Targeted Therapy for Orbital and Periocular Basal Cell Carcinoma and Squamous Cell Carcinoma

Abstract

Purpose To review the literature on targeted therapy for orbital and periocular basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) and provide examples of patients recently treated with such therapy. Methods We reviewed the literature on clinical results of targeted therapy and the molecular basis for targeted therapy in orbital and periocular BCC and cutaneous SCC. We also present representative cases from our practice. Results Mutation in the patched gene (PTCH1) has been implicated in BCC, and overexpression of epidermal growth factor receptor (EGFR) has been shown in SCC. Vismodegib, an inhibitor of smoothened, which is activated upon binding of hedgehog to Ptc, has been shown to significantly decrease BCC tumor size or even produce complete resolution, especially in cases of basal cell nevus syndrome. Similarly, EGFR inhibitors have been shown to significantly decrease SCC tumor size in cases of locally advanced and metastatic disease. We describe successful outcomes after vismodegib treatment in a patient with basal cell nevus syndrome with numerous bulky lesions of the eyelid and periocular region and erlotinib (EGFR inhibitor) treatment in a patient with SCC who was deemed not to be a good surgical candidate because of advanced SCC of the orbit with metastasis to the regional lymph nodes, advanced age, and multiple medical comorbidities. Conclusion Targeted therapy using hedgehog pathway and EGFR inhibitors shows significant promise in treatment of orbital and periocular BCC and cutaneous SCC, respectively. Such targeted therapy may be appropriate for patients who are not good candidates for surgery.

Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survival

“…Vismodegib (Erivedge), a hedgehog pathway inhibitor approved by for the treatment of metastatic and locally advanced BCC, has been shown to produce either a complete or partial response in 30-60 percent of patients with metastatic or locally advanced BCC, 37 and has also been used as neoadjuvant therapy for patients with orbital invasion to make globe-sparing surgical resection possible. 38,39 For patients with SCC with orbital invasion who are unable or unwilling to undergo exenteration, the prognosis is traditionally quite poor, 40 but various epidermal growth factor receptor (cetuximab) and tyrosine kinase (gefitinib, erlotinib) inhibitors have been studied in small series and shown efficacy in either reducing or stabilizing cutaneous SCC, 41 and may have a neoadjuvant application as well.…”

Increased gene copy number of HER2 and concordant protein overexpression found in a subset of eyelid sebaceous gland carcinoma indicate HER2 as a potential therapeutic target

“…However, there have been few studies of eyelid SbGC describing the expression levels or molecular alterations of RTKs (Cho et al 2000;Erovic et al 2012;Ivan et al 2010). Overexpression of EGFR has been observed in some cases of cutaneous and conjunctival squamous cell carcinomas, and clinical trials using tyrosine kinase inhibitors (TKIs) or anti-EGFR antibodies are still ongoing (Lewis et al 2012;Shepler et al 2006;Yin et al 2013).…”

Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome

“…7,12,13 Ptch-1 also plays a role in basal cell nevus syndrome, which is secondary to an autosomal-dominant mutation in the PTCH1 gene. 9,11,14 Vismodegib (Erivedge, Genentech, South San Francisco, CA, GDC-0449) is a selective Hedgehog pathway inhibitor that blocks Hedgehog signaling by binding to Smo, inhibiting downstream activation of Hedgehog target genes. 15,16 Vismodegib was first studied in humans in 2008 and was approved by the US Food and Drug Administration in January 2012 for treatment of metastatic or locally advanced unresectable BCC.…”

“…[5][6][7][8][9] The Hedgehog pathway includes the Patched-1 transmembrane receptor (Ptch-1), a tumor suppressor that normally inhibits the downstream receptor Smoothened (Smo). 7,10,11 A mutation in the Hedgehog pathway may lead to Hedgehog protein binding to Ptch-1, and reversal of the normal inhibition of Smo leading to cellular proliferation and tumorigenesis as well as expression of the downstream product GLI1, which is thought to lead to the formation of BCC.…”