Comprehensive molecular landscape of anal squamous cell carcinoma: analysis of tissue and liquid biopsies from 1844 patients

Anal squamous cell carcinoma (aSCC) is a rare, predominantly HPV-driven cancer with limited treatment options. This study aimed to define its genomic landscape, identify actionable targets (AT), and highlight the clinical value of molecular profiling-especially liquid biopsy (LB)-based on Gustave Roussy's (GR) experience. In this retrospective analysis, 1844 patients from the U.S. and France underwent tissue biopsy (TB, n = 1733) and/or LB (n = 140), analyzed using the FoundationOne®CDx or FoundationOne® Liquid CDx assays both comprehensive genomic profiling assays for solid tumors covering ~324 genes. Twenty-nine patients had paired TB/LB, and 44 LB patients formed the clinically annotated GR subgroup. HPV was detected in 86.6% of cases, predominantly HPV-16 (75.6%). High tumor mutational burden (≥10 mut/Mb) was found in 17.1% of patients; microsatellite instability was rare (1.7%). Frequent mutations included PIK3CA (34.5%), KMT2D (18.0%), PTEN (13.1%), FBXW7 (12.9%), and TP53 (12.0%). ATs were identified in BRCA1/2, FGFR2/3, EGFR, KRAS, BRAF, and NRAS. Mutation patterns varied by HPV subtype. LB showed high concordance with TB, including HPV detection. At GR, LB informed treatment decisions in 18.2% of cases. Four clinical examples illustrated LB-guided therapies. This largest-to-date aSCC cohort reinforces molecular profiling-especially LB-as a key tool for guiding personalized therapy.