Hedgehog pathway antagonists such as vismodegib and sonidegib may lead to secondary malignancies in patients being treated for locally advanced basal cell carcinoma (laBCC), according to 2 case reports published in the European Journal of Cancer.1

In the first case, a women aged 82 years with infiltrative laBCC of the centro-facial area who was not a candidate for surgery or radiotherapy initiated vismodegib 150 mg orally once daily. Because of adverse events, the patient’s dose was reduced to 150 mg twice per week, and was subsequently discontinued.

Eight months after treatment discontinuation, the patient presented with a rapidly growing non-pigmented nodule on her right forearm. Histological examination after excision of the lesion confirmed an exophytic, ulcerated melanoma with a tumor thickness of 10 mm.

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To determine whether activation of the hedgehog signaling pathway was involved in the new skin cancer, researchers analyzed the BCC and melanoma specimens; the genetic profile was then compared with the patient’s healthy skin.

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The findings suggested, however, that there was no direct relationship between the 2 tumors, and that the BCC and melanomas were likely 2 independent neoplastic events.

In the second case, a male patient aged 80 years who was diagnosed with laBCC received vismodegib 150 mg orally daily. Despite a partial reduction in tumor size after 2 months, treatment was discontinued because of toxicity after 3 months.

About 10 months later, the patient was diagnosed with an exophytic, ulcerated, pigmented, nodular melanoma in proximity to the primary BCC. The patient died from the secondary cancer 6 months later.

Despite the results of the former patient’s sequencing tests, these cases raise the question of whether abnormal activation of the hedgehog signaling pathway can lead to a protective effect on melanomas.