PTCH1 mutations and tumor-agnostic clinical outcomes with hedgehog pathway inhibitors across cancer types.

Loss-of-function (LOF) alterations in PTCH1 are a hallmark of basal cell carcinoma (BCC) and drive activation of the Hedgehog (Hh) signaling pathway. Hh inhibitors are approved to treat advanced BCC, but little is known about the frequency, biology, and treatment of PTCH1 alterations in other cancers. We analyzed PTCH1 LOF alterations across diverse solid tumors and evaluated outcomes of patients with non-BCC tumors who received Hh inhibitors. Among 121,490 tumor samples, 2064 (1.7%) harbored PTCH1 LOF alterations. Among 13 patients with non-BCC tumors treated with an Hh inhibitor, the response rate was 31%, with responses seen in sebaceous adenocarcinoma, squamous cell lung cancer (SCC), cutaneous SCC and glioblastoma. Median progression-free survival was 4.1 months, and median overall survival was 9.8 months. PTCH1 LOF alterations may identify a tumor-agnostic subset of patients who could derive benefit from Hh inhibitors beyond BCC, supporting further prospective evaluation.