Anal Cancer

Epidemiology & Impact

Anal cancer is relatively uncommon, accounting for approximately 10,540 new cases and 2,190 deaths annually in the United States. However, incidence rates have been rising steadily — approximately 2-3% per year over the past two decades — making it one of the fastest-growing cancer diagnoses. The disease disproportionately affects certain populations: incidence is 20 to 30 times higher in men who have sex with men, and HIV-positive individuals face a significantly elevated risk even in the era of antiretroviral therapy. Women also experience higher overall incidence than men (approximately 60% of cases). Human papillomavirus (HPV) infection, particularly HPV-16, is the dominant risk factor and is detectable in approximately 90% of anal squamous cell carcinomas. Other risk factors include immunosuppression, cigarette smoking, chronic anal fistulae, and a history of receptive anal intercourse. The rising incidence underscores the potential impact of HPV vaccination programs, which may reduce future disease burden.

Molecular Biology & Biomarkers

Squamous cell carcinoma accounts for approximately 85% of anal malignancies, with the remainder including adenocarcinomas, melanomas, and neuroendocrine tumors. The molecular pathogenesis of anal squamous cell carcinoma is intimately linked to HPV oncoproteins E6 and E7, which inactivate the tumor suppressors p53 and Rb respectively, driving uncontrolled cell proliferation. Unlike cervical cancer, the role of specific HPV genotypes beyond HPV-16 is less well characterized in anal cancer. Genomic profiling has revealed that anal cancers frequently harbor PIK3CA mutations (approximately 30-40% of cases), amplification of SOX2 at 3q26, and alterations in the EGFR pathway. PD-L1 expression is observed in approximately 50-70% of anal squamous cell carcinomas, providing a biological rationale for the activity of checkpoint inhibitors in this disease. The immune microenvironment is particularly relevant, as HPV-driven tumors typically exhibit higher immune cell infiltration and may be more responsive to immunotherapy.

Evolving Treatment Landscape

The standard of care for localized anal cancer is the Nigro protocol — concurrent chemoradiation with 5-fluorouracil and mitomycin C — which achieves sphincter-sparing cure rates of 60-80% depending on stage. For patients with metastatic or recurrent disease after chemoradiation, treatment options were historically limited to platinum-based chemotherapy with modest efficacy. Immunotherapy has transformed the treatment of advanced anal cancer: pembrolizumab (Keytruda) demonstrated a 24% overall response rate in the KEYNOTE-158 trial and nivolumab (Opdivo) showed a 24% response rate in the CheckMate 358 trial, leading to FDA approval for previously treated metastatic disease. The POD1UM-303 trial evaluating retifanlimab recently demonstrated the first positive phase 3 result in anal cancer, establishing checkpoint inhibition as a standard in this setting. Active areas of investigation include the combination of anti-PD-1 therapy with anti-CTLA-4 agents, HPV-directed therapeutic vaccines, and the incorporation of immunotherapy into earlier treatment settings.

Note: FDA-approved options for anal cancer are limited. Immunotherapy is approved for metastatic squamous cell carcinoma of the anal canal. Pembrolizumab is available via the MSI-H/TMB-H tumor-agnostic approval for eligible patients.

EMA-Approved Therapies for Anal Cancer

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key therapies with comparative information to FDA approvals.

For complete European drug information, visit ema.europa.eu ↗