Hedgehog Pathway Inhibitor Therapy for Locally Advanced and Metastatic Basal Cell Carcinoma

Abstract

IMPORTANCE Hedgehog pathway inhibitors (HPIs) were made available by US Food and Drug Administration approval in 2012 for vismodegib and 2015 for sonidegib. Both target the Smoothened molecule and are indicated for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC). OBJECTIVE To evaluate clinical experience with HPIs, including efficacy and adverse effects. DATA SOURCES We conducted a systematic review in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EMBASE, using search terms "vismodegib," "sonidegib," "Erivedge," "Odomza," "basal cell carcinoma," and "BCC." STUDY SELECTION We included clinical trials, retrospective medical record reviews, and prospective case series that used HPIs for the treatment of laBCC or mBCC in human subjects. Individual case reports and limited, retrospective case series were excluded from our review. DATA EXTRACTION AND SYNTHESIS Data were extracted independently by 2 reviewers on a predesigned, standardized form. MAIN OUTCOMES AND MEASURES The following data were recorded: number of patients with laBCC or mBCC, dose and frequency of drug administration, median duration of treatment, clearance and recurrence rates, and adverse effects. RESULTS Eleven vismodegib articles (published between 2009 and 2015) met criteria for inclusion, and 8 articles were able to be pooled for analysis. The 8 pooled articles included 744 total patients with 704 patients clinically evaluable. Sonidegib did not yield enough publications for a formal analysis. Objective response to vismodegib for laBCC had a weighted average of 64.7% (95% CI, 63.7%-65.6%); complete response averaged 31.1% (95% CI, 30.4%-31.8%). Objective response for mBCC was 33.6% (95% CI, 33.1%-34.2%); complete response averaged 3.9% (95% CI, 3.3%-4.4%). Median duration of therapy was 35.8 weeks (95% CI, 35.1-36.5 weeks). CONCLUSIONS AND RELEVANCE In a systematic review of HPIs for laBCC and mBCC, vismodegib, but not sonidegib, had enough studies to warrant a pooled analysis. Vismodegib was identified to have a significant, consistent effect on the median duration of therapy of laBCC and mBCC. While mBCC responses are superior to any traditional approach, the response rate for laBCC might be considered in the context of other standard treatment options including surgery and radiation therapy.

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

“…32 SMO, one of critical molecules in the Hh signaling pathway, has been a major target for pharmaceutical intervention in cancer therapy, and has been clinically proved to be effective in basal cell cancer and other malignancies although drug resistance has been reported in basal cell cancer against vismodegib. 15,33 As one of Gli-1/2 target genes, BCL-2 exerts its anti-apoptosis effects by binding to pro-apoptotic proteins and preventing the release of cytochrome c from mitochondria. 34 Consistent with the expression trend of ABCC1 protein, Huh-7-DN subpopulation had the highest BCL-2 expression level, which was followed by Huh-7-trans subpopulation.…”

“…Overexpression of Hh pathway molecules, such as sonic Hh, PTCH1, SMO, and Gli-1/2, has been reported in 60-70% of HCC specimens, 11,12 and dysregulated expression of Hh molecules is one of disordered signaling mechanisms crucial for hepatic carcinogenesis 13 and highly metastatic behavior of HCC. 14 Hh signaling inhibitors, such as vismodegib (GDC--0449) and sonidegib (LDE225), are approved for the treatment of advanced basal cell carcinoma; 15 and sonidegib is in phase I-II clinical trials for the treatment of a variety of malignancies, including esophageal, pancreatic, ovarian cancers, and hepatocellular carcinoma. 16 However, whether abnormal hedgehog signaling has a critical role in modulating drug resistance through ABC transporter molecules has not been thoroughly investigated.…”

Guidelines of care for the management of basal cell carcinoma

“…The recommendations for the treatment of metastatic BCC are shown in Table XI, and the level of evidence/ strength of the recommendations are in Table XII. [106][107][108][109][110][111][113][114][115] …”

Treatments for Basal Cell and Squamous Cell Carcinoma of the Skin

“…15 In clinical practice, these lesions are routinely treated with surgical excision with or without intraoperative margin evaluation, and in most cases are considered appropriate for Mohs surgery in the American Academy of Dermatology appropriate use criteria. 16 Radiation is also used for invasive SCC.…”

“…Photodynamic therapy involves application of a topical photosensitizer (such as 5-aminoleveulinic acid (ALA) and methyl-ALA) followed by exposure to specific wavelengths of light to destroy tumor cells. New targeted systemic agents, such as vismodegib, for BCC 15 are also available, but are reserved for advanced or metastatic cases and are used much less commonly than the modalities listed above. Additionally, active nonintervention (watchful waiting) has recently been advanced as a therapeutic strategy, particularly for patients with decreased life expectancy.…”