The development of biomarkers is essential in the rare neoplasm squamous cell carcinoma of the anal canal (SCCA) to predict response to immunotherapy and other targeted therapies in metastatic patients.
A recent review addressed the molecular characterization of SCCA and discussed potential diagnostic, predictive, and prognostic biomarkers of this complex, challenging disease. The review was led by Maria Cecilia Mathias-Machado, MD, of the University of Sao Paulo in Brazil, and published in Biomedicines (2022; doi: 10.3390/biomedicines10082029).
The main risk factors for SCCA development are immunosuppression and human papillomavirus (HPV) infection, which is present in 95 percent of cases. Additional risk factors include an increased number of sexual partners and anal intercourse, which may be linked to HPV infection, they stated.
"Fluoropyrimidine-based chemoradiotherapy has been the cornerstone of the treatment of localized disease for the past 4 decades. However, systemic therapy of metastatic or recurrent SCCA is an unmet clinical need," the researchers stated.
Despite sharing common molecular aspects with other HPV-related malignancies, such as cervical and head and neck cancers, SCCA presents specific epigenomic, genomic, and transcriptomic abnormalities. This suggests that genome-guided, personalized therapies should be specifically designed for this disease, they stated. Actionable mutations are rare in SCCA and immune checkpoint inhibition has not yet been proven useful in an unselected population of patients.
The researchers identified a series of potential predictive biomarkers in SCCA.
HPV. HPV detection could presumably be applied as a biomarker for both early diagnosis and treatment response in locally advanced and metastatic disease. HPV16 is the most frequently encountered genotype in SCCA, detected in 68-94 percent of cases. The evaluation of tumor HPV16 viral load has demonstrated prognostic value in SCCA patients treated with chemoradiotherapy, they stated.
A recent systematic review and meta-analysis of 17 retrospective cohort studies demonstrated that HPV+ and p16+ tumors had improved overall survival (OS) compared to tumors with negative profiles (Clin Oncol 2019; https://doi.org/10.1016/j.clon.2019.06.013). Currently, there are no recommendations for treatment modification based on HPV or p16 status, they noted.
Circulating Tumor DNA (ctDNA). HPV DNA appears to assess the presence of ctDNA in SCCA and can be detected in plasma with sensitivity up to 93 percent in HPV-positive cancers.
HIV. A low CD4 count has been associated with an increased risk of anal cancer, and immunosuppression is critical in the early stages of SCCA development due to the persistent infections and decreased clearance of anal HPV, researchers stated. A systematic review and meta-analysis of 122 studies included data on 417,006 people living with HIV on the association of HIV-related exposures (ART, HIV-RNA plasma viral load, and CD4 cell count) with outcomes of anal high-risk HPV prevalence, incidence, and persistence (Lancet HIV 2020; https://doi.org/10.1016/S2352-3018(19)30434-5). A high nadir CD4 cell count of >=200 cells per [mu]L was associated with a 67 percent decreased risk of anal cancer incidence.
Ki-67. Ki-67 may be an independent predictor of disease-free survival (DFS), with one study demonstrating that a higher Ki-67 index correlated with improved DFS in patients treated with chemoradiotherapy (Dig Dis Sci 2021; https://doi.org/10.1007/s10620-009-0812-6). Patients presenting a higher ratio (Ki-67 expression and EGFR staining) had a statistically significant lower OS, disease-free failure, and a higher risk of locoregional failure when compared to patients with a lower ratio, suggesting a possible role of this ratio as a possible biomarker, according to researchers.
Programmed Death-Ligand 1 (PD-L1). Some retrospective studies have evaluated the programmed cell death protein ligand 1 (PD-L1) expression in tumor cells of patients with SCCA, with PD-L1 positivity varying from 56 percent to 69 percent. The prognostic role of the biomarker has been reported in those studies, with conflicting results, they stated. Immune checkpoint blockade with monoclonal antibodies against programmed death-1 (PD-1) and PD-L1 has also been investigated in metastatic SCCA with encouraging results. However, not all studies demonstrated the application of PD-1/PD-L1 values in tumor specimens as a marker of response.
"Therefore, PD-1/PD-L1 status has not proven to be a reliable biomarker to predict patient response to treatment with immune checkpoint inhibitors and, as such, the question remains on how to better select patients for immunotherapy," the researchers stated.
Tumor-Infiltrating Lymphocytes (TILs). A retrospective analysis of 284 patients treated with radiation therapy with or without chemotherapy for locally advanced non-metastatic SCCA analyzed the prognostic value of TILs in this tumor subtype (Br J Cancer 2016; https://doi.org/10.1038/bjc.2015.448). It demonstrated that, in p16+ patients, tumors with absent/low levels of TILs presented a relapse-free rate of 63 percent, compared to 92 percent of patients with high levels of TILs.
Mark L. Fuerst is a contributing writer.