Gene-Related Response of Basal Cell Carcinoma to Biologic Treatment with Vismodegib

Amir Sternfeld,Yoav Vardizer,Hila Kreizman Shefer,Asaf Olshinka,Shirel Rosenwasser-Weiss,Jacob Bejar,Iftach Yassur,Gil Tauber,Dean Ad El,Moran Friedman-Gohas,Gur Ben-Yehuda,Nitza Goldenberg-Cohen

doi:10.1038/s41598-020-58117-0

Abstract

We aimed to characterise the response of locally advanced basal cell carcinoma (BCC) to systemic treatment with Vismodegib, a Hedgehog pathway inhibitor, by changes in the expression levels of Hedgehog pathway genes. Data were collected prospectively on 12 patients treated systemically for locally advanced BCC. Biopsy samples taken on admission and after treatment cessation were analysed pathologically and with the NanoString nCounter system to quantify the expression of 40 Hedgehog signaling pathway genes. Findings were compared before and after treatment, between complete and partial responders, and with localised BCC samples from 22 patients. Sixteen Hedgehog pathway genes changed significantly from before to after treatment. GAS1 was the only gene with a significantly different expression at baseline between complete responders (6 patients) and partial responders (4 patients) to Vismodegib (P = 0.014). GAS, GLIS2 and PRKACG1 showed different expression before treatment between the locally advanced and localised BCCs. The baseline expression level of GAS1 appears to be predictive of the response of locally advanced BCC to systemic Vismodegib treatment. A change in expression of many Hedgehog pathway genes, albeit expected by the known activity of Vismodegib, may nevertheless serve as an indicator of the response potential of the tumour.

Highlights

Basal cell carcinoma (BCC) is the most common cancer in the world, with a lifetime risk of 20% and an incidence that has grown continuously over recent decades[1,2]
This study presents a comprehensive analysis of the response of Hh signalling pathway genes to treatment with Vismodegib in patients with laBCC
We found that before treatment, laBCCs were characterised by a significantly higher level of expression of three Hh pathway genes compared to localised basal cell carcinoma (BCC)

Summary

Introduction

Basal cell carcinoma (BCC) is the most common cancer in the world, with a lifetime risk of 20% and an incidence that has grown continuously over recent decades[1,2]. The activated SMO inhibits the negative regulator Suppressor of Fused protein which binds glioma associated (GLI) transcription factors in the cytoplasm. 90% of sporadic BCCs demonstrate mutations in the PTCH1 gene, often associated with loss of heterozygosity; most of the remaining 10% show a gain-of-function SMO gene mutation. Both these mutations cause uncontrolled proliferation of skin basal cells[9,10]. In 2012, the ERIVANCE study reported a 30% response rate to Vismodegib for metBCC and a 43% response rate for laBCC11. The aim of the present study was to investigate the effect of Vismodegib on the expression levels of Hh pathway genes in laBCC and to search for potential predictors of tumour response

Objectives

Methods

Results

Conclusion