Liquid biopsy in head and neck squamous cell carcinoma: Prognostic significance of circulating tumor cells and circulating tumor DNA. A systematic review

Liquid biopsy represents a great promise for its potential to detect cancer before clinical signs occur. It represents a very advantageous tool, as it is rapid and minimally invasive in monitoring cancer: in particular its main applications should concern the early diagnosis of cancer, the prognostic evaluation, the assessment of treatment response and the evaluation of recurrences. In relation to HNSCC compared to other cancer anatomic locations, the impact of liquid biopsy in the clinical setting is still limited: the study of CTCs and ctDNA has been increased in order to identify precise correlations between the tumor burden and biomarkers levels and to assess how these levels vary during and after treatments. However, in order to do this, it is necessary to overcome the pro- blem of tumor heterogeneity, by identifying the main mutations un- derlying head and neck cancers: in this regard an appropriate addition to the TNM staging system would be the inclusion of the molecular typing of the tumor, which would help to personalize therapies, de- creasing the risk of overtreatment or undertreatment [94,95]. Despite the numerous analyzed biomarkers in these studies, we can consider as reliable only a limited number of these: for that concern CTCs the only standardized and reliable method that could be applied to HNSCC is the detection of EPCAM, while in relation to ctDNA, the main genetic alterations that can be correlated to head and neck can- cers are those related to EGFR, RAS and TP53 genes, or viral DNA de- tection (HPV). Finally, despite the several methods and technologies for CTCs and ctDNA detection, there is still a lack of standardized methods. In ad- dition, there are no studies evaluating the influence that different therapies and different types of cancer may have on the detection of CTCs and ctDNA: the heterogeneity of the sample populations, the different therapeutic protocols and the different stages of the tumors included in the clinical trials still represent important limitations. Anyway, results are promising and provide ground for more large- scale studies with standardized serial assessment of patient samples in the future.