Secondary cutaneous malignancy after treatment of basal cell carcinoma with hedgehog pathway inhibitor: a systematic review

Several studies have been published describing development of cutaneous malignancy after vismodegib therapy; no systematic review has been conducted to interpret these data. Our objective was to systemically review reported cases of same-site or different-site cutaneous malignancy after smoothened inhibitor (SMOi) therapy for primary basal cell carcinoma (BCC). PubMed, CINAHL, and Scopus were systematically searched January 1, 2012 – March 28, 2024. Inclusion criteria: primary BCC, SMOi therapy, and biopsy-proven secondary malignancy. Exclusion criteria: non-human subjects. Bias was assessed using Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. Twenty-three cases describing same-site secondary malignancy were included. Average patient age was 67.2 years, mean treatment time 8.4 months, and average latency period to secondary malignancy development of 10.2 months. Five cases describing different-site secondary cutaneous malignancies were included. Mean patient age was 80.4 years, mean treatment time 2.9 months, and mean latency period 4.5 months. Twenty-seven cases were associated with vismodegib, while one case described vismodegib then sonidegib therapy. Pathologies included squamous cell carcinoma, BCC, basosquamous carcinoma, and malignant melanoma. The mechanism(s) by which same-site and different-site secondary malignancy occur are not known; mechanisms may differ depending on location type and secondary tumor type. We discuss multiple mechanistic hypotheses including pharmacologic selective pressure leading to hedgehog pathway mutant cells and activation of pro-growth signaling, and potential protective effect of hedgehog inhibition from melanoma given reports of rapid growth after SMOi discontinuation. This study is limited by the small number of reported cases. Additional research is needed to investigate these hypotheses.