Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects. In this review, the potential of specific biomarkers will be explored to address two key questions—1) Can the prognosis of patients that will fare well or poorly be determined beyond currently recognized prognostic indicators? and 2) Can an individual patient’s response to therapy be predicted and those who will most likely benefit from treatment/s be identified? Identifying and validating key prognostic and predictive biomarkers and an understanding of the underlying mechanisms of drug resistance and toxicity in CRC are important steps in order to personalize treatment. This review addresses recent data on biological prognostic and predictive biomarkers in CRC. In addition, patient cohorts most likely to benefit from currently available systemic treatments and/or targeted therapies are discussed in this review.

Biomarkers in Colorectal Cancer: Current Research and Future Prospects

“…In the emerging field of radiogenomics, a combination of radiological and genetic features may give greater prognostic sensitivity than either of these modalities in isolation [ 53 , 54 ]. Finally, the carcinoembryonic antigen (CEA), a high molecular weight glycoprotein is used as a biomarker to predict early recurrence in post-operative patients despite low sensitivity and specificity [ 55 , 56 ]. Thus, using prognostic markers may alter thresholds for further investigation of recurrent disease and provide opportunities for early intervention.…”

“…Homozygosity for UGT1A1*28 allele is associated with dose dependent increase in toxicity compared to UGT1A1*1 genotype [ 59 ]. Moreover, dihydropyrimidine dehydrogenase (DPD) is responsible for metabolizing more than 80% of 5-FU [ 56 ]. DYPD*2A and DPYD*13 variants lead to increased toxicity with evidence that reducing 5-FU dose by 25–50% can lead to a reduction in toxicity [ 60 ].…”

“…Molecular subtyping of colorectal cancer has led to several categories of potential biomarkers through somatic mutations, germline pharmacogenomics, cancer stem cells, microRNA, and long non-coding RNA (lncRNA) [ 10 , 56 , 62 , 63 ].…”

“…In addition, over-expression of the pro-apoptotic BCL-2 gene is associated with an improved overall and disease-free survival in CRC, highlighting its potential as a prognostic marker [ 81 ]. Finally, there is limited evidence that quantification of tumor infiltrating lymphocytes (TILs) and mutations in the POLE gene encoding the DNA Polymerase epsilon subunit, may have prognostic value in overall or disease-free survival [ 56 ].…”

“…A second category of biomarkers are alterations in the germline pharmacogenes [ 56 ]. The utility of germline mutations has been shown in predicting CRC risk.…”