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Mini et al. Cancer Drug Resist 2020;3:225-31 I http://dx.doi.org/10.20517/cdr.20220.10 Page 227

dihydropyrimidine dehydrogenase (DPYD), and drugs substrate of cytochrome P450 family members
whose polymorphisms have been associated with drug response (i.e., efficacy and toxicity) are described.

[12]
The review by Crisafulli et al. deals with the several strategies currently available to study germline
polymorphisms, tumor biomarkers, cancer drivers, and actionable targets for cancer treatment, in relation
to specific endpoints of response related to efficacy and/or toxicity. Researchers are today called to plan
the optimal identification strategy (e.g., candidate genes and whole genome analysis) based on the aims
of their studies. In particular, the availability of several next generation sequencing technologies allows
the discovery of novel cancer-driving mutations as well as druggable mutations. Evidence found using
these approaches has to undergo validation processes before their application in the clinical practice as
diagnostic or prognostic biomarkers. Thus, regulatory agencies have established recommendations to adopt
pharmacogenetic and pharmacogenomic methods in research and diagnostics.

Pharmacogenetics and pharmacogenomics may also successfully drive the discovery and development
process of new anticancer agents by greatly reducing the attrition rate issue, as reported in the review by
[13]
Tarantino et al. . A strategy to decrease this occurrence is represented, for instance, by alternative trial
designs such as the basket and umbrella trials, in which the histology-oriented approach is replaced by
the molecular alteration-centered ones [14,15] . The introduction of pharmacogenetics/pharmacogenomics
principles in the early drug developmental phases may also contribute to the reduction of the high attrition
rates, although not every early phase of clinical trials benefits to the same extent from pharmacogenetics/
pharmacogenomics implementation. The more promising phase of clinical trials for identifying efficacy
biomarkers is probably represented by phase II studies due to the possibility to include biomarkers in
the trial design and to randomize patients. Liquid biopsy, which is today routinely used to detect specific
somatic mutations predictive of anticancer drug efficacy/resistance, may also be implemented in biomarker-
driven clinical trials in order to avoid multiple traditional biopsies that should be performed longitudinally.
All these opportunities have the potential to make easier and faster translation of findings from clinical
[16]
trials into clinical practice benefits .

Fluoropyrimidines (i.e., 5-fluorouracil and capecitabine) that still represent a backbone in the treatment of
several solid tumors, including colorectal cancer, have been widely investigated from a pharmacogenetic
point of view since polymorphisms of genes that codify for enzymes involved in their complex metabolism
and mechanism of action have been related to their adverse events and, to a lesser extent, their efficacy.
[17]
The review by De Mattia et al. points out the current recommendations on the use of genetic tests for
the detection of deleterious variants in DPYD. These authors also provided information based on their
previously published data on the higher economic burden of toxicity management for colorectal cancer
patients harboring DPYD polymorphisms and treated with fluoropyrimidines compared with wild-
type patients. Polymorphisms of two major pharmacogenes, namely thymidylate synthase (TYMS) and
5,10-methylentetrahydrofolate reductase (MTHFR), which are involved in the mechanism of action of
fluoropyrimidines, have been suggested in the last decades to have a role not only in their efficacy but
also in their toxicity. The authors critically reviewed the available evidence on these aspects. Although
genetic variants of various other activating or inactivating metabolism enzymes of fluoropyrimidines
have been suggested to play a role in fluoropyrimidine toxicity (e.g., uridine monophosphate synthase,
cytidine deaminase, and carboxylesterase 1 and 2), as have immune-related genes [e.g., human leukocyte
antigen (HLA)], the authors concluded that, overall, only loss of function DPYD polymorphisms represent
recognized pharmacogenetic markers with statistical and clinical significance for the prediction of
[18]
fluoropyrimidine-induced toxicity .

[19]
The review of Franca et al. tackles similar issues on the use of another class of antimetabolite drugs.
Thiopurines include mercaptopurine and thioguanine, which are active in several forms of leukemia