Somatic pharmacogenomics in the treatment prognosis of locally advanced rectal cancer patients: a narrative review of the literature

Introduction: Standard treatment for patients with locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT) with fluoropyrimidines, followed by surgical excision. The newly introduced therapeutic strategies propose intensified regimens or more conservative approaches based on risk stratification algorithms that currently include clinicoradiological criteria but not molecular variables. How to better stratify patients is a burning clinical question, and pharmacogenomics may prove useful in identifying new genetic markers that could be incorporated into clinical algorithms to personalize nCRT. An emerging area could be the evaluation of somatic mutations as potential genetic markers that correlate with patient prognosis. Tumor mutations in the RAS/BRAF genes, as well as microsatellite instability (MSI) status, are currently used in treatment selection for colorectal cancer (CRC); however, their clinical value in LARC is still unclear. Area covered: This literature review discusses the relevant findings on the prognostic role of mutations in the key oncogenes RAS, KRAS, BRAF, PIK3CA, SMAD4 and TP53, including MSI status in LARC patients treated with nCRT. Expert opinion: KRAS proved to be the most promising marker, consistently associated with poorer disease-free survival and overall survival. Therefore, KRAS could be a good candidate for integration into the risk stratification algorithm to develop a personalized treatment.