Promises and Challenges of Predictive Blood Biomarkers for Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy

The treatment of locally advanced rectal cancer (LARC) requires a multimodal approach combining neoadjuvant radiotherapy or chemoradiotherapy (CRT) and surgery. Predicting tumor response to CRT can guide clinical decision making and improve patient care while avoiding unnecessary toxicity and morbidity. Circulating biomarkers offer both the advantage to be easily accessed and followed over time. In recent years, biomarkers such as proteins, blood cells, or nucleic acids have been investigated for their predictive value in oncology. We conducted a comprehensive literature review with the aim to summarize the status of circulating biomarkers predicting response to CRT in LARC. Forty-nine publications, of which forty-seven full-text articles, one review and one systematic review, were retrieved. These studies evaluated circulating markers (CEA and CA 19-9), inflammatory biomarkers (CRP, albumin, and lymphocytes), hematologic markers (hemoglobin and thrombocytes), lipids and circulating nucleic acids (cell-free DNA [cfDNA], circulating tumor DNA [ctDNA], and microRNA [miRNA]). Post-CRT CEA levels had the most consistent association with tumor response, while cfDNA integrity index, MGMT promoter methylation, ERCC-1, miRNAs, and miRNA-related SNPs were identified as potential predictive markers. Although circulating biomarkers hold great promise, inconsistent results, low statistical power, and low specificity and sensibility prevent them from reliably predicting tumor response following CRT. Validation and standardization of methods and technologies are further required to confirm results.