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Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25 Page 55

drug combinations that qualify for level 2B where the variant is within a very important pharmacogene as
defined by PharmGKB, so functional significance is more likely. In Level 2B variant-drug combinations, the
association must be replicated but there may be some studies that do not show statistical significance, and/
or the effect size may be small. Level 3 and level 4 clinical associations are not strong enough to be used
for clinical translation, under our point of view. Level 3 annotation based on a single significant (not yet
replicated) study or annotation for a variant-drug combination evaluated in multiple studies but lacking
clear evidence of an association; and finally, level 4 annotations are based on a case report, non-significant
[7]
study or in vitro, molecular or functional assay evidence only .

DRUGS AND GUIDELINES
Guidelines are not always easy to interpret, mainly if the reader is not used to the usual terms and
nomenclature in PGx. It is crucial that the recommendations arrive to the prescribing clinicians in a rigorous
but at the same time, simple and easy-to-interpret manner, otherwise clinical implementation of PGx would
be hardly impossible.

Following with our aim, we focus now on the existing PGx guidelines for chemotherapy treatment and
some associated drugs. Table 1 summarizes the content of CPIC and DPWG published documents, being
these, and specially the first, the most active and experienced consortia in providing this kind of tools for
PGx translation to the clinic. The description of the procedures employed by each consortium to evaluate
the evidence and apply recommendations is described in a couple of publications [12,13] . Currently, and being
aware that these consortia employ different criteria for nomenclature and also for rising recommendations,
they are making efforts for harmonization, with a descriptive publication just comparing their statements
[14]
and showing the differences as a first step .
Other guidelines, elaborated by other professional groups, are commented afterwards in the text. These
guidelines have not received the approval or reached a consensus with other societies or consortia, so the
[15]
robustness of the way they evaluate the evidences is not recognized in the manner that CPIC is.
Again, it is very important to remark that Table 1 aims to provide a rigorous but user-friendly content, and
therefore, translation of asterisk or phenotype-way nomenclatures into “rs” SNP nomenclature is given when
possible. Also, some of the guidelines include very low frequent variants that are not considered in Table 1
either, so if a deeper detail is needed, the original guidelines referenced in this work should be consulted.

Regarding CYP2D6, it is necessary to state that it is one of the most complicated genes to analyze in terms
of genotyping and in knowing with high certainty, the genotype-phenotype correlation. Many groups are
working on this point worldwide, trying to clearly identify which genetic variants lead to poor, intermediate,
normal or ultrarapid metabolizers (UM). This gene is highly polymorphic, but not only regarding SNPs
content, but also in duplications, deletions, etc. Drug-drug interactions and ethnic variability are very
[16]
important for every pharmacogene, but we could say that for CYP2D6 the impact is the highest . That is
why in Table 1, the information regarding ondansetron, oxycodone, tamoxifen and tramadol has been kept
with the typical CYP2D6 nomenclature including haplotypes and asterisks.

Thiopurines and TPMT
Thiopurine drugs such as azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine, are cytotoxic
drugs employed in the treatment of severe diseases as childhood acute lymphoblastic leukemia and
inflammatory bowel disease . AZA is converted almost completely to 6-MP through a non-enzymatic
[23]
[24]
reaction within the liver .