Posted: Monday, February 28, 2022
Locally advanced basal cell carcinoma appears to be characterized by an increased level of genomic instability and aneuploidy in comparison with other types of skin cancer, according to Sergey I. Nikolaev, MD, of Université Paris Saclay, Villejuif, France. Additionally, the investigators propose that mechanisms of intrinsic resistance to the Hedgehog pathway inhibitor vismodegib appear to be heterogeneous. The study findings were published in Clinical Cancer Research.
“Intrinsic resistance to vismodegib is a rare event in locally advanced basal cell carcinoma,” said the authors. “Intrinsically resistant to vismodegib, basal cell carcinomas frequently harbor resistance mutations in the Hedgehog pathway but [are] also characterized by hyperactivation of Hippo-YAP and Wnt pathways. The role of Hippo-YAP is not very clear in basal cell carcinoma but appears to be important from our previous large-scale study of genetic drivers in basal cell carcinoma. Now, we observed that this pathway was upregulated in aggressive intrinsically resistant to vismodegib samples.”
The phase II STEVIE study enrolled patients with locally advanced basal cell carcinoma between 2011 and 2013. The study included tumors that recurred at the same location after two or more surgical procedures and for which curative resection was deemed unlikely. Patients were given 150 mg of vismodegib orally once a day. The study assessed the frequency of intrinsic resistance to vismodegib and its underlying genomic mechanism. Additionally, it measured the frequency of basal cell carcinoma cases with intrinsic response, acquired response, complete response, partial response, and stable disease.
Of the 148 patients enrolled in the study, 6% demonstrated intrinsic resistance and 9%, acquired resistance. Prior treatment with chemotherapy was associated with an eightfold higher incidence of intrinsic resistance. Of five intrinsically resistant cases subjected to whole-exome sequencing, two had vismodegib-resistance genetic events in the Hedgehog pathway, which were previously described in acquired-resistance basal cell carcinoma. All five intrinsically resistant cases demonstrated a particular hyperactivation of Hippo-YAP and Wnt pathways as compared with other basal cell carcinomas, suggesting the inhibition of these pathways may prove to be a treatment option in the future.
Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.