Advanced Dermatofibrosarcoma Protuberans Research Articles

Neoadjuvant Imatinib Therapy for Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans (DFSP) is an unusual soft-tissue tumor with a propensity for subclinical extension and local recurrence. Surgical excision, even with tissue-sparing techniques, may cause significant deformity or disability because of the infiltrative nature of DFSP. In this study, we evaluate retrospective data obtained from 4 patients with locally advanced or recurrent DFSP who received neoadjuvant imatinib mesylate therapy before undergoing Mohs micrographic surgery. Patients treated with neoadjuvant imatinib therapy had an average tumor size reduction of 36.9%. This clinical response was paralleled by histopathologic changes, including decreased cellularity in 100% of the total area as well as significant hyalinization. Imatinib therapy for DFSP before Mohs micrographic surgery was associated with 100% local control at a maximum follow-up of 4 years. Neoadjuvant imatinib therapy is a well-tolerated, novel approach to DFSP that reduces tumor burden and facilitates resection. Larger prospective studies are needed to confirm and expand on these results.

Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP)

10520 Background: DFSP is an infiltrative, low-grade, dermal tumor with propensity to recur locally and occasionally metastasize. Translocation between COL1A1 on chromosome 17 and PDGFB on chromosome 22, which results in transcriptional upregulation of PDGFB, is characteristic of DFSP. Autocrine/paracrine PDGFB-mediated activation of PDGFRB drives DFSP proliferation. Two distinct phase II trials of imatinib in patients (pts) with locally advanced or metastatic DFSP were conducted, 1 in North America (SWOG) with confirmed objective response rate and 1 in Europe (EORTC) with 14 week progression-free rate as primary end-points. Methods: Pts with locally advanced or metastatic DFSP were eligible. In the EORTC trial confirmation of t(17;22) by FISH was prospectively required for participation, imatinib was started at 400mg bid, surgery was undertaken after 14 weeks if feasible and response was assessed at 14 weeks. Full accrual was to be 44 pts in one step. In the SWOG trial confirmation of t(17;22) by RT-PCR was performed after enrollment, imatinib was started at 400mg daily and response was assessed every 8 weeks. Full accrual was to be 40 pts in 2 steps. Results: 16 pts were enrolled in EORTC and 8 pts enrolled in SWOG trial. The studies were closed early because of slow accrual and regulatory approval of imatinib in DFSP. Pts age ranged from 24 to 70 yrs, DFSP was located on head/neck, trunk and extremity in 7, 11 and 6 pts, respectively, ranged in size from 1.2–49 cm and was classic, pigmented and fibrosarcomatous DFSP in 13, 1 and 7 pts, respectively. One patient did not have DFSP on central review, lacked t(17;22) and thus was ineligible. Metastases were present in 7 pts involving lung in 6 pts. 11 pts (46%) had partial response, 9 pts had stable disease and 4 pts had progressive disease as best response. Median time to progression was 1.7 yrs. Response and progression-free at 1 yr rates were similar between studies. Imatinib was stopped in 11 pts for progression, 1 pt for toxicity, 2 pts resected free of gross disease and 1 pt withdrew. Conclusions: Imatinib is active in DFSP harboring t(17;22) with an objective response rate approaching 50% and is active in fibrosarcomatous DFSP. Response rates and time to progression did not appear to differ between pts taking 400 mg daily versus 400 mg bid. [Table: see text]

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP) is a rare tumor but still the most common cutaneous sarcoma. DFSP is a tumor of fibroblastic origin, characterized by a slow, undermining and locally destructive growth pattern, which only rarely metastasizes. The clinical appearance, especially of smaller lesions, is often not characteristic, so that diagnosis is often made late and only on biopsy findings. The standard treatment of DFSP is excision with safety margins of 2 to 3 cm. If smaller margins are employed, the risk of local relapse is high. Surgically incurable or metastatic DFSP can be irradiated; the cells are generally radiation-sensitive. 90% of DFSP carry a chromosome translocation of 17 and 22, harboring a gene fusion, which results in a continuous activation of the PDGFbeta signal transduction pathway. This finding led the way to a new molecular targeted therapy of DFSP using inhibitors of the PDGFbeta pathway. The first drug to be registered for targeted treatment of locally advanced or metastasized DFSP is the multikinase inhibitor imatinib, showing a response of about 70% in clinical trials.

Dermatofibrosarcoma Protuberans: Recent Clinical Progress

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor of low malignant grade characterized by a pattern of slow, infiltrative growth and a marked tendency to recur locally after surgical excision. Wide surgical resection is generally accepted as optimal treatment for DFSP. However, despite optimal surgical management, distant metastases may develop in up to 5% of patients. More than 90% of DFSP are characterized by a reciprocal chromosomal translocation, t(17;22). This rearrangement leads to constitutive activation of the platelet-derived growth factor receptor (PDGFR) as a result of deregulated ligand expression, thus providing a rationale for targeted inhibition of PDGFR as a treatment strategy for patients with unresectable locally advanced or metastatic DFSP. This article reviews the current understanding of DFSP, with emphasis on molecular-level pathogenetic events and their implications for management, and evidence for the role of tyrosine kinase inhibition in improving the outcomes of patients with unresectable locally advanced or metastatic DFSP. Surgery with wide margins remains the cornerstone in the management of DFSP. Recently, imatinib, a potent, selective inhibitor of the PDGFR alpha and PDGFR beta protein-tyrosine kinases, has been reported to induce complete or partial remissions in most patients treated for advanced DFSP. Imatinib is approved for treatment of adult patients with unresectable, recurrent, and/or metastatic DFSP who are not eligible for surgery. Future investigations will determine whether imatinib can also be used in the neoadjuvant setting to reduce tumor volume, thereby allowing resection of very large DFSP that would otherwise not be resectable.

Imatinib in locally advanced dermatofibrosarcoma protuberans (DFSP): A phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)

9561 Background: DFSP is known for its low metastatic potential but locally infiltrative growth, hereby enforcing extensive and often multiple surgical procedures. DFSP cells were recently shown to display chromosomal translocations of the regions 17q22 and 22q13, resulting in an autocrine growth stimulation loop via the platelet-derived growth factor (PDGF) pathway. The tyrosine kinase inhibitor imatinib blocks PDGF signal transduction, thus offering a new therapeutic option for DFSP patients. This multicenter phase II trial was aimed to investigate the efficacy of imatinib in locally advanced DFSP. Methods: The primary study endpoint was objective response, secondary endpoints were safety and relapse-free survival. Patients with histological proof of locally advanced primary or relapsed DFSP, measurable tumor parameters according to RECIST, and no evidence of distant metastases were eligible. Patients received imatinib 600 mg/d PO. Tumor measurements were performed at week 6 and 12, and every 8 weeks thereafter. At the end of imatinib treatment, at the earliest after week 12, residual tumors were surgically excised with histological proof of tumor-free margins. Results: By January 2006, nine out of 13 recruited patients were evaluable for response (per protocol, PP), three are still on treatment and one stopped treatment after 12 days due to side effects. Among the nine PP patients, seven partial responses, one stabilization, and one progression were observed. Five responders showed an ongoing tumor shrinkage until complete surgical excision, whereas two patients revealed an initial response at 6 weeks, followed by a disease progression at 12 weeks. None of the patients developed distant metastases under treatment or thereafter. Side effects were mostly mild to moderate (CTC grade 1–2). Severe side effects (CTC grade 3–4), reversible angina pectoris and septicemia, respectively, were observed in two patients. Conclusions: The study results indicate imatinib as a potent systemic treatment option in locally advanced DFSP. However, a subset of DFSP patients appeared resistant to imatinib, either primarily after treatment onset, or secondarily after showing an initial response. No significant financial relationships to disclose.

Molecular and Clinical Analysis of Locally Advanced Dermatofibrosarcoma Protuberans Treated With Imatinib: Imatinib Target Exploration Consortium Study B2225

The cutaneous malignant tumor dermatofibrosarcoma protuberans (DFSP) is typically associated with a translocation between chromosomes 17 and 22 that places the platelet-derived growth factor-B (PDGFB) under the control of the collagen 1A1 promoter. The purpose of this study was to evaluate molecular, cytogenetic, and kinase activation profiles in a series of DFSPs and to determine whether these biologic parameters are correlated with the clinical responses of DFSP to imatinib. We analyzed the objective radiologic and clinical response to imatinib at 400 mg twice daily in eight patients with locally advanced DFSP and two patients with metastatic disease. Each of eight patients with locally advanced DFSP had evidence of t(17;22) and showed a clinical response to imatinib. Four of these patients had complete clinical responses. The two patients with metastatic disease had fibrosarcomatous histology and karyotypes that were substantially more complex than those typically associated with localized DFSP. One patient with metastatic DFSP and an associated t(17;22) had a partial response to imatinib but experienced disease progression after 7 months of therapy. In contrast, the other patient with metastatic disease had a tumor lacking t(17;22), and there was no clinical response to imatinib. Unexpectedly, there was minimal platelet-derived growth factor receptor-beta phosphorylation in the untreated DFSP, despite the documented presence of a PDGFB autocrine mechanism. Imatinib has clinical activity against both localized and metastatic DFSP with t(17;22). However, fibrosarcomatous variants of DFSP lacking t(17;22) may not respond to imatinib.

28 Molecular and clinical analysis of response to imatinib for locally advanced dermatofibrosarcoma protuberans

The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC50 value of 56 nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR.