The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

Abstract

The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely affect patients’ survival. The difficulty in separating in advances responder from non-responder patients affected by LARC highlights the need for valid biomarkers that guide clinical decision-making. In this context, microRNAs (miRNAs) seem to be promising candidates for predicting LARC prognosis and/or therapy response, particularly due to their stability, facile detection, and disease-specific expression in human tissues, blood, serum, or urine. Although a considerable number of studies involving potential miRNA predictors to nCRT have been conducted over the years, to date, the identification of the perfect miRNA signatures or single miRNA, as well as their use in the clinical practice, is still representing a challenge for the management of LARC patients. In this review, we will first introduce LARC and its difficult management. Then, we will trace the scientific history and the key obstacles for the identification of specific miRNAs that predict responsiveness to nCRT. There is a high potential to identify non-invasive biomarkers that circulate in the human bloodstream and that might indicate the LARC patients who benefit from the watch-and-wait approach. For this, we will critically evaluate recent advances dealing with cell-free nucleic acids including miRNAs and circulating tumor cells as prognostic or predictive biomarkers.

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

“…Optimal timing of surgical resection after nCRT also remains debatable, as longer intervals from nCRT to surgery appeared to lead to a greater potential of achieving a pCR in a meta-analysis [ 35 ], but delaying surgery was significantly associated with increased morbidity in a randomized trial [ 36 ]. Histological tumor regression grade is assessed using various grading systems with subjective categorization to reflect therapeutic response, leading to interobserver variability [ 37 , 38 ]. Such considerable variabilities among previously-published studies and datasets, including nCRT regimens, intervals from CRT to surgery, grading systems for tumor regression, and definitions of non-responder might also be a potential bias.…”

Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer

“…Then, clinicians could manage differently those subgroups of patients candidate to be resistant to chemoradiotherapy or those that likely reach a pCR before treatment in order to reduce undesirable observed morbidities and mortalities as well as delays in the resection of the primary tumor [ 9 ]. Although researchers have identified several postsurgical prognostic markers as well as few preoperative markers, none of them have been established clinically to date [ 10 , 11 , 12 ]. Thus, a major current limitation for clinical management of LARC patients is the absence of effective predictors of pathological tumor response before neoadjuvant CRT.…”

“…They can also be used to predict the tumor resistance to therapeutic agents [ 17 ]. In rectal cancer, miRs have shown to be potential useful biomarkers based on their detection in both tumor tissue and liquid biopsies [ 12 ]. Consequently, the assessment of levels of a single miR or miRNAs-based signatures in tumor specimens or circulating miRs/tumor cells in body fluids could improve the classification of LARC patients according to the CRT response, thus facilitating the clinical decision [ 18 , 19 , 20 , 21 ].…”

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

“…miRNAs can be quantified in non-invasive specimens such as body fluids, which renders them easily detectable biomarkers [ 13 , 90 , 91 , 92 ]. Indeed, miRNAs are highly stable and circulate in the bloodstream as cell-free miRNAs or packaged inside microvesicles, such as exosomes [ 9 , 93 ]. Advances in liquid biopsy technologies (i.e., digital PCR and microfluidic single-cells technologies) enable their accurate detection [ 94 ].…”

“…The clinical potential of miRNAs as diagnostic and prognostic, as well as predictive biomarkers, has been widely described, especially in the context of human cancer [ 6 , 8 , 9 , 10 ]. Moreover, potential therapeutics harness the deregulation of miRNAs in disease conditions by means of miRNA mimics, so-called antimiRs [ 11 , 12 ].…”