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Targeted treatment modalities for skin cancer

Hauschild, A.

doi: 10.1097/01.cmr.0000382741.38344.55
INVITED SPEAKERS ABSTRACTS
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Department of Dermatology, University of Kiel, Germany

The evidence-based treatment of primary skin cancer is uncomplicated in the majority of cases. Typically, surgery is the therapy of choice. However, in more advanced primary tumors and/or in the metastatic setting an efficacious systemic treatment is mandatory and urgently requested.

Recently it was highlighted that primary melanomas represent different subtypes, which are characterized by different mutations. For example, the majority of melanomas, who are linked to intermittent sun exposure are carrying a B-Raf mutation, whereas acral lentiginous melanomas and mucosal melanomas are going along with c-kit mutations in 15% of the cases. Very recently a specific inhibitor of the oncogenic V600E B-Raf mutation (PLX 4032) has been reported as a new successful therapeutic tool in an early clinical trial. 70% of treated patients got either a partial or a complete response of the treated metastatic lesions. For c-kit-mutated melanomas the probability to respond from c-kit inhibitors like Imatinibmesylate is more than 50%, too. Several other agents targeting relevant molecules of the melanoma signalling transduction pathways are currently tested within clinical trials.

Basal cell carcinomas are known to carry mutations in the so-called Sonic-Hedgehog signaling pathway. An early phase I study published in 2009 reported on tumor responses in pretreated, unresectable basal cell carcinomas (BCCs) and metastatic BCCs in 18/33 of the patients with the use of GDC 0449, an oral Hedgehog inhibitor. A global phase II-study to evaluate the efficacy is currently conducted. Furthermore, another formulation of a Hedgehog inhibitor to be used as a topical therapy will be investigated in a clinical trial on Gorlin-Goltz patients in due time. Of interest, tumor responses seem to be unrelated to potential Hedgehog mutations and therefore these new and innovative agents might also play a role in sporadic BCCs.

Small-sized clinical trials have evaluated the efficacy of epidermal growth factor receptor (EGF-R) inhibitors in cutaneous squamous cell carcinomas (SCC) with some success. However, data from larger clinical trials are needed to determine the value of these targeted agents further.

Imatinibmesylate is already approved for dermatofibrosarcoma protuberans (DFSP) as a neo-adjuvant or potential curative attempt. DFSP is known to carry PDGF mutations, which are affected by small molecules like Imatinib. Anti-tumor responses in DFSP with this intravenously applied agent are observed in approx. 70% of the treated patients and appear to indicate a major advance in the treatment of this disease.

The oldest approach for targeted therapies in dermato-oncology is certainly the use of the CD20-antibody Rituximab for cutaneous B-cell lymphomas (CBCL) either as an intralesional or systemic approach. The response rate comes close to 100% in selected cases with disseminated disease, particularly if Rituximab is combined with standard chemotherapy as CHOP.

In conclusion, targeted agents represent a major breakthrough in oncology for many malignant diseases. They were already coming from bench to bedside for cutaneous malignancies like CBCL and DFSP, but however for BCC and metastatic melanoma confirmatory trials are still needed in order to get these innovations approved for the routine use.

© 2010 Lippincott Williams & Wilkins, Inc.