Abstract B246: Responses to sorafenib in patients with advanced basal cell carcinoma
Authors: Tibes Raoul , Korn Ronald , Blaydorn Lisa , Von Hoff Daniel D. 
Published: June 2012

Abstract
Basal cell carcinoma (BCC) is the most common cancer. BCC's are generally cured by surgical resection. However, for patients (pts) with locally advanced and metastatic BCC, treatment options are limited. We recently reported on the substantial clinical activity of the hedgehog pathway inhibitor (HPI) GDC-0449 in patients with advanced BCC (Von Hoff et. al, NEJM Sept. 2009). A molecular context was established based on the knowledge that BCC'fs are frequently driven by aberration of the Hedgehog pathway (Hh) with inactivating mutations in PTCH1 and occasionally, activating mutations in Smoothened (SMO). Here we report the first cases of clinical (symptomatic, tumor skin healing) and radiographic responses of patients with advanced BCC to the multi-targeted kinase inhibitor sorafenib. Two patients who achieved a very good, long-lasting response to treatment with hedgehog pathway inhibitor (HPI) ultimately progressed. Biomarker analysis in tumor tissue at progression revealed that the Hh pathway was still activated. No novel mutations in Hh pathway genes have been detected yet. Subsequently both pts were treated with another experimental HPI without significant responses. One pt went on to receive a cisplatin based regimen as well as imatinib with further progression. Immuno-histochemical analysis of both patients' tumors showed weak to moderate expression of PDGF- and EGF-receptors, c-Kit and Her2-Neu and both pts were eventually placed on 400mg sorafenib twice daily. On sorafenib, the pt with extensive metastatic disease to the lungs experienced a radiographic response by CT scan with decreased size in some of the metatstatic lesions and cavitation in others, as well as reduced FDG uptake on PET scan (∼30% reduced SUVmax). The pt also had a clinically meaningful improvement in his symptoms (reduced oxygen requirements, improvement in well being) before ultimately progressing 5 months into treatment. At which time the SUV's increased again, indicating PET progression as well. The second pt had extensive skin disease with large non-healing, biopsy proven BCC skin lesions. On sorafenib, healing of ulcerated lesions and shrinkage of BCC tumor nodules was observed within the first 1–2 months. PET scan showed reduction in FDG avidity on sorafenib (decrease of SUVmax by ∼30–35%). Interestingly reductions in SUV were also seen while both pts were on HPI and responding, indicating that PET scan may be a novel way of following responses in metastatic and skin disease in pts with BCC.
Herein we present the first report of clinical and radiographic responses of pts with BCC to sorafenib. This observation has potential immediate as well as long-reaching implications for this most common cancer and warrants further follow up in additional pts with advanced inoperable BCC. Causes for the observed clinical responses to sorafenib are unknown and additional biomarker analysis, i.e. B-raf mutation sequencing, is ongoing. In addition, PET scans may be a novel way of following and assessing responses in pts with BCC's.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B246.