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Page 44 Tarantino et al. Cancer Drug Resist 2019;2:43-52 I http://dx.doi.org/10.20517/cdr.2018.22

molecular and clinical features, namely Precision Medicine (PM). Tumor staging and histology, classically
considered the main factors influencing the therapeutic decision, where integrated by a large number of new
identified prognostic and predictive biomarkers. Some of these where found to predict response or resistance
[2]
[1]
to certain drugs (e.g., Estrogen receptor expression for Tamoxifen , HER2 amplification for trastuzumab ),
some others predicted instead a propensity in experimenting side effects from the treatments (e.g., UGT1A1
[3]
polymorphisms and irinotecan toxicity ). Both of these types of biomarkers are today studied by the
discipline of pharmacogenomics (PGx), which evolved from a pre-existing branch of pharmacology called
pharmacogenetics. The term pharmacogenetics was originally coined by the German pharmacologist
Friedrich Vogel, referring to polymorphisms of specific genes inducing individual drug response or
susceptibility to adverse drug reactions. With the availability of genome-wide sequence data, and the advent
of the “omics” era, this branch evolved into what we today call pharmacogenomics. As these terms are often
used interchangeably in literature, in this text we’ll use the same abbreviation (PGx) as a referral to both.

Nowadays, several FDA-approved drugs contain pharmacogenomics information in their labeling, and more
[4]
than seventy approved oncological drugs present one or more genetic biomarker to keep in consideration .
As we’re going to discuss further in the review, this circumstance is due to the fact that cancer PGx involves
the study of both the germline genome and cancer’s somatically mutated genome. Both germline and
somatic mutations can be, in different ways, responsible for the outcome of cancer treatments, and for this
[4]
reason FDA’s Table of Pharmacogenomic Biomarkers includes both .

PHARMACOGENOMICS IN CANCER DRUG DEVELOPMENT
Pharmacogenomics in the medical fields
The discipline of PGx studies the relationship between specific DNA-sequence variation and the effect of
drugs in terms of efficacy and toxicity. These variations include single nucleotide polymorphisms, deletions,
insertions, tandem repeats, copy number variations and chromosomal translocations. Each of these changes
can be germline or acquired: the first circumstance is common in drug-metabolizing enzymes, whose
polymorphisms affect drug activation and excretion, or predictive biomarker of response, like BRCAs or
mismatch-repair germline genes; the latter usually refers to accidental changes in DNA which ultimately
cause cancer, with consideration of driver genomic alterations potentially druggable.

PGx have led to an improvement in various fields of medicine, with special regard to Psychiatry, Neurology,
Infectious diseases and Cardiology [Figure 1] . One field benefiting greatly by the implementation of
[5]
PGx biomarkers is Oncology, with almost 40% of the PGx labels concerning antineoplastic drugs. Many
reasons lead to the success of this approach in Oncology: in this field, in fact, we more often find drugs
with a narrow therapeutic index, which can lead to severe and sometimes life-threatening adverse events;
identifying toxicity biomarkers is therefore critical. Moreover, the pipelines of developing oncological drugs
have been extremely active lately, with a progressive increase of cancer drugs being evaluated in clinical
trials . Finally, while most of the medical disciplines are predominantly interested in germline alterations,
[6]
the oncological field provides two different but related genomes to be studied, namely the somatic tumoral
and germline genome, adding a factor of complexity and opportunity to PGx research. Indeed, the intensive
study of cancer’s somatic mutations, together with improving our understanding of tumor development,
provided a wide set of druggable alterations which ultimately explain why such a vast past of FDA’s Table
is dedicated to Oncology. Nonetheless, each branch of medicine is moving toward a PM approach, and
advancements in PGx are expected to affect the way all drugs are prescribed in a wider sense.

Pharmacogenomics in cancer drug development
[7]
The application of PGx principles is clearly beneficial in the treatment of certain cancers , but its role
might be even more crucial in the setting of drug development. Cancer drug development is a time and
resources consuming process: it takes around ten years for a new drug to complete its path from initial
discovery to the approval, accounting for an average cost from research and development to market approval