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Comprehensive molecular landscape of anal squamous cell carcinoma: analysis of tissue and liquid biopsies from 1844
Cristina Smolenschi1,2, Saumya D Sisoudiya3, Antoine Hollebecque4
1Drug Development Department (DITEP) Gustave Roussy, Villejuif, France. cristina.smolenschi@gustaveroussy.fr.
Abstract:
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.
Insights
This study reveals the genomic landscape of anal squamous cell carcinoma (aSCC), identifying actionable targets and highlighting the value of molecular profiling, including liquid biopsy (LB), for personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Anal squamous cell carcinoma (aSCC) is a rare cancer with limited therapeutic options.
- Human Papillomavirus (HPV) is a primary driver in the majority of aSCC cases.
- Understanding the genomic profile of aSCC is crucial for developing targeted therapies.
Purpose of the Study:
- To define the genomic landscape of aSCC.
- To identify actionable targets (ATs) for potential therapeutic intervention.
- To evaluate the clinical utility of molecular profiling, particularly liquid biopsy (LB), in guiding treatment decisions.
Main Methods:
- Retrospective analysis of 1844 patients with aSCC from the U.S. and France.
- Comprehensive genomic profiling using FoundationOne®CDx and FoundationOne® Liquid CDx assays.
- Analysis included tissue biopsy (TB) and liquid biopsy (LB) data, with paired TB/LB analysis in 29 patients.
Main Results:
- HPV was detected in 86.6% of cases, predominantly HPV-16.
- Frequent mutations identified in PIK3CA (34.5%), KMT2D (18.0%), PTEN (13.1%), FBXW7 (12.9%), and TP53 (12.0%).
- Actionable targets (ATs) were found in genes including BRCA1/2, FGFR2/3, EGFR, KRAS, BRAF, and NRAS.
- Liquid biopsy (LB) demonstrated high concordance with tissue biopsy (TB) and informed treatment decisions in 18.2% of cases at Gustave Roussy.
Conclusions:
- Molecular profiling, especially liquid biopsy (LB), is a valuable tool for guiding personalized therapy in aSCC.
- The genomic landscape of aSCC reveals several potential therapeutic targets.
- HPV status influences mutation patterns, underscoring the need for HPV-specific considerations in treatment.
