The Impact of Inoperable Advanced Basal Cell Carcinoma: the Economic, Physical, and Psychological Burden of the Disease

October 2013 | Volume 12 | Issue 10 | Supplement Individual Articles | 151 | Copyright © October 2013

Arielle W. Haves BA, Panta Rouhani Schaffer MD PhD MPH, and John A. Carucci MD PhD

Ronald O. Perelman Department of Dermatology, New York University, New York, NY

secreted SHh protein binds to its receptor, PTCH1, it activates SMO. Once activated, SMO promotes downstream transcription of target genes and activates other transcription factors in the glioma-associated oncogene (GLI) family, including GLI1 which is specifically involved in cellular proliferation and growth.8,12 Glioma-associated oncogene 1 serves as a transcription factor for itself, as well as inducing PTCH1 transcription, creating a negative feedback loop.13 In an individual with BCNS, however, PTCH1 genes are mutated and inappropriately inactivated, leading to unregulated simulation of the SHh pathway because the PTCH1 protein cannot effectively inhibit SMO. Constitutive activation of SHh causes abnormal cell growth and carcinogenesis, leading to multiple BCCs.13 In cases of sporadic BCC, not only have loss-of-function mutations in PTCH1 been implicated in 30% to 40% of cases, but also gain-of-function mutations activating SMO are also a possible mechanism as SMO is mutated in about 10% of sporadic BCC cases.5,11
Because radiation is contraindicated in BCNS and other genetic syndromes that predispose one to skin cancer, few treatment options remain for these patients. Topical therapy, such as 5-florouracil and imiquimod, photodynamic therapy, and cryotherapy, may be used, but they are less effective than the conventional treatments of surgery and radiation.9 Prior therapies have included chemotherapy (ie, cisplatin-based chemotherapy) as well as molecular targeted therapies (ie, cetuximab).
One of the most recent additions to the armamentarium of therapies for patients with BCNS has been vismodegib (Erivedge ®; Genentech). Vismodegib was approved by the United States Food and Drug Administration in January 2012 as the first oral medication for adults with metastatic or locally advanced BCC that has recurred after surgery or for patients who are not candidates for surgery or radiation.9 This medication is particularly promising as a prophylactic agent because the number of BCCs among patients with BCNS is high, ranging from hundreds to thousands in a single patient.14 Tang et al studied the use of vismodegib in patients with BCNS and found that the drug significantly reduced existing BCC tumor burden as well as blocked the growth of new BCCs.14 However, adverse events (AEs), such as dysgeusia, hair loss, muscle cramps, and weight loss, led to discontinuation of over half the patients enrolled in the study.14 In addition to these AEs, there are recent reports in the literature of patients on vismodegib experiencing secondary (acquired) resistance to treatment, even in patients with BCNS.15 Chang et al studied 28 patients with advanced BCC on continuous vismodegib therapy and found that 21% developed at least one tumor regrowth.16 While the molecular mechanism for this acquired resistance is still unclear, it is important to closely monitor patients on vismodegib as this may be an increasing phenomenon that is only beginning to be described.16 Additionally, there have been reports in the literature of the development of rapid new onset keratoacanthomas (KAs) and squamous cell carcinomas (SCCs) associated with vismodegib treatment.17 While KAs and SCCs have previously not been associated with SMO inhibitors, such cases warrant further investigation,especially since hereditary disorders such as BCNS would require long-term therapy. As promising as vismodegib may be, systemic therapy for advanced BCC is not curative, requires long-term treatment, and should not take the place of curative procedures such as surgery.10


John A. Carucci MD PhD has served as an advisory board participant and clinical investigator for Genentech, Novartis, and Pfizer. Arielle W. Haves BA and Panta Rouhani Schaffer MD PhD MPH have no conflicts of interest to disclose.


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Panta Rouhani Schaffer MD PhD