Basal Cell Carcinoma

Epidemiology & Impact

Basal cell carcinoma (BCC) is the most common human cancer worldwide, with an estimated 3.6 million new cases diagnosed annually in the United States alone. It accounts for approximately 80% of all non-melanoma skin cancers. BCC incidence has increased by 10% per year over recent decades, driven by cumulative ultraviolet (UV) radiation exposure, indoor tanning use, and an aging population. The disease overwhelmingly affects fair-skinned individuals and is rare in people with darker skin tones. Peak incidence occurs in the seventh decade of life, with men affected approximately 1.5 times more often than women. While BCC is rarely fatal (mortality rate less than 0.1%), locally advanced or neglected tumors can cause significant morbidity through tissue destruction, and the disease places an enormous burden on healthcare systems. Patients diagnosed with one BCC face a 40-50% risk of developing another within five years, underscoring the importance of ongoing surveillance.

Molecular Biology & Biomarkers

The molecular hallmark of BCC is aberrant activation of the Hedgehog (Hh) signaling pathway, present in virtually all cases. Approximately 90% of sporadic BCCs harbor loss-of-function mutations in PTCH1 (the Hedgehog receptor that normally suppresses pathway signaling) or gain-of-function mutations in SMO (Smoothened). This understanding led directly to the development of Hedgehog pathway inhibitors. Gorlin syndrome (nevoid basal cell carcinoma syndrome), caused by germline PTCH1 mutations, predisposes to hundreds of BCCs beginning in adolescence and provided the initial biological link to pathway-targeted therapy. TP53 mutations are also common (approximately 50% of BCCs) but are considered UV-induced passenger mutations rather than primary drivers. BCC has one of the highest tumor mutational burdens of any cancer type due to chronic UV exposure, which paradoxically may contribute to immune recognition and the generally indolent behavior of most tumors.

Evolving Treatment Landscape

Surgical excision and Mohs micrographic surgery remain the primary treatments for BCC and are curative in over 99% of cases. However, a subset of patients develop locally advanced disease unsuitable for surgery or radiation, or rarely, metastatic BCC. The Hedgehog pathway inhibitors vismodegib (Erivedge) and sonidegib (Odomzo) represented a breakthrough for these patients, with response rates of approximately 30-40% in locally advanced BCC and 5-15% in metastatic disease. However, acquired resistance (often through SMO mutations) and tolerability issues (muscle spasms, dysgeusia, alopecia) limit long-term utility. Immunotherapy with cemiplimab (Libtayo) has emerged as a significant advance for advanced BCC that has progressed on or is intolerant to Hedgehog inhibitor therapy, achieving response rates of approximately 30% in this post-HHI setting. The high mutational burden of BCC may explain its responsiveness to checkpoint blockade. Active investigation continues into combination approaches and novel agents to address Hedgehog inhibitor resistance.

EMA-Approved Therapies for Basal Cell Carcinoma

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key therapies with comparative information to FDA approvals.

For complete European drug information, visit ema.europa.eu ↗