Importance: Smoothened inhibitors (SIs) are a new type of targeted therapy for advanced basal cell carcinoma (BCC), and their long-term effects, such as increased risk of subsequent malignancy, are still being explored.
Objective: To evaluate the risk of developing a non-BCC malignancy after SI exposure in patients with BCC.
Design, setting, and participants: A case-control study at Stanford Medical Center, an academic hospital. Participants were higher-risk patients with BCC diagnosed from January 1, 1998, to December 31, 2014. The dates of the analysis were January 1 to November 1, 2015.
Exposures: The exposed participants (cases) comprised patients who had confirmed prior vismodegib treatment, and the nonexposed participants (controls) comprised patients who had never received any SI. Because vismodegib was the first approved SI, only patients exposed to this SI were included.
Main outcomes and measures: Hazard ratio for non-BCC malignancies after vismodegib exposure, adjusting for covariates.
Results: The study cohort comprised 180 participants. Their mean (SD) age at BCC diagnosis was 56 (16) years, and 68.9% (n = 124) were male. Fifty-five cases were compared with 125 controls, accounting for age, sex, prior radiation therapy or cisplatin treatment, Charlson Comorbidity Index, clinical follow-up time, immunosuppression, and basal cell nevus syndrome status. Patients exposed to vismodegib had a hazard ratio of 6.37 (95% CI, 3.39-11.96; P < .001), indicating increased risk of developing a non-BCC malignancy. Most non-BCC malignancies were cutaneous squamous cell carcinomas, with a hazard ratio of 8.12 (95% CI, 3.89-16.97; P < .001), accounting for age and basal cell nevus syndrome status. There was no significant increase in other cancers.
Conclusions and relevance: Increased risk for cutaneous squamous cell carcinomas after vismodegib therapy highlights the importance of continued skin surveillance after initiation of this therapy.