Vismodegib-resistant basal cell carcinomas in basal cell nevus syndrome: Clinical approach and genetic analysis

Basal cell nevus syndrome (BCNS, Gorlin syndrome) is a rare inherited disorder characterized by the development of multiple basal cell carcinomas (BCCs), odontogenic keratocysts, and palmar pits.1 BCC development is caused by sonic hedgehog pathway (SHH) activation caused by mutations in tumor suppressor gene patched 1 (PTCH1) or activating mutations in the oncogene smoothened (SMO).2 Because patients with BCNS carry a germ-line mutation in PTCH1, one additional somatic mutation (second hit) results in BCC development at a young age. In 2012, the US Food and Drug Administration approved vismodegib for treatment of locally advanced BCC (laBCC) or metastatic BCC (mBCC). Vismodegib prevents activation of the SHH pathway by binding and inhibiting the SMO protein.3 Vismodegib resistance, mainly caused by SMO mutations, is an important problem seen in laBCC or mBCC in patients with and without BCNS.4, 5 Vismodegib resistance in smaller BCCs, which are far more frequent in BCNS patients, is only described once.6 Here, vismodegib resistance of those smaller BCCs in a BCNS patient is genetically explained, and a clinical treatment approach is given.