Recent Advances in Desmoid Tumor Therapy

Napolitano, Andrea; Mazzocca, Alessandro; Ceruso, Mariella Spalato; Minelli, Alessandro; Baldo, Francesca; Badalamenti, Giuseppe; Silletta, Marianna; Santini, Daniele; Tonini, Giuseppe; Incorvaia, Lorena; Vincenzi, Bruno

doi:10.3390/cancers12082135

Cited by 29 publications

(24 citation statements)

References 77 publications

(101 reference statements)

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“…Traditional cytotoxic chemotherapies include doxorubicin/dacarbazine (ADIC), pegylated liposomal doxorubicin, and methotrexate (MTX) with vinca alkaloids, most commonly vinblastine. Newer therapies include tyrosine kinase inhibitors (TKI) such as imatinib, sorafenib, and pazopanib, and multiple novel treatments including gammasecretase inhibitors, Wnt/b-catenin inhibitors, and even immune checkpoint inhibitors are being studied in clinical trials (23). A few studies have examined the susceptibility of CTNNB1 mutation subtypes to various chemotherapies, with S45F mutations having worse outcomes with meloxicam, and no difference observed in different mutations in patients treated with MTX/vinblastine and imatinib (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations inCTNNB1orAPC: A Multi-institutional Retrospective Study

Nathenson

Ratan

et al. 2022

Clinical Cancer Research

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Purpose: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.Experimental Design: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or nextgeneration sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen.Results: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First-and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APCmutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or "other" therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations.Conclusions: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated.

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Section: Introductionmentioning

confidence: 99%

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations inCTNNB1orAPC: A Multi-institutional Retrospective Study

Nathenson

Ratan

et al. 2022

Clinical Cancer Research

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“…MUC4 has also been reported as a highly sensitive and specific marker for low-grade fibromyxoid sarcoma [ 18 ]. Besides Wnt/β-catenin signaling, the Notch pathway has also been reported as a potential therapeutic approach for desmoid tumors [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Prognostic Factors and Integrated Multi-Omics Studies Identify Potential Novel Therapeutic Targets for Pediatric Desmoid Tumor

Ning

Huang

Zhu³

et al. 2022

Biol Proced Online

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Background Desmoid tumor (DT), also known as desmoid-type fibromatosis (DTF) or aggressive fibromatosis (AF) is a rare mesenchymal tumor affecting both children and adults. It is non-metastasis but infiltrative, growing with a high recurrence rate to even cause serious health problems. This study investigates the biology of desmoid tumors through integrated multi-omics studies. Methods We systematically investigated the clinical data of 98 extra-abdominal cases in our pediatric institute and identified some critical clinical prognostic factors. Moreover, our integrated multi-omics studies (Whole Exome Sequencing, RNA sequencing, and untargeted metabolomics profiling) in the paired PDT tumor/matched normal tissues identified more novel mutations, and potential prognostic markers and therapeutic targets for PDTs. Results The top mutation genes, such as CTNNB1 (p.T41A and p.S45F) and MUC4 (p.T3775T, p.S3450S, etc.), were observed with a mutation in more than 40% of PDT patients. We also identified a panel of genes that are classed as the FDA-approved drug targets or Wnt/β-catenin signaling pathway-related genes. The integrated analysis identified pathways and key genes/metabolites that may be important for developing potential treatment of PDTs. We also successfully established six primary PDT cell lines for future studies. Conclusions These studies may promote the development of novel drugs and therapeutic strategies for PDTs.

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“…Although the exact mechanism(s) by which tyrosine kinase inhibitors (TKIs) act in DT has not been fully elucidated, 70 overexpression of platelet-derived growth factor receptor β (PDGFRβ), which is inhibited by the TKI imatinib, has been postulated to drive DT development and growth. 71 Initial case reports suggested that imatinib had efficacy in patients with DT. 72 Subsequently, multiple prospective trials evaluated the safety and efficacy of TKIs in patients with DT (Table 1).…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Evolving strategies for management of desmoid tumor

Riedel

Agulnik

2022

Cancer

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Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease course can be unpredictable. Most DTs are sporadic, harboring somatic mutations in the gene that encodes for βcatenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of βcatenin. Pathology review by an expert soft tissue pathologist is critical in making a diagnosis. Magnetic resonance imaging is preferred for most anatomic locations. Surgery, once the standard of care for initial treatment of DT, is associated with a significant risk of recurrence as well as avoidable morbidity because spontaneous regressions are known to occur without treatment. Consequently, active surveillance in conjunction with pain management is now recommended for most patients. Systemic medical treatment of DT has evolved beyond the use of hormone therapy, which is no longer routinely recommended. Current options for medical management include tyrosine kinase inhibitors as well as more conventional cytotoxic chemotherapy (e.g., anthracyclinebased or methotrexate-based regimens). A newer class of agents, γsecretase inhibitors, appears promising, including in patients who fail other therapies, but confirmation in Phase 3 trials is needed. In summary, DTs present challenges to physicians in diagnosis and prognosis, as well as in determining treatment initiation, type, duration, and sequence. Accordingly, evaluation by a multidisciplinary team with expertise in DT and patient-tailored management are essential. As management strategies continue to evolve, further studies will help clarify these issues and optimize outcomes for patients.

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Recent Advances in Desmoid Tumor Therapy

Cited by 29 publications

References 77 publications

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations inCTNNB1orAPC: A Multi-institutional Retrospective Study

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations inCTNNB1orAPC: A Multi-institutional Retrospective Study

Clinical Prognostic Factors and Integrated Multi-Omics Studies Identify Potential Novel Therapeutic Targets for Pediatric Desmoid Tumor

Evolving strategies for management of desmoid tumor

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