Is Genomic testing an option for better chemotherapy?

By
Gowhar Shafi
(gowharshafi@gmail.com)
For years physicians have known that medication to a given disease yields different
and varied response in different patients. There are cases where there is no response in
some. Hence the question has always been: Why is this variation in response seen to
the same standardized and medically approved treatment strategies? Now in this
genomic era, we know that the probable cause is the difference in the genetic makeup
of different individuals which may be responsible for a wide range of drug reactions.
With the completion of the Human Genome project and the development of molecular
biology techniques, genomic tests now exist to answer some of these questions. By
examining the genomic differences between individuals, we can understand the
impact of diagnosis and treatment. The expanding knowledge of the molecular basis
of cancer has shown that variation in gene expression patterns can guide therapy not
only for treating neoplastic condition but also for a variety of diseases including
inflammatory disorders, cardiovascular disease and neurodegenerative processes. As a
result, the fields of pharmacogenetics and pharmacogenomics have emerged as
potential new testing platforms for the customized management of patients.

In oncology, pharmacogenomics is based on somatic molecular alterations; which can

be inherited by subsequent cancer cell generations and forms the basis of molecular
targeting of novel therapeutic agents. The management of cancer involves procedures
which include surgery, radiotherapy and chemotherapy. Development of
chemoresistance is a persistent problem during the treatment of local and
disseminated diseases. Numerous genes may play a role in drug response and toxicity,
introducing a daunting level of complexity into the search for candidate genes. The
high speed and specificity associated with newly emerging genetic technology enables
the search for relevant genes and their variants to include the entire genome. These
new technologies have essentially spawned a new discipline, termed
pharmacogenomics, which seeks to identify the variant genes affecting the response to
drugs in individual patients. Pharmacogenomics is a large-scale systematic approach
using a variety of technologies to discover drug response determinants and promote a
better understanding of the genetic and molecular basis underlying variable drug
response among patients. Drug interactions in oncology are of particular importance
owing to the narrow therapeutic index and the inherent toxicity of anticancer agents.
Interactions with other medications can cause small changes in the pharmacokinetics
or pharmacodynamics of a chemotherapy agent that could significantly alter its
efficacy or toxicity. Improvements in in-vitro methods and early clinical testing have
made the prediction of potentially clinically significant drug interactions possible.

A drug interaction is defined as the pharmacological or clinical response to the

administration or co-exposure of a drug with another substance that modifies the
patient's response to the drug. It is reported that 20-30% of all adverse reactions to
drugs are caused by interactions between drugs. This incidence increases among the
elderly and patients who take two or more medications. Patients with cancer are
particularly at risk of drug interactions as they could be taking many different
medications as part of their cancer treatment or for the management of other illnesses.
A common example of a pharmacokinetic interaction occurs when two drugs compete
for the same metabolic pathway. When the pathway becomes saturated neither drug
can be metabolized fully, which results in higher serum concentrations of the agents
and can lead to clinically unfavourable consequences. Pharmacodynamic interactions
occur when two drugs or substances have similar molecular targets, but do not affect
the pharmacokinetic parameters of each other.

When two or more drugs that have similar pharmacodynamic activity are co-
administered, the additive effects might result in an excessive response or toxicity.
Pharmacodynamic interactions between drugs with opposing effects can reduce the
response to one or both drugs. Chemotherapy-induced cytopenia, adverse drug
reactions and susceptibility to disease due to inherited SNPs is one of the primary
causes of morbidity and mortality in the treatment of cancer. We have reported such
cases in our previous studies. Although the term drug interaction usually has a
negative connotation, it is important to note that drug interactions can have various
outcomes. Interactions between drugs can increase or decrease the therapeutic or
adverse response, or result in an unique response that does not occur when either
agent is given alone.
The most recent attempts at improving cancer treatment have taken the
pharmacogenetic approach of identifying biochemical response determinants for
response, so that patients with suboptimal determinants who unlikely to respond can
be identified prior to treatment. One could generate criteria for selecting patients most
likely to benefit from a drug without incurring unnecessary risk. Early or preventive
therapy guided by genotyping could significantly enhance clinical outcome. The need
for a new, individualized approach to drug development and therapy is clear. A
plethora of cytotoxic drugs that selectively, but not exclusively, target actively
proliferating cells include such diverse groups as DNA alkylating agents,
antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a
lack of response to drug-induced tumour growth inhibition; it may be inherent in a
subpopulation of heterogeneous cancer cells or be acquired as a cellular response to
drug exposure.

Polymorphism is simply the variation in the structure of a gene or an allele. Variations

in gene structure can occur in several ways. The most common is the single
nucleotide polymorphism in which a single nucleotide base is substituted. This type of
gene modification usually leads to loss of function. Other types of polymorphisms
include gene deletion or gene duplication. How are variations in a specific enzyme
designated? A specific nomenclature has evolved that describes each variant. The
study of the influence of genotype on drug efficacy (pharmacogenetics) and the novel
approach to targeted drug discovery are gaining momentum in understanding the
unpredictable activity of cancer chemotherapy and help in the selection of drugs best
suited for cancer patients.

Indeed, genetic variability may alter drug uptake. Moreover, increased expression of
transporter systems can be associated with reduction of the cytoplasmic levels of
drugs that may be unable to exert a cytotoxic effect. Additional systems could protect
tumor cells from drug-induced cytotoxicity, including the DNA repair machinery,
antiapoptotic systems, and several signal transduction pathways. Finally, alterations of
drug targets may be associated with a decrease in the effectiveness of chemotherapy.

Therefore, the future challenge of chemotherapy of cancer relies in the identification

of molecular and genetic markers that are predictive of response and may help in the
selection of chemotherapeutic agents best suited to the individual patient. Indeed,
pharmacogenetics studies may explain how the responses of patients to drugs are
affected by their genetic profile, and due to the developments in this area, promising
agents are coming up and this strategy is slowly gaining momentum, including
inhibitors of intracellular signal transduction proteins. "This new genomic test is a
clear example of personalized medicine, where we use the unique molecular
characteristics of each patient's tumor to guide treatment decisions," The promise of
personalized medicine in cancer is on the horizon.

I predict that this radical shift in medical diagnostics will take several years to filter
throughout the medical community and enter common usage among the general
populace. For widespread acceptance to occur, physicians and patients alike will be
forced to take giant strides in their conceptualizations of why we get sick. The very
idea that patients can be tested before the fact for the disease to which they are
predisposed represents a very big first step. Taking it to the next level and realizing
that patients themselves are largely responsible for their own fates may take an even
greater stretch of the imagination. It will definitely represent a major paradigm shift in
thinking for patients and physicians alike. Such a drastic alteration in our concept of
health and disease --that we are each largely responsible for our destiny--will make
many folks very uncomfortable indeed.

In a nutshell, progress is always slower than patients, physicians, and basic scientists
would like. Current trials, which are exploring new molecular targeted therapy alone
and combined with chemotherapy to have synergistic effect, continue to offer a
realistic expectation of accelerated progress in the control of cancer in the decades
ahead.