Basal cell carcinoma (BCC) is the most common human cancer and represents a growing public health care problem.,Several tumor suppressor genes and proto-oncogenes have been implicated in BCC pathogenesis, including the key components of the Hedgehog pathway, PTCH1 and SMO, the TP53 tumor suppressor, and members of the RAS proto-oncogene family.,Aberrant activation of the Hedgehog pathway represents the molecular driver in basal cell carcinoma pathogenesis, with the majority of BCCs carrying somatic point mutations, mainly ultraviolet (UV)-induced, and/or copy-loss of heterozygosis in the PTCH1 gene.,Recent advances in sequencing technology allowed genome-scale approaches to mutation discovery, identifying new genes and pathways potentially involved in BCC carcinogenesis.,Mutational and functional analysis suggested PTPN14 and LATS1, both effectors of the Hippo-YAP pathway, and MYCN as new BCC-associated genes.,In addition, emerging reports identified frequent non-coding mutations within the regulatory promoter sequences of the TERT and DPH3-OXNAD1 genes.,Thus, it is clear that a more complex genetic network of cancer-associated genes than previously hypothesized is involved in BCC carcinogenesis, with a potential impact on the development of new molecular targeted therapies.,This article reviews established knowledge and new hypotheses regarding the molecular genetics of BCC pathogenesis.
In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively.,ORRs by investigator review were 45% (mBCC) and 60% (laBCC).,Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC.,One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity.,The primary end point was IRF-assessed ORR.,Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety.,At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up).,Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response).,ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC).,Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC).,Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort.,Adverse events remained consistent with clinical experience.,Thirty-three deaths (31.7%) were reported; none were related to vismodegib.,This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC.,This study was registered prospectively with Clinicaltrials.gov, number NCT00833417 on January 30, 2009.,The online version of this article (doi:10.1186/s12885-017-3286-5) contains supplementary material, which is available to authorized users.