TY - JOUR
T1 - Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition
T2 - Follow up to the VISORB trial
AU - Unsworth, Shelby P.
AU - Tingle, Christina F.
AU - Heisel, Curtis J.
AU - Eton, Emily A.
AU - Andrews, Christopher A.
AU - Chan, May P.
AU - Bresler, Scott C.
AU - Kahana, Alon
N1 - Publisher Copyright:
© 2022 Unsworth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85143182652
U2 - 10.1371/journal.pone.0265212
DO - 10.1371/journal.pone.0265212
M3 - Article
C2 - 36455049
AN - SCOPUS:85143182652
SN - 1932-6203
VL - 17
JO - PLOS ONE
JF - PLOS ONE
IS - 12 December
M1 - e0265212
ER -