desmoid Working Group. An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG). Ann Oncol 2017; 28(10): 2399–2408

[2] Otero S, Moskovic EC, Strauss DC, Benson C, Miah AB, Thway K, Messiou C. Desmoid-type fibromatosis. Clin Radiol 2015; 70(9): 1038–1045

[3] Bertario L, Russo A, Sala P, Eboli M, Giarola M, D’amico F, Gismondi V, Varesco L, Pierotti MA, Radice P; Hereditary Colorectal Tumours Registry. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 2001; 95(2): 102–107

[4] Skubitz KM. Biology and treatment of aggressive fibromatosis or desmoid tumor. Mayo Clin Proc 2017; 92(6): 947–964

[5] Lazar AJ, Tuvin D, Hajibashi S, Habeeb S, Bolshakov S, Mayordomo-Aranda E, Warneke CL, Lopez-Terrada D, Pollock RE, Lev D. Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol 2008; 173(5): 1518–1527

[6] Alman BA, Li C, Pajerski ME, Diaz-Cano S, Wolfe HJ. Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol 1997; 151(2): 329–334

[7] Salas S, Chibon F, Noguchi T, Terrier P, Ranchere-Vince D, Lagarde P, Benard J, Forget S, Blanchard C, Dômont J, Bonvalot S, Guillou L, Leroux A, Mechine-Neuville A, Schöffski P, Laë M, Collin F, Verola O, Carbonnelle A, Vescovo L, Bui B, Brouste V, Sobol H, Aurias A, Coindre JM. Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors. Genes Chromosomes Cancer 2010; 49(6): 560–568

[8] Le Guellec S, Soubeyran I, Rochaix P, Filleron T, Neuville A, Hostein I, Coindre JM. CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics. Mod Pathol 2012; 25(12): 1551–1558

[9] Colombo C, Miceli R, Lazar AJ, Perrone F, Pollock RE, Le Cesne A, Hartgrink HH, Cleton-Jansen AM, Domont J, Bovée JV, Bonvalot S, Lev D, Gronchi A. CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study. Cancer 2013; 119(20): 3696–3702

[10] van Broekhoven DL, Verhoef C, Grünhagen DJ, van Gorp JM, den Bakker MA, Hinrichs JW, de Voijs CM, van Dalen T. Prognostic value of CTNNB1 gene mutation in primary sporadic aggressive fibromatosis. Ann Surg Oncol 2015; 22(5): 1464–1470

[11] Lacroix-Triki M, Geyer FC, Lambros MB, Savage K, Ellis IO, Lee AH, Reis-Filho JS. β-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast. Mod Pathol 2010; 23(11): 1438–1448

[12] Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3′ end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of β-catenin in the desmoid tumor. Clin Genet 2000; 57(3): 205–212

[13] Harvey JC, Quan SH, Fortner JG. Gardner’s syndrome complicated by mesenteric desmoid tumors. Surgery 1979; 85(4): 475–477

[14] Colombo C, Miceli R, Le Péchoux C, Palassini E, Honoré C, Stacchiotti S, Mir O, Casali PG, Dômont J, Fiore M, Le Cesne A, Gronchi A, Bonvalot S. Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients. Eur J Cancer 2015; 51(2): 186–192

[15] Kasper B, Baumgarten C, Bonvalot S, Haas R, Haller F, Hohenberger P, Moreau G, van der Graaf WT, Gronchi A; Desmoid Working Group. Management of sporadic desmoid-type fibromatosis: a European consensus approach based on patients’ and professionals’ expertise — a sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group initiative. Eur J Cancer 2015; 51(2): 127–136

[16] Bonvalot S, Eldweny H, Haddad V, Rimareix F, Missenard G, Oberlin O, Vanel D, Terrier P, Blay JY, Le Cesne A, Le Péchoux C. Extra-abdominal primary fibromatosis: aggressive management could be avoided in a subgroup of patients. Eur J Surg Oncol 2008; 34(4): 462–468

[17] Fiore M, Rimareix F, Mariani L, Domont J, Collini P, Le Péchoux C, Casali PG, Le Cesne A, Gronchi A, Bonvalot S. Desmoid-type fibromatosis: a front-line conservative approach to select patients for surgical treatment. Ann Surg Oncol 2009; 16(9): 2587–2593

[18] Briand S, Barbier O, Biau D, Bertrand-Vasseur A, Larousserie F, Anract P, Gouin F. Wait-and-see policy as a first-line management for extra-abdominal desmoid tumors. J Bone Joint Surg Am 2014; 96(8): 631–638

[19] Kasper B, Gruenwald V, Reichardt P, Bauer S, Rauch G, Limprecht R, Sommer M, Dimitrakopoulou-Strauss A, Pilz L, Haller F, Hohenberger P. 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

[20] Penel N, Le Cesne A, Bui BN, Perol D, Brain EG, Ray-Coquard I, Guillemet C, Chevreau C, Cupissol D, Chabaud S, Jimenez M, Duffaud F, Piperno-Neumann S, Mignot L, Blay JY. 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(2): 452–457

[21] Kummar S, O’Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical activity of the g-secretase inhibitor PF-03084014 in adults with desmoid tumors (aggressive fibromatosis). J Clin Oncol 2017; 35(14): 1561–1569

[22] Szucs Z, Messiou C, Wong HH, Hatcher H, Miah A, Zaidi S, van der Graaf WT, Judson I, Jones RL, Benson C. Pazopanib, a promising option for the treatment of aggressive fibromatosis. Anticancer Drugs 2017; 28(4): 421–426

[23] Brogsitter C, Faulhaber D, Kotzerke J. Intraarterial treatment of GEP NET: (68)Ga-DOTATOC SUV cannot predict (90)Y-DOTATOC uptake. Clin Cancer Res 2011; 17(7): 2065

[24] Skubitz KM, Manivel JC, Clohisy DR, Frolich JW. Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors. Cancer Chemother Pharmacol 2009; 64(3): 635–640

[25] Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000; 295(1): 139–145

[26] Mace J, Sybil Biermann J, Sondak V, McGinn C, Hayes C, Thomas D, Baker L. Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer 2002; 95(11): 2373–2379

[27] Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, Gilliland DG, Druker BJ. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997; 90(12): 4947–4952

[28] Heinrich MC, McArthur GA, Demetri GD, Joensuu H, Bono P, Herrmann R, Hirte H, Cresta S, Koslin DB, Corless CL, Dirnhofer S, van Oosterom AT, Nikolova Z, Dimitrijevic S, Fletcher JA. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 2006; 24(7): 1195–1203

[29] Wcislo G, Szarlej-Wcislo K, Szczylik C. Control of aggressive fibromatosis by treatment with imatinib mesylate. A case report and review of the literature. J Cancer Res Clin Oncol 2007; 133(8): 533–538

[30] Chugh R, Wathen JK, Patel SR, Maki RG, Meyers PA, Schuetze SM, Priebat DA, Thomas DG, Jacobson JA, Samuels BL, Benjamin RS, Baker LH; Sarcoma Alliance for Research through Collaboration (SARC). 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(19): 4884–4891

[31] Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364(9440): 1127–1134

[32] Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR; EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005; 41(12): 1751–1757

[33] Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008; 26(4): 626–632

[34] Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 2006; 94(12): 1765–1769

[35] Blay JY, von Mehren M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin Oncol 2011; 38(Suppl 1): S3–S9

[36] Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M, Wiesmann M, Woodman R, Gallagher N. Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg Med Chem 2010; 18(19): 6977–6986

[37] Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 2010; 1804(3): 445–453

[38] van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE Study Group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379(9829): 1879–1886

[39] Martin-Liberal J, Benson C, McCarty H, Thway K, Messiou C, Judson I. Pazopanib is an active treatment in desmoid tumour/aggressive fibromatosis. Clin Sarcoma Res 2013; 3(1): 13

[40] Gounder MM, Lefkowitz RA, Keohan ML, D’Adamo DR, Hameed M, Antonescu CR, Singer S, Stout K, Ahn L, Maki RG. Activity of sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res 2011; 17(12): 4082–4090

[41] Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004; 279(13): 12876–12882

[42] Pollack SJ, Lewis H. Secretase inhibitors for Alzheimer’s disease: challenges of a promiscuous protease. Curr Opin Investig Drugs 2005; 6(1): 35–47

[43] Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a γ-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin 2014; 30(10): 2021–2032

[44] Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991; 66(4): 649–661

[45] Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306(5694): 269–271

[46] Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA 1995; 92(14): 6414–6418

[47] Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD. Notch mediates TGF α-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003; 3(6): 565–576

[48] Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernández-Majada V, Grilli A, López-Bigas N, Bellora N, Albà MM, Torres F, Duñach M, Sanjuan X, Gonzalez S, Gridley T, Capella G, Bigas A, Espinosa L. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA 2009; 106(15): 6315–6320

[49] Kim HA, Koo BK, Cho JH, Kim YY, Seong J, Chang HJ, Oh YM, Stange DE, Park JG, Hwang D, Kong YY. Notch1 counteracts WNT/b-catenin signaling through chromatin modification in colorectal cancer. J Clin Invest 2012; 122(9): 3248–3259

[50] Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137(2): 216–233

[51] Yao J, Qian C, Shu T, Zhang X, Zhao Z, Liang Y. Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/b-catenin. Cancer Biol Ther 2013; 14(9): 833–839

[52] Arcaroli JJ, Quackenbush KS, Purkey A, Powell RW, Pitts TM, Bagby S, Tan AC, Cross B, McPhillips K, Song EK, Tai WM, Winn RA, Bikkavilli K, Vanscoyk M, Eckhardt SG, Messersmith WA. Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a g-secretase inhibitor, in a preclinical colorectal explant model. Br J Cancer 2013; 109(3): 667–675

[53] Messersmith WA, Shapiro GI, Cleary JM, Jimeno A, Dasari A, Huang B, Shaik MN, Cesari R, Zheng X, Reynolds JM, English PA, McLachlan KR, Kern KA, LoRusso PM. A Phase I, dose-finding study in patients with advanced solid malignancies of the oral g-secretase inhibitor PF-03084014. Clin Cancer Res 2015; 21(1): 60–67

[54] Roussin S, Mazouni C, Rimareix F, Honoré C, Terrier P, Mir O, Dômont J, Le Péchoux C, Le Cesne A, Bonvalot S. Toward a new strategy in desmoid of the breast? Eur J Surg Oncol 2015; 41(4): 571–576

[55] Okuno S. The enigma of desmoid tumors. Curr Treat Options Oncol 2006; 7(6): 438–443

[56] Lev D, Kotilingam D, Wei C, Ballo MT, Zagars GK, Pisters PW, Lazar AA, Patel SR, Benjamin RS, Pollock RE. Optimizing treatment of desmoid tumors. J Clin Oncol 2007; 25(13): 1785–1791

[57] Rodriguez-Bigas MA, Mahoney MC, Karakousis CP, Petrelli NJ. Desmoid tumors in patients with familial adenomatous polyposis. Cancer 1994; 74(4): 1270–1274

[58] Ballo MT, Zagars GK, Pollack A, Pisters PW, Pollack RA. Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy. J Clin Oncol 1999; 17(1): 158–167

[59] Gronchi A, Casali PG, Mariani L, Lo Vullo S, Colecchia M, Lozza L, Bertulli R, Fiore M, Olmi P, Santinami M, Rosai J. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003; 21(7): 1390–1397

[60] Johnson JG, Gilbert E, Zimmermann B, Watne AL. Gardner’s syndrome, colon cancer, and sarcoma. J Surg Oncol 1972; 4(4): 354–362

[61] Leibel SA, Wara WM, Hill DR, Bovill EG Jr, de Lorimier AA, Beckstead JH, Phillips TL. Desmoid tumors: local control and patterns of relapse following radiation therapy. Int J Radiat Oncol Biol Phys 1983; 9(8): 1167–1171

[62] Pignatti G, Barbanti-Bròdano G, Ferrari D, Gherlinzoni F, Bertoni F, Bacchini P, Barbieri E, Giunti A, Campanacci M. Extraabdominal desmoid tumor. A study of 83 cases. Clin Orthop Relat Res 2000; (375): 207–213

[63] Posner MC, Shiu MH, Newsome JL, Hajdu SI, Gaynor JJ, Brennan MF. The desmoid tumor. Not a benign disease. Arch Surg 1989; 124(2): 191–196

[64] Reitamo JJ. The desmoid tumor. IV. Choice of treatment, results, and complications. Arch Surg 1983; 118(11): 1318–1322

[65] Sørensen A, Keller J, Nielsen OS, Jensen OM. Treatment of aggressive fibromatosis: a retrospective study of 72 patients followed for 1−27 years. Acta Orthop Scand 2002; 73(2): 213–219

[66] Crago AM, Denton B, Salas S, Dufresne A, Mezhir JJ, Hameed M, Gonen M, Singer S, Brennan MF. A prognostic nomogram for prediction of recurrence in desmoid fibromatosis. Ann Surg 2013; 258(2): 347–353

[67] Fiore M, Colombo C, Radaelli S, Callegaro D, Palassini E, Barisella M, Morosi C, Baldi GG, Stacchiotti S, Casali PG, Gronchi A. Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis. Eur J Cancer 2015; 51(18): 2800–2807

[68] Quast DR, Schneider R, Burdzik E, Hoppe S, Möslein 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(1): 31–40

[69] Desurmont T, Lefèvre JH, Shields C, Colas C, Tiret E, Parc Y. Desmoid tumour in familial adenomatous polyposis patients: responses to treatments. Fam Cancer 2015; 14(1): 31–39

[70] 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(3): 612–620

[71] Howard JH, Pollock RE. Intra-abdominal and abdominal wall desmoid fibromatosis. Oncol Ther 2016; 4(1): 57–72

[72] Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90(18): 1371–1388

[73] de Camargo VP, Keohan ML, D’Adamo DR, Antonescu CR, Brennan MF, Singer S, Ahn LS, Maki RG. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor). Cancer 2010; 116(9): 2258–2265

[74] Gega M, Yanagi H, Yoshikawa R, Noda M, Ikeuchi H, Tsukamoto K, Oshima T, Fujiwara Y, Gondo N, Tamura K, Utsunomiya J, Hashimoto-Tamaoki T, Yamamura T. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 2006; 24(1): 102–105

[75] Constantinidou A, Jones RL, Scurr M, Al-Muderis O, Judson I. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009; 45(17): 2930–2934

[76] Garbay D, Le Cesne A, Penel N, Chevreau C, Marec-Berard P, Blay JY, Debled M, Isambert N, Thyss A, Bompas E, Collard O, Salas S, Coindre JM, Bui B, Italiano A. Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG). Ann Oncol 2012; 23(1): 182–186

[77] Weiss AJ, Horowitz S, Lackman RD. Therapy of desmoid tumors and fibromatosis using vinorelbine. Am J Clin Oncol 1999; 22(2): 193–195

[78] Azzarelli A, Gronchi A, Bertulli R, Tesoro JD, Baratti D, Pennacchioli E, Dileo P, Rasponi A, Ferrari A, Pilotti S, Casali PG. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer 2001; 92(5): 1259–1264

[79] Bertagnolli MM, Morgan JA, Fletcher CD, Raut CP, Dileo P, Gill RR, Demetri GD, George S. Multimodality treatment of mesenteric desmoid tumours. Eur J Cancer 2008; 44(16): 2404–2410

[80] Tanaka K, Yoshikawa R, Yanagi H, Gega M, Fujiwara Y, Hashimoto-Tamaoki T, Hirota S, Tsujimura T, Tomita N. Regression of sporadic intra-abdominal desmoid tumour following administration of non-steroidal anti-inflammatory drug. World J Surg Oncol 2008; 6(1): 17

[81] Bocale D, Rotelli MT, Cavallini A, Altomare DF. Anti-oestrogen therapy in the treatment of desmoid tumours: a systematic review. Colorectal Dis 2011; 13(12): e388–e395

[82] Li S, Fan Z, Fang Z, Liu J, Bai C, Xue R, Zhang L, Gao T. Efficacy of vinorelbine combined with low-dose methotrexate for treatment of inoperable desmoid tumor and prognostic factor analysis. Chin J Cancer Res 2017; 29(5): 455–462

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature