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Emerging advances and future opportunities in the molecular and therapeutic landscape of anal cancer
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Emerging advances and future opportunities in the molecular and therapeutic landscape of anal cancer
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Journal Article
Emerging advances and future opportunities in the molecular and therapeutic landscape of anal cancer
2025
Overview
Anal squamous cell carcinoma (ASCC) is a rare malignancy with an increasing incidence. Primary chemoradiotherapy (CRT) is the standard-of-care treatment for patients with localized ASCC. In the metastatic setting, trials testing immune-checkpoint inhibitor monotherapy have demonstrated outcomes similar to those of patients receiving chemotherapy. Conversely, adding the anti-PD-1 antibody retifanlimab to chemotherapy in patients with recurrent or metastatic ASCC has been shown to significantly improve outcomes. Despite considerable efforts to develop personalized therapy, treatment guidance and prognosis remain reliant on baseline clinical characteristics. An improved understanding of the molecular characteristics of ASCC has provided insights into the mechanisms that mediate tumour progression and response to CRT. For example, human papillomavirus (HPV) infection is known to have an aetiological role in most ASCCs and can modulate cellular responses to CRT via several distinct mechanisms. In this Review, we summarize emerging advances in the molecular and therapeutic landscape of ASCC, including the implementation of biomarkers for treatment guidance and translation into new therapeutic approaches, with HPV infection constituting a global determinant of both tumour biology and clinical outcome. We also discuss the rationale for combining immune-checkpoint inhibitors with CRT in patients with HPV
+
tumours.
Anal squamous cell carcinoma (ASCC) is a rare malignancy, albeit with an increasing prevalence in most economically developed countries. Despite considerable advances in our understanding of the biology of ASCC, chemoradiotherapy (CRT) remains the standard-of-care therapy for most patients, albeit with promising data emerging on the role of CRT plus immune-checkpoint inhibitors in the metastatic setting. In this Review, the authors describe the biology of ASCC and relate this to the various attempts to improve outcomes via the development of more effective systemic therapies and/or combinations.
Key points
Anal squamous cell carcinoma (ASCC) is associated with human papillomavirus (HPV) infection, with approximately 70–90% of all patients having HPV
+
disease.
Despite advances in our understanding of the molecular landscape of ASCC, prognosis and treatment decision-making continue to rely on baseline clinical characteristics.
HPV infection has a role in the development of most ASCCs, although paradoxically, patients with HPV
+
tumours and high viral loads have better responses and outcomes on standard chemoradiotherapy.
The immunomodulatory effects of HPV infection provide a rationale for combining chemoradiotherapy with immunotherapies in patients with HPV
+
ASCC.
Assessments of molecular biomarkers and the development of molecularly targeted therapies in line with that of emerging immunotherapies might further improve the outcomes of patients with ASCC.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Cancer
/ Carcinoma, Squamous Cell - genetics
/ Carcinoma, Squamous Cell - pathology
/ Carcinoma, Squamous Cell - therapy
/ Carcinoma, Squamous Cell - virology
/ Genomics
/ Humans
/ Immune checkpoint inhibitors
/ Immune Checkpoint Inhibitors - therapeutic use
/ Kinases
/ Medicine
/ Mutation
/ Oncology
/ Papillomavirus Infections - complications
/ Papillomavirus Infections - virology
/ Patients
/ Proteins
/ Tumors
