Advanced and Metastatic Non-Melanoma Skin Cancer: Epidemiology, Risk Factors, Clinical Features, and Treatment Options

Abstract

Non-melanoma skin cancers (NMSC) form the majority of skin cancers, with basal cell carcinoma (BCC) being the most common and cutaneous squamous cell carcinoma (cSCC) being second. Prolonged ultraviolet (UV) exposure, aging, male gender, and immunosuppression represent most of the causes of this category of diseases. BCCs and cSCCs both include different types of skin cancers, such as nodular or morpheaform BCC or flat cSCC. Locally advanced and metastatic NMSCs cannot be treated surgically; thus, systemic therapy (TKI and Immunotherapy) is needed. Interestingly, NMSCs are frequently linked to abnormal Hedgehog (HH) signaling which most systemic immunotherapies for these cancers are based upon. Of note, the first line therapies of BCC, sonidegib and vismodegib, are HH inhibitors. Programmed death receptor 1 antibody (PD-1) inhibitors such as cemiplimab, pembrolizumab, and nivolumab have been approved for the treatment of cSCC. Thus, this paper reviews the epidemiology, risk factors, clinical features, and treatment options for both BCC and cSCC.

Keywords: basal cell carcinoma; cemiplimab; cutaneous squamous cell carcinoma; hedgehog; nivolumab; non-melanoma skin cancers; pembrolizumab; sonidegib; vismodegib.

Figure 3

Outline of the European guidelines for the main therapeutic options for cSCC [51,52]. This review focuses on systemic treatment for locally advanced and metastatic cSCC, which are considered if the tumor is inoperable or if surgery is insufficient. Within systemic treatment, there are different options, which are described in Table 2 above.

Figure 1

Outline of the HH signaling pathway [16]. If an Hh ligand is present, SMO is phosphorylated, and SUFU is re-activated, while GLI2 induces Hh target genes of transcription. However, if an Hh ligand is absent, GLI is phosphorylated by PKA, GSK3, and CK1, forming GLI3R (GLI repressor), thus inhibiting the Hh target genes.

Figure 2

Immune checkpoint inhibitors approved by the FDA. Pembrolizumab, Nivolumab, and Cemiplimab as anti-PD-1 antibodies, Ipilimumab as an anti-CTLA-4 antibody, as well as Atezolizumab, Avelumab, and Durvalumab as anti-PD-L1 antibodies [48].