Evidence of Basal to Squamous Cell Phenotype Switch Under Vismodegib Treatment for Basal Cell Carcinoma
In a letter to The New England Journal of Medicine, Ransohoff et al describe genetic evidence of phenotype switching from basal cell to squamous cell carcinoma in a patient receiving vismodegib (Erivedge) for basal cell carcinoma.
Hedgehog signaling pathway activation, a central feature of development of basal cell carcinoma, commonly occurs through mutations in PTCH1 or SMO. The SMO inhibitor vismodegib is active in advanced basal cell carcinoma, but a high proportion of tumors develop resistance, commonly by acquiring mutations in SMO. It has been observed that squamous cell carcinomas may occur in the same tumor bed as an original basal cell lesion during vismodegib treatment, but it has not been clear in such cases whether the squamous cell lesion is independent of or related to the basal cell clone.
Characteristics of Basal Cell and Recurrent Squamous Cell Lesions
A 62-year-old patient with a 7-cm by 7-cm basal cell carcinoma on the back and metastasis to a left axillary lymph node was treated with vismodegib. After 9 months of treatment, complete response was observed in the primary carcinoma and the nodal metastasis, with the original tumor site subsequently being excised.
Examination 13 months later showed a recurrent 3.5-cm left axillary mass, with excision showing a keratinizing squamous cell carcinoma. Exome sequencing of DNA from the primary basal cell tumor, lymph node basal cells before vismodegib, and recurrent lymph node squamous cells showed somatic mutations in PTCH1 in the original tumor and lymph node basal cells, consistent with the known pathogenesis of basal cell carcinoma; the PTCH1 mutations and identical TP53 mutations were detected in the recurrent node squamous cell carcinoma, indicating that it shared the same tumor drivers as the basal cell tumor.
Mediators of Phenotype Switch
The recurrent node squamous cell carcinoma had a similar mutation rate of 35 mutations per megabase and shared 90% genomic identity with the original basal cell carcinoma. However, it also exhibited new mutations in genes frequently mutated in cutaneous squamous cell carcinoma, including NOTCH1/2 and KMT2C, suggesting that these genes may have been involved in the squamous transition.
Analysis of hedgehog pathway activity via assay of expression of mRNA from GLI1 (a gene encoding effectors in hedgehog signaling) showed high levels of GLI1 mRNA in the recurrent node squamous cell lesion, suggesting that maintenance of hedgehog signaling is also important for cell survival in squamous tumors. No SMO mutations were observed in the squamous cell lesion, but mutations that may contribute to vismodegib resistance were identified in downstream hedgehog pathway genes.
The investigators concluded: “[C]ells in a basal-cell carcinoma can switch to squamous cells under vismodegib selection, potentially as a mechanism of tumor escape.”
Jean Y. Tang, MD, PhD, of Stanford University School of Medicine, is the corresponding author for the New England Journal of Medicine letter.
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