Screening for mutations of the adenomatous polynosis coli (APC) gene in 67 Italian familial adenomatous polyposis: Further evidence of complex genotype-phenotype correlations

Bertario, Lucio; Giarola, Monica; Stagi, L; Presciuttini, Silvano; Mondini, P; Sala, Paolo; Eboli, M.; Radice, Paolo

doi:10.1016/s0016-5085(98)82301-9

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“…4 Desmoid tumors and aggressive fibromatosis may arise sporadically as a result of somatic mutations in the CTNNB1 (b-catenin) proto-oncogene or via germline mutations in the regulator of b-catenin APC (adenomatous polyposis coli) gene. [5][6][7] The prevalence of specific CTNNB1 mutations (T41A, S45F, and S45P) in sporadic desmoid tumors may be as high as 86%, 6,8,9 whereas germline mutations in APC lead to accumulation of b-catenin and cause familial adenomatous polyposis (FAP) or Gardner syndrome, a phenotypical variant of FAP. 10,11 These conditions are associated with a significant increase in the risk of developing desmoid tumors-the incidence rate is 10% to 30% for individuals with FAP.…”

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confidence: 99%

Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)

Kummar

Coyne

Khánh

et al. 2017

JCO

150

104

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Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

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