Pharmacogenomics in cancer therapy

Published on October 29, 2015   31 min

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Other Talks in the Series: Cancer Genetics

Hello, I'm Sharon Marsh from the University of Alberta in Edmonton, Canada. And this lecture is on Pharmacogenomics in Cancer Therapy.
First, we will go through some background on pharmacogenomics. Then we'll discuss the types and sources of genetic variation. We will discuss the techniques used to measure genetic variation. And then we will go through examples of cancer pharmacogenomics and drug selection, drug toxicity and drug outcomes. And then we will summarize the lecture. We will now discuss the background to cancer pharmacogenomics.
As you can see from this slide, adverse drug reactions are a significant problem to the healthcare system. Adverse drug reactions are a reaction to the medication itself, not the disease that the medication is trying to treat. This can be particularly problematic in cancer patients where the therapeutic window for treatment is very narrow. Reduction in dosage or reduction of medication or removal of medication can be detrimental and potentially fatal if this has to occur due to an adverse reaction.
So what are the causes of individual variability in drug response? They are many. They range from the environment, concurrent medications, stress, smoking status, age, diet and exercise, metabolic issues and, of course, genetics. Although genetics can play a major role in drug disposition and response, it is by far not the only explanation for failure of a medication or for an adverse drug reaction. And it needs to be taken into account that genetics will never be able to explain 100 percent of all of the variability in drug response.
Further to the causes of individual variability in drug response, in cancer patients, the tumor itself can provide a unique environment that can affect the disposition of medications. There can chromosomal rearrangements, gene amplifications, gene deletions, and specific mutations to the particular tumor. In all of these instances, this could affect how well a medication that is targeted at that particular cancer will work.
So bearing in mind that there are many causes for the individual variability in drug response, what is pharmacogenomics? Well, pharmacogenomics is specifically the genetic basis for interindividual variations in drug response.
So how does pharmacogenomics relate to adverse drug reactions? Well, it's been estimated that over 60 percent of the most frequent drugs cited in adverse drug reactions are metabolized by at least one enzyme with an inherited DNA variant known to cause poor metabolism.
Here we see the problem that pharmacogenomics is attempting to fix. Typically, we take all patients with the same diagnosis and give them the same treatment combination. A portion of these patients would be expected to successfully complete treatment, whereas a portion of the patients may not respond at all to the treatment and some may get unacceptable toxicities. For these patients, we would either select an alternative treatment or reduce the dose. In this case, we would then expect a portion of those patients to respond successfully. However, there will still be some patients who do not respond or who get toxicity from the alternative treatment. Consequently, we continue along this path until we run out of treatments. This involves no preselection, no predetermination and no filtering as to whether or not the treatment is the most relevant treatment up front for the patient at the start of their therapy.
So this is what we are attempting to do with pharmacogenomics. We would like to filter patients in advance based on their genomics profile and based on other demographic data that can be incorporated into an algorithm and predict the right medication and the right dose up front. This is particularly important for cancer patients because the therapeutic window is extremely narrow. It would be extremely detrimental to the patient if they had to wait, while a treatment failed, to start on the most appropriate treatment or wait while they recovered from an adverse drug reaction before having a dose reduction. Individualized therapy is not even a new concept. Hippocrates said, "It is more important to know what sort of person has a disease than to know what sort of disease the person has."
In addition to having a narrow therapeutic window, oncology pharmacogenomics is a burgeoning field because for many cancers there are actually multiple treatment options available, and yet there is no clear rationale for treatment selection. Consequently, it is unclear which of the multiple variations and combinations would be the most appropriate for each patient.
Indeed as of 2014, the vast majority of the United States Food and Drug Administration approved genomics tests. These are genomics tests that are included in the package inserts of medications as recommendations to screen patients before selecting the treatment or the dose have been in oncology. The red circle shows the number of tests in oncology that are available versus all of the other disease types.

Pharmacogenomics in cancer therapy

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