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Pursuing Therapeutic Targets Beyond the Hedgehog Pathway in Basal Cell Carcinoma

By: Gavin Calabretta, BS
Posted: Friday, May 6, 2022

Although most basal cell carcinoma are treated with Hedgehog pathway inhibitors, there is variation in patient response, with approximately 30% of tumors developing resistance to or relapsing after treatment. In search of more effective therapeutic targets, Priyanka R. Kumar, MD, of the University of California Irvine and colleagues surveyed the American Association for Cancer Research (AACR) GENIE database for targetable genomic alterations in patients with basal cell carcinoma.

“Survey of the GENIE database found most patients had targetable alterations,” the study authors noted in their presentation at the AACR Annual Meeting 2022 (Abstract 1186/16). “Targets other than PTCH1 were common and may support the use of targeted therapies other than SMO inhibitors or in combination with SMO inhibitors in [basal cell carcinoma].”

A total of 73 patients with basal cell carcinoma (median age, 66 years) were included in the analysis. Sample tissue was collected from both primary tumor sites (54.8%) and metastases (34.2%). Reportedly, the median number of alterations was 35 (standard deviation = 67.54, range = 0–52), and the median number of oncogenic alterations was 6 (standard deviation = 6.86, range = 0–52). The investigators observed that 71.6% of samples had OncoKB Evidence Level 4 (potential biomarker) mutations, the most frequent being ARID1A (17.6%), CDKN2A (9.5%), MTOR (4.1%), and NF1 (2.7%). Further, Cancer Genome Atlas pan-cancer pathways were altered in 93.2% of cases, with a median number of six (standard deviation = 2.7, range = 0–9) variants in each sample. The most commonly altered pathways were RTK-RAS (76.7%), TP53 (71.2%), and cell cycle (69.9%).

Notably, of 57 patients with potentially actionable Level 3B and 4 alterations, 45.6% had a PTCH1 alteration alone. However, 36.8% had other alterations concurrent with PTCH1.

Disclosure: The study authors reported no conflicts of interest.


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