Advanced Basal Cell Cancer: Concise Review of Molecular Characteristics and Novel Targeted and Immune Therapeutics

M. Nikanjam; P. R. Cohen; S. Kato; J. K. Sicklick; R. Kurzrock


Ann Oncol. 2018;29(11):2192-2199. 

In This Article

Abstract and Introduction


Metastatic basal cell carcinoma is an ultra-rare manifestation of a common disease, appearing in 0.0028%–0.5% of basal cell carcinomas. Initial therapeutic efforts focused on cytotoxic chemotherapy administration. However, it is now known that the Hedgehog signaling pathway is crucial for basal cell proliferation and Hedgehog pathway mutations may lead to tumorigenesis; thus, small-molecule inhibitors of alterations in the components of this pathway, including smoothened (SMO) and GLI, have been the focus of recent therapeutic developments. Indeed, the European Medicines Agency and the Food and Drug Administration have approved the SMO inhibitors, vismodegib and sonidegib, with additional GLI inhibitors currently in clinical trials. Molecular profiling of these tumors has revealed other potential targets for therapy, including high tumor mutational burden and PD-L1 amplification, which predict response to immune checkpoint blockade (PD-1 and PD-L1 inhibitors). An illustrative patient with a giant, advanced, unresectable basal cell carcinoma who obtained an ongoing complete remission after treatment with a combination of an immune checkpoint inhibitor (due to the tumor's high mutational burden) and the Hedgehog inhibitor vismodegib is described. A fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.


Basal cell carcinomas (BCCs) are the most common malignancy diagnosed. They are estimated to account for 80% of non-melanoma skin cancers with over 4 million cases per year.[1] UV light exposure,[2] immunosuppression,[3] photosensitizing drugs,[4] and ionizing radiation[5] contribute to the risk of developing these tumors. Most BCCs arise from sun-exposed areas and 80% develop in the head and neck. The majority present as localized disease and are treated surgically in the outpatient setting. However, despite the indolent nature of BCC, metastatic disease can occur, albeit rarely. In addition, unresectable/advanced BCC requires systemic therapy. Recent breakthroughs in understanding advanced and metastatic BCC biology have led to advances in treatment, including the European Medicines Agency (EMA) and Food and Drug Administration (FDA) approval of two Hedgehog pathway inhibitors that target SMO (vismodegib and sonidegib), and reports of responses to other treatments such as checkpoint inhibitor immunotherapy.[6] This review summarizes the clinical characteristics, molecular alterations, and innovative treatment options for metastatic BCC.