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De Mattia et al. Cancer Drug Resist 2019;2:116-30 I http://dx.doi.org/10.20517/cdr.2019.04 Page 125

of severe overall toxicity after capecitabine administration. The role of ABCB1 markers as predictors of
the inter-individual variability in the capecitabine toxicity profile is a novel finding that should be further
investigated. On the contrary the involvement of CDA rs2072671variant in determining the FPs related
adverse reactions in more controversial since the existence of discrepant results [39,68] probably due to
differences in performed studies (study design, sample size, criteria severe toxicity cut-off establishment,
concomitant medication). Two other functionally-relevant CDA polymorphisms in the promoter region,
rs532545 and rs602950 variants, were associated with an increased risk to develop severe toxicity, and
specifically grade 2-4 diarrhea and grade ≥ 3 HFS, by a studies on a large cohort of capecitabine-treated
patients [69,70] . Another polymorphism, the rs3215400 that corresponds to a promoter insertion associated with
enhanced CDA expression, in combination with a CDA ultra rapid phenotype, was suggested to contribute
[71]
to a toxic deathdespite being DPYD and TYMS wild-type status in a patient treated with capecitabine .

Hence, variants in CDA gene represent a good candidate targets for future pharmacogenetic investigation
aiming at determining whether testing for these variants is clinically useful.

An additional investigated marker in the folate pathway is the TYMP enzyme and the related genetic variants.
However, most of the studies failed to find an association between TYMP polymorphisms and capecitabine-
[39]
related adverse events . Only an investigation on 254 Caucasian CRC patients treated with 5-FU or
capecitabine reported that the missense TYMP rs11479 variant was associated with FP dose modifications and/
or severe adverse events. However a further analysis evaluating the potential value of testing the combined
TYMP rs11479 and DYPD mutations signature revealed a still poor clinical impact highlighting the need to
[68]
discover further novel genetic markers that could improve the predictive algorithm .
A multi gene approach was attempted by the group of Pellicer et al. , that investigated 23 TagSNP in FPs-
[63]
pharmacodynamics genes on 301 Caucasian CRC patients receiving capecitabine-based chemotherapy,
in order to find new genetic variants predicting individual risk of chemotherapy-induced severe adverse
reactions. This study revealed ten polymorphisms associated with severe capecitabine toxicity: CDA
rs1048977, rs12726436, and rs2072671; DPYD rs12119882; TYMS rs2853741; TYMS/ENOSF1 rs699517;
SLC22A7 rs2270860 and rs4149178; UMPS rs2279199 and rs4678145. Except for rs2072671, all the observed
associations were not previously reported, suggesting that the use of TagSNPs method could be a successful
strategy to find new predictors of adverse reactions to capecitabine improving the power of currently
available tests. All these promising candidate proteins involved in the FPs pathway should represent the
target of future research aiming at discovering and validating additional biomarkers to be integrated in
the pharmacogenetic test. A similar approach was adopted in a study conducted on a small group of CRC
patients receiving triplet (irimotecan, 5-FU, and oxaliplatin) hepatic artery infusion plus intravenous
cetuximab for unresectable liver metastases . The analysis, conducted within the prospective European
[72]
trial OPTILIV (NCT00852228) pointed out six ADME genes (i.e., CYP2C9, CYP2E1, UGT1A6, SLCO1B3,
SLC22A1, and ABCB1) which polymorphisms were associated with the risk of developing severe toxicity.
Patients in a phase III randomized clinical trial (NCT00486213) were also investigated in a genome-wide
[73]
association study to find novel genetic determinants of capecitabine-related HFS . A set of exploratory
markers, including three novel DPYD variants, were significantly associated with grade 2 or higher HFS.
If validated, these markers could further improve the management of patients receiving capecitabine.
[37]
Another more recent work by Pellicer et al. already mentioned above, moved from a candidate SNP
to an exome NGS approach to obtain a global profiling of the germline variability of genes involved in
capecitabine transport, metabolism and mechanism of action. Beside confirming the pivotal role of DPYD
and MTHFR polymorphism as predictors of FP-related toxicity, this study highlighted also some previously
unreported genetic variantsas potential additional toxicity markers. These findings suggest the utility to
adopt sequencing-based strategies to provide a broad pharmacogenetic overview and to expand the actual
knowledge about genetic markers of FPs-related toxicity.