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

PLoS One. 2022 Dec 1;17(12):e0265212. doi: 10.1371/journal.pone.0265212. eCollection 2022.


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: Identifier: NCT02436408.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Basal Cell* / drug therapy
  • Carcinoma, Basal Cell* / genetics
  • Follow-Up Studies
  • Hedgehog Proteins / genetics
  • Humans
  • Neoplasm Recurrence, Local
  • Neoplasm, Residual
  • Neoplasms, Basal Cell*
  • Prospective Studies


  • Hedgehog Proteins
  • HhAntag691

Associated data


Grants and funding

AK: Research Grants from Genentech, Research to Prevent Blindness, Kellogg Eye Center, and The University of Michigan Rogel Comprehensive Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.