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Page 46 Tarantino et al. Cancer Drug Resist 2019;2:43-52 I http://dx.doi.org/10.20517/cdr.2018.22

Figure 2. Proposal of a “five Rs” framework applied to cancer drug development

to better tailor pharmacological treatments. The most common identified factors where genetic variants
influencing drug’s pharmacokinetics and pharmacodynamics: landmark examples are the discovery of
[15]
thiopurine S-methyltransferase (TMPT) polymorphisms conditioning 6-mercaptopurine (6-MP) toxicity
and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphisms leading to irinotecan
[16]
toxicity . 6-MP is a commonly prescribed drug in the treatment of acute lymphocytic leukaemia; the
individuation of germline genetic variants of TMPT inducing poor metabolization and increased toxicity
lead to FDA recommendation of routinely genotyping this gene ahead of the therapy, to reduce 6-MP doses
[16]
if an inactive allele is found . Regarding irinotecan, certain polymorphisms of UGT1A1 are associated to
increased toxicities in patients treated with this drug (irinotecan is commonly prescribed in the treatment
of colorectal cancer and small-cell lung cancer), as a result of the increased concentrations of its active
[17]
metabolite SN-38 . A similar case is the one of dihydropyrimidine dehydrogenase (DPD) deficiency, which
leads to increased toxicity in case of treatment with 5-fluorouracil or capecitabine (two widely used drugs
[18]
in the treatment of various cancers) . A recently published trial showed that prospective DPD genotype-
based dose reductions - in patients receiving fluoropyrimidine-based anticancer therapy - improved overall
[19]
safety of the treatment, proposing this strategy as a new standard of care . Such findings supported the
idea of an earlier investigation of PGx signals, in order to avoid mistreatment of vulnerable patients and
unnecessary withdrawal of promising agents or combinations. A recent example is the stratification for
[20]
UGT1A1 genotype in a Phase 1 trial studying CAPIRINOX combination , which found different toxicity
rate and dose-limiting-toxicity according to UGT1A1 polymorphism, leading to different doses to employ
during the Phase 2, and assuring the best safety for both strong and poor metabolizers, with no loss in
terms of survival. In contrast with these attempts of biomarker-based personalization of doses, a different
trend is arising on the drug market, with flat doses being promoted with the promise of shortening drugs
preparation time and improving ease of administration (e.g., pembrolizumab was first approved for treating
melanoma at the dose of 2mg/kg q3w, but a 200mg q3w dose was later approved and is now commonly
prescribed). Although flat doses might not increase treatment toxicity, they can be associated to a substantial
financial toxicity, since they promote the administration of an unneeded drug excess, which increases drug
and treatment costs.

Despite their preeminent importance, germline genetic variants conditioning drug toxicities are found only
[17]
in a minority of patients, with less then 10% of patients harboring deleterious TMPT polymorphisms ,
[21]
approximately the same percentage of patients with deleterious UGT1A1 polymorphisms and less than
[22]
1% of patients being affected by DPD . For this reason, such PGx labels are still scarcely implemented in
clinical trials, with most of the studied biomarkers referring instead to somatic alterations in oncogenes and
oncosuppressors. Therefore, for the purpose of this review, a major focus will be put on somatic PGx labels
and the way they are changing the way we conduct clinical trials.