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Background: Basal cell carcinoma (BCC) is the most common form of skin cancer and poses treatment challenges in advanced stages. Treatment options include surgery, radiotherapy, and systemic therapies, but tumor location and prior interventions can limit these methods. Hedgehog pathway inhibitors (HPIs) are used for patients unsuitable for conventional treatments.

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Basal cell carcinomas (BCC) are driven primarily by cumulative ultraviolet (UV) radiation exposure resulting in activation of the Hedgehog (Hh) signaling pathway, often as a result of UV-mediated Patched-1 (PTCH1) gene inactivation. Accordingly, BCCs most commonly arise at sun-exposed sites such as the head and neck. Very rarely, BCCs can arise at sun-protected sites such as the genital skin and perianal area.

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Patients diagnosed with metastatic basal cell carcinoma (BCC) have a poor prognosis. The current standard of care for adults with locally advanced or metastatic BCC who are not candidates for surgery or radiation therapy is treatment with hedgehog pathway inhibitors (HHIs). For patients who progress while on this therapy, further treatment options are limited.

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Department of Dermatology and Allergology, Paracelsus Medical University, Muellner Hauptstraße 48, 5020 Salzburg, Austria.

Basal cell carcinoma (BCC) accounts for 80% of skin cancer cases. Although mostly curable by simple excision, the treatment of advanced disease can be challenging, as curative surgery or radiotherapy may not always be feasible. The scope of this review is to summarize current knowledge on molecular mechanisms in BCC pathogenesis, to elaborate on the definition of advanced/difficult-to-treat BCC, and to outline systemic treatment options.

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