Advanced Basal Cell Carcinoma: Review-Driven Topic Cluster for Clinical Translation

A concise review of metastatic basal cell carcinoma describes an advanced presentation the authors characterize as ultra-rare, reported to appear in 0.0028%–0.5% of basal cell carcinomas.

The abstract centers on three themes: molecular drivers involving Hedgehog pathway signaling, targeted inhibition directed at pathway components, and tumor-profiling signals the authors associate with immunotherapy responsiveness. Overall, the abstract highlights Hedgehog signaling, pathway-directed inhibitors (including SMO and GLI), and emerging immune-based approaches as recurring themes in metastatic basal cell carcinoma.

The abstract presents Hedgehog signaling as a key pathway supporting basal cell proliferation, with Hedgehog pathway mutations noted as a route to tumorigenesis. Within that framework, the authors identify discrete nodes in the pathway—smoothened (SMO) and GLI—as therapeutic targets, linking target selection to the pathway’s role in disease biology. Recent therapeutic development is described in the abstract as focusing on small-molecule inhibitors targeting Hedgehog pathway components, including SMO and GLI. As summarized by the authors, this rationale connects pathway alteration to a focused strategy of pathway-directed intervention.

Small-molecule inhibition of Hedgehog pathway components is described in the abstract as the centerpiece of recent therapeutic development. The authors report that the European Medicines Agency and the US Food and Drug Administration have approved the SMO inhibitors vismodegib and sonidegib, positioning SMO-directed therapy within the regulatory landscape they summarize. Beyond SMO, the abstract notes that additional GLI inhibitors are currently in clinical trials, indicating ongoing efforts to extend pharmacologic inhibition downstream within the same signaling axis. In this depiction, the targeted-therapy landscape spans from approved SMO inhibition to investigational GLI-focused strategies along a single pathway continuum.

Molecular profiling is also emphasized in the abstract as a way to identify targets outside canonical Hedgehog components. The authors report that profiling has revealed high tumor mutational burden and PD-L1 amplification, and they link these features to predicted response to immune checkpoint blockade with PD-1 and PD-L1 inhibitors. As an illustrative clinical example, the abstract describes a patient with a giant, advanced, unresectable basal cell carcinoma who achieved an ongoing complete remission after combined treatment with an immune checkpoint inhibitor (given the tumor’s high mutational burden) and the Hedgehog inhibitor vismodegib. Looking forward, the authors state that a fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.

Key Takeaways:

• The abstract reports an ultra-rare incidence range for metastatic disease and frames its scope around molecular characteristics and evolving systemic strategies.
• Hedgehog pathway biology is highlighted as a driver of proliferation and tumorigenesis, with SMO and GLI described as therapeutic targets; the abstract reports regulatory approval of vismodegib and sonidegib and notes GLI inhibitors in clinical trials.
• High tumor mutational burden and PD-L1 amplification are reported as profiling features the authors associate with checkpoint blockade responsiveness, alongside an illustrative ongoing complete remission described after combining an immune checkpoint inhibitor with vismodegib and a stated priority for fuller genomic profiling.