Abstract

Background: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune‐checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection.

Methods: Evaluation was done retrospectively of the landscape of somatic alter-ations and ICI‐related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV‐dependent oncogenesis. The pSCC tumors were analyzed by using next‐generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD‐L1) expression was evaluated by immunohisto- chemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)–high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole‐exome sequencing (WES) when available. Significance was adjusted for multiple compari- sons (q value < .05).

Results: NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD‐L1þ, 10.7% had high TMB, and 1.1% had mismatch repair–deficient (dMMR)/MSI‐high status. Twenty‐nine patients had their HPV status made available by WES (HPV16/18þ, n = 13; HPV16/18−, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18þ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18− tumors. TMB‐high was exclusively found in the HPV16/18þ group (30.8%). The two groups had comparable PD‐L1 and dMMR/MSI‐H status.