Page 84 - Read Online

Page 126 De Mattia et al. Cancer Drug Resist 2019;2:116-30 I http://dx.doi.org/10.20517/cdr.2019.04

Immuno-related genes
Immune system has been extensively investigated for its role in cancer treatment, and some data suggest
that it could also contribute to determine the severity of drug related toxicity, including FPs. The immune
system has been reported to play a key role in the pathogenesis of the gastrointestinal toxicity subsequent to
FPs administration. In particular, inflammatory mediators such as tumor necrosis factor-α and interleukin 1
beta, seemed to be implicated in the complex mechanism underlying the toxic damage to the GI epithelium
[15]
(i.e., mucositis) induced by some chemotherapeutics including 5-FU . In this context, we recently published
discovery/replication study on more than 400 mCRC patients treated with a first-line 5-FU containing
regimen adopting a TagSNP approach to evaluate the systemic variability of 22 inflammation-related
genes. The study highlighted that a polymorphism in thesignal transducer and activator of transcription 3
(STAT-3) encoding gene (i.e., rs1053004), a transcriptional factor triggered in response to the binding of some
pro-inflammatory, and in the vitamin D receptor (i.e., rs11574077), a nuclear receptor acting as inflammation
sensor, were significantly associated with the risk of developing severe GI toxicity. These findings highlight
the importance of the inflammatory response mediators in the pathobiology of drug-induced mucosal
[74]
injury, a topic that requires more attention in further pharmacogenetic investigations .

We have also reported in another study that polymorphisms (rs371194629, rs1610696) in the gene encoding
the Human Leukocyte Antigen G (HLA-G), involved in the immune modulation, could contribute in
explaining the inter-individual differences in toxicity profiles of CRC patients receiving FPs containing
therapy . HLA polymorphisms as well as variants in the gene encoding for the pro-inflammatory cytokine
[75]
[78]
interferon-γ (IFNG-rs1861494) [76,77] and KIR-HLA have been also reported to be associated with the
recurrence risk and OS of stage II-III patients receiving 5-FU-containing adjuvant therapy further stressing
the relevance of immunogenetic markers for treatment personalization. The involvement of the immune
system and inflammation process in determining FPs-based therapy clinical outcome administration is
surely a intriguing topic warranting further pharmacogenetic investigation.

CONCLUSION
The role of germline variants in the prediction and management of drug-related adverse events in CRC
has been a matter of widespread investigation. Despite the well-established clinical validity of some
pharmacogenetic markers and the publication of shared guidelines for FP and irinotecan, their use in
the clinical practice is still object of debate. We have herein reported already available pharmacogenomic
guidelines with ongoing efforts to implement them in the clinical practice, and new exploratory markers on
the way to clinical validation, to move forward the fields of pharmacogenomics and precision medicine.

Collectively, the current literature data indicate that the loss of function DPYD polymorphisms are the
only pharmacogenetic markers that have been found to have clinical and statistical significance for the
predication of FPs-induced toxicity. However, neither the National Comprehensive Cancer Network, nor the
European Society of Medical Oncology currently recommend their use in the clinical practice reflecting the
challenge to integrate pharmacogenomics in clinical practice. Several research projects are currently ongoing
to bring the ultimate proofs of the clinical validity and utility of pharmacogenomics implementation to
improve patients management and to increase drug safety. Several clinical implementation projects are on-
going in Europe and in the US and the results of some genotype directed clinical trials have been published
demonstrating the feasibility of this approach and its applicability in the clinical practice [79-81] .

Other genetic targets as TYMS and MTHFR genotypes have only a small role to play in this context. TYMS
and MTHFR markers could probably have a feasible application when integrated in a polygenic model that
[82]
combines the effect of the single variants . As example a discovery/validation study conducted on 302
Caucasian Dukes’ stage B2 and C colon cancer patients homogeneously treated with 5-FU based regimen,