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Liquid biopsy
Another field of major interest is the rapid development of liquid biopsies technology and the analysis of ctDNA
as a more comprehensive and less invasive approach to pharmacogenomic profiling in CRC patients [187,188] .
Allowing large-scale genomic profiling and being able to capture the molecular heterogeneity of different
tumor sub-clones coexisting in the same patients, these techniques are expected to play a pivotal role in
improving patients stratification and selection for targeted treatments. Moreover, the possibility to perform
seriated testing over time represents a valid opportunity to guide treatment strategies through an early
[189]
detection of the emergence of treatment resistance and a dynamic tumor molecular profiling . Indeed, data
from repeated ctDNA analyses have been able to show the emergence of RAS and/or BRAF mutations during
treatment with anti-EGFRs in KRAS WT patients, closely dependent on treatment exposure, with a dynamic
increase during EGFR blockade followed by a rapid decline after treatment withdrawal . Recently, a large
[190]
study on genomic profiling through liquid biopsy analyzing next generation sequencing data from cell-free
DNA of 1397 CRC patients, confirmed the reliability of this methodology in detecting genomic alterations
when compared with corresponding tissue-based sequencing. Additionally, results of this study highlighted
the possibility of detecting the development of multiple distinct concomitant mechanisms of resistance after
targeted treatment with anti-EGFRs in the same subject, proving that ctDNA sequencing can generate a
valuable insight into tumor heterogeneity and therapeutic resistance . Although still needing extensive
[191]
investigations and prospective validation, liquid biopsy approaches to profile tumor dynamics and response
to treatment and to guide rechallenge strategies based on detection of circulating genomic alterations are
currently under investigation in several clinical trials.

MiRNAs
Finally, noncoding RNAs represent an evolving field in cancer diagnosis and prognosis, and several studies
have suggested their possible role as treatment target in different diseases [192,193] . miRNAs are noncoding
single-stranded RNA molecules, less than 200 nucleotides in length, with a post-transcriptional regulatory
function involved in the modulation of a broad range of biological processes comprising cellular signaling,
metabolism, proliferation and differentiation . The role of several miRNAs has been implied in CRC
[194]
evolution and progression, moreover different miRNAs have been identified as predictive of treatment
response to standard chemotherapy (i.e. miR-429 and miR-148a with 5-FU) and targeted agents (i.e. miR-7
[195]
and miR-375 with anti-EGFRs) . Although promising these findings still need validation; nevertheless, the
possible clinical application of miRNAs as biomarkers or as a potential target of treatment in CRC deserves
further investigation. Of note, new strategies are currently under study to develop miRNA based inference
methods to extensively infer drug-disease causal relationship (miRDDCR) to assist in experimental design
for drug discovery and disease treatment .
[196]

CONCLUSION
In the era of precision medicine, optimizing therapeutics and drugs combination for a narrow subset of patients
based on patients’ and tumors genetic makeup is of paramount importance in order to improve outcomes and
minimize unrequired toxicities. The field of pharmacogenomics is constantly growing, and with the availability
of new technologies it has been moving beyond candidate gene approaches and genome-wide association
studies towards a comprehensive evaluation of genomic and epigenomic markers to drive treatment choices
and optimize targeted therapies. Several biomarkers have entered clinical practice so far, and many more are
currently being tested in clinical trials. Biomarker discovery and validation however still encounter many issues,
due often to the small subsets of patients bearing selected alterations, the retrospective nature of most studies
and the difficulty in proving the cost-effectiveness of a specific novel marker. Implementing biomarker-driven
clinical trials and prospective pharmacogenomic profiling in clinical research, possibly integrating companion
diagnostic tests since the early stages of novel drug development, is thus a priority for future research. Finally,
dynamic profiling of tumor genomics under treatment pressure will play a critical role in uncovering acquired
mechanism of resistance and directing personalized treatment strategies.