Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

Stacchiotti, Silvia; Pantaleo, Maria Abbondanza; Negri, Tiziana; Astolfi, Annalisa; Tazzari, Marcella; Dagrada, Gian Paolo; Urbini, Milena; Indio, Valentina; Maestro, Roberta; Gronchi, Alessandro; Fiore, Marco; Tos, Angelo Paolo Dei; Conca, Elena; Palassini, Elena; Vincenzi, Bruno; Grosso, Federica; Pilotti, Silvana; Castelli, Chiara; Casali, Paolo G.

doi:10.1158/1078-0432.ccr-15-1243

Cited by 80 publications

(61 citation statements)

References 37 publications

(55 reference statements)

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“…To this end, we initially compared the transcriptome profile of 5 DFSPs and of 5 FS-DFSPs. All samples expressed the COL1A1-PDGFB fusion transcript, with no significant variation in its expression levels between DFSP and FS-DFSP, as previously reported (4,8). No other recurrent fusion transcripts that may hallmark the FS-DFSP variant were detected.…”

Section: Discussionsupporting

confidence: 77%

“…Cases of fibrosarcomatous transformation occurring over time in DFSP after multiple local relapses are described in other reports (8). We cannot challenge this possibility, as the proportion of patients who relapsed was very low.…”

Section: Discussionmentioning

confidence: 82%

“…COL1A1-PDGFB rearrangement is of major help in confirming the diagnosis in those cases in which the classic component is completely lost (4,8). COL1A1-PDGFB retainment in FS-DFSP suggests that other still undetermined genetic abnormalities account for progression of DFSP to FS-DFSP.…”

Section: Introductionmentioning

confidence: 99%

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Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

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Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases.Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 82%

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Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

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“…Scarce data exists on the role of imatinib specifically in these metastatic FS-DFSP tumors. A recent retrospective study evaluating 10 metastatic FS-DFSP patients treated with imatinib showed that 90% of patients achieved clinical benefit (8 partial responses and 1 stable disease) with a median of 11 months PFS [87]. However, the duration of response observed in this study was lower than that reported ina previous series containing a mix of cases with both low-grade and FS-DFSP [88].…”

Section: Targeted Therapycontrasting

confidence: 53%

Advances in sarcoma diagnostics and treatment

2016

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The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed. Transcriptome sequencing techniques have brought forward new diagnostic tools for identifying fusions and/or characterizing unclassified entities. Next-generation sequencing and advanced molecular techniques were also applied to identify potential targets for directed and epigenetic therapy, where preclinical studies reported results for agents active within the receptor tyrosine kinase, mTOR, Notch, Wnt, Hedgehog, Hsp90, and MDM2 signaling networks. At the level of clinical practice, modest developments were seen for some sarcoma subtypes in conventional chemotherapy and in therapies targeting the pathways activated by various receptor tyrosine kinases. In the burgeoning field of immune therapy, sarcoma work is in its infancy; however, elaborate protocols for immune stimulation are being explored, and checkpoint blockade agents advance from preclinical models to clinical studies.

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“…Imatinib mesylate is also used in metastatic tumors in which resection is not possible or may have unacceptable functional and cosmetic results and radiotherapy cannot be performed. [12][13][14] This study aimed to review the literature for DFSP cases.…”

Section: Introductionmentioning

confidence: 99%

Dermatofibrosarcoma Protuberans: A Rare Malignancy

Üyetürk¹

2017

TJ Oncol

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OBJECTIVEDermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor characterized by protuberant growth pattern of skin and subcutaneous tissue. The annual incidence is 4.2 per million. It is often seen between the ages of 20-50 years. This study aimed to evaluate the characteristics of patients with DFSP. METHODSPatients who visited our clinic were retrospectively evaluated. RESULTSAll patients were females and the median age was 42 (29-60) years. The evaluated tumor sites were observed in the body/trunk in one patient, at the hip in two, and at the proximal lower extremity in two. Surgical excision was done in all of them as initial treatment. Re-excision was needed in three patients. One of the patients underwent punch biopsy for diagnosis and surgical removal of the tumor with a negative surgical margin. One of the patients underwent radiotherapy. The median follow-up time was 10 (6-26) months. During the median follow-up, there was no local recurrence or metastasis. CONCLUSIONAs initial treatment, it is important to surgically remove tumors that had no distant metastasis. Positive or near surgical margins should be resected again. If a negative surgical margin cannot be achieved, radiotherapy should be used as the treatment. Imatinib mesylate is used for treatment in unresectable, recurrent, and/or metastatic tumors.

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Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

Cited by 80 publications

References 37 publications

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Advances in sarcoma diagnostics and treatment

Dermatofibrosarcoma Protuberans: A Rare Malignancy

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