Journal
ANNALS OF ONCOLOGY
Volume 29, Issue 11, Pages 2192-2199Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdy412
Keywords
metastatic basal cell carcinoma; Hedgehog inhibitor; PD-L1; immunotherapy; SMO; PTCH1
Categories
Funding
- National Cancer Institute [P30 CA023100]
- National Institutes of Health [4T32HL066992]
- Tower Cancer Research Foundation Career Development Award
- NIH [K08CA168999, R21CA192072]
- FoundationMedicine
- Joan and Irwin Jacobs philanthropic fund
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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.
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