Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: Follow up to the VISORB trial

• Published in: PloS one Vol. 17; no. 12; p. e0265212
• Main Authors: Unsworth, Shelby P, Tingle, Christina F, Heisel, Curtis J, Eton, Emily A, Andrews, Christopher A, Chan, May P, Bresler, Scott C, Kahana, Alon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2022; Public Library of Science (PLoS)
• Subjects: Basal cell carcinoma; Biology and Life Sciences; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - genetics; Care and treatment; Causes of; Complications and side effects; Development and progression; Dosage and administration; Excision (Surgery); Follow-Up Studies; Hedgehog Proteins - genetics; Humans; Medicine and Health Sciences; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms, Basal Cell; Prospective Studies; Testing; Vismodegib; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0265212

Basal cell carcinoma (BCC) is a common skin cancer caused by deregulated hedgehog signaling. BCC is often curable surgically; however, for orbital and periocular BCCs (opBCC), surgical excision may put visual function at risk. Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically. However, further analysis of excision samples uncovered keratin positive, hedgehog active (Gli1 positive), proliferative micro-tumors. Sequencing of pre-treatment tumors revealed resistance conferring mutations present at low frequency. In addition, one patient with a low-frequency SMO W535L mutation recurred two years post study despite no clinical evidence of residual disease. Sequencing of this recurrent tumor revealed an enrichment for the SMO W535L mutation, revealing that vismodegib treatment enriched for resistant cells undetectable by traditional histology. In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02436408.