“Aberrant activation of the hedgehog pathway in adult tissue has been implicated in the pathogenesis of several cancers including BCC, squamous cell carcinoma (SCC), and melanoma,” explained senior author Iris Zalaudek, MD, in an interview with Cancer Therapy Advisor. Dr Zalaudek is a board-certified dermatologist and head of the dermatology clinic at Hospital Maggiore and a professor at the University of Trieste in Italy.
“Moreover, data suggest a role for hedgehog signaling in melanoma progression as inhibition of the hedgehog signaling pathway results in decreased melanoma cell growth in vivo and in vitro,” said Dr Zalaudek. “On the other hand, there are studies suggesting an increased risk of cancer development secondary to inhibition of the hedgehog signaling pathway.”
Dr Zalaudek noted recent data suggesting that hedgehog pathway inhibition may activate the RAS/MAPK pathway, circumventing the hedgehog pathway altogether. Hedgehog pathway inhibition as a treatment for BCCs could therefore promote the development of secondary malignancies, including melanoma. It remains unclear, however, whether hedgehog pathway antagonists promote secondary cancers in patients with laBCCs.
No studies to date have demonstrated an increased risk for secondary melanoma in patients treated with a hedgehog pathway inhibitor for BCC, though hedgehog pathway inhibition may be associated with an increased incidence of SCCs.2-10
To evaluate the risk of developing a non-BCC malignancy after exposure to a hedgehog pathway inhibitor (also called a “smoothened inhibitor”), researchers conducted a case-control study of 180 higher-risk patients with BCC, including 55 with confirmed prior vismodegib treatment and 125 who never received a smoothened inhibitor.2
Patients who received vismodegib were over 6 times more likely to develop a non-BCC malignancy than were controls (hazard ratio [HR], 6.37; 95% CI, 3.39-11.96; P < .001). After accounting for age and basal cell nevus syndrome status, the researchers noted that cutaneous SCCs (HR, 8.12; 95% CI, 3.89-16.97; P < .001) drove the elevated risk of non-BCC malignancies, with no significant increase in other malignancies.