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Dr. William Douglass Figg On Pharmacogenomics

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Dr. William Douglas Figg is the Deputy Chief of the Genitourinary Malignancies Branch and Head of the Molecular Pharmacology Section and Head of the Clinical Pharmacology Program at the National Cancer Institute (NCI).

Dr. Figg applies pharmacological principles to anti-cancer drug and biomarker development. A large part of his research focuses on the development of novel therapies for prostate cancer.

Prostatepedia spoke with him recently about pharmacogenomics for our March issue on using genomics to guide treatment.

How did you come to focus on prostate cancer?

Dr. Figg: I finished my Fellowship in drug development at the University of North Carolina at Chapel Hill in 1992 and went to work for Dr. Charles “Snuffy” Myers in the Clinical Pharmacology Branch of the NCI. Dr. Myers was one of the leaders in prostate cancer at the time. I quickly developed a research interest in metastatic prostate cancer and in developing new agents to treat the disease. As a trained pharmacologist, I approached the discovery and development of new anti-cancer agents via a logical flowchart of Go/No-Go decisions.

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What is pharmacogenomics?

Dr. Figg: Many physicians don’t fully understand pharmacogenomics.

If you’re talking to a clinical pharmacologist, pharmacogenomics are variances in genes that handle drugs. Metabolism enzymes and transporters have genetic variances. These variances may mean you need to change the drug dosages, because your body can’t get rid of the drug quickly enough or the drug doesn’t transport well into the cell.

On the other side, there are somatic mutations associated with a tumor. Somatic mutations are genetic variances inside of a patient’s tumor cell that are different from the patient’s normal DNA. We are now able to target those somatic mutations with drugs that may work in that particular tumor.

Is pharmacogenomics used to guide treatment?

Dr. Figg: On the clinical pharmacology side, there are 150 drugs that include pharmacogenetics-related information in the approved label. However, about 30% state a requirement or recommendation for genetic biomarker testing. That is not a lot. Many patients haven’t had these tests. (See a list of these drugs.)

Some of these are anti-cancer drugs, but most are drugs for other indications that have pharmacogenomic testing in their package insert. It is becoming more widely recognized that we have to do germline DNA testing in order to specify the right dose that works and is safe for an individual.

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With regards to tumors, we have several drugs for which we look at biomarker or genomic indicators of variances in order to specify if you can or shouldn’t take a drug. This is pretty limited for prostate cancer. We’ve done a lot of testing, but the vast majority of our drugs for prostate cancer don’t have a biomarker indicator yet. For other tumors, the biomarkers HER2, BCR-ABL, BRAF, EGFR, PD1, RET, ER, PR and MGMT have been validated.

What are the barriers to patients receiving pharmacogenomics testing before taking these drugs?

Dr. Figg: Some of it is cost. Some of it is been lack of appreciation that pharmacogenomics testing is important. Some physicians say, “I’ve given this drug for years without a problem.”

For example, Coumadin (warfarin) has been around for decades. Doctors tend to adjust Coumadin (warfarin) dosages based on bleeding time. We now have genetic markers that can make that first dose specific, so you don’t have to do trial-and-error dosing—increasing and decreasing dosage until you get it right.

My vision for pharmacogenomics   is that eventually we will genotype a child at birth; that information would then go into an electronic medical record (EMRs). Then, every time a physician needs to prescribe something, he or she will already know if that individual can safely take the drug or not.

Inova Fairfax Hospital in Virginia offers pharmacogenomics testing to all infants born at their hospital (approximately 10,000/year); about 80% of parents consent to the test. Those children will now always have that information in their electronic medical records.

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Would that reflect a cost-saving? If you could get the right dose for a patient…

Dr. Figg: That’s the selling point. For around $500 you can get a panel of about 200 genes that encompasses all of the drug metabolism and transport genes for an individual. Insurance companies are now realizing that it is probably in their interest to do this: it is much better if you can prevent someone from having a bleed or prevent a hospitalization or get more efficacy from a drug. There was a case report in the

New England Journal of Medicine in 2009 about a toddler who had an adenotonsillectomy. Doctors gave him Tylenol 3 (acetaminophen plus codeine) after surgery. Codeine

is metabolized to morphine via CYP2D6. It turns out this child was an ultra rapid metabolizer of codeine. He died from morphine toxicity. This case struck home with a lot of healthcare providers: we should be doing pharmacogenomics testing more often.

Camptosar (irinotecan), a colon cancer drug, offers another example. Diarrhea is one of the main limiting factors associated with the drug. We can now genotype the enzyme UGT to predict who will not tolerate Camptosar (irinotecan) because of diarrhea.

Another example: Mercaptopurine (6MP) is used to treat childhood leukemia and is metabolized by the enzyme thiopurine S-methyltransferase (TPMT), which is polymorphic. That means a small percentage of individuals cannot metabolize through TPMT (0.01% to 1%) and 2% to 20% are intermediate metabolizers. For those deficient in TPMT, you need to give them 10% to 15% of the original dose and give approximately 65% of the normal dose to intermediate metabolizers. Everyone else can tolerate the full dose of that drug quite well. If you happen to give a full dose to a child with a variant for the enzyme TPMT, you could cause serious harm and possible death.

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Are there any implications for prostate cancer patients? Many men with prostate cancer are on a variety of medications for conditions not related to prostate cancer.

Dr. Figg: Yes. One, your doctor has to look at drug interactions. There are drugs that inhibit or increase metabolism of anti-prostate cancer drugs.

My lab at the NCI is at the forefront of trying to understand the variances that predict who responds to chemotherapies such as Taxotere (docetaxel). We are very interested in transporters that may move androgens into the cell. We know that these transporters become up-regulated in advanced prostate cancer.

We have identified one variant in that genome that could predict your response to androgen deprivation therapy. We’re not at the point   of having any kind of guideline for saying you should be doing this type of testing, though. This is still in the research phase. But we’re working towards the end-goal of being able to say, “Let’s genotype you as soon as you’re diagnosed with prostate cancer. We’ll then adjust your therapy based upon that information.”

What would you say to a reader who’d like to get tested now?

Dr. Figg: I recommend readers talk to their doctors. Depending upon the drug therapy they’re currently on, it may not be necessary right now. If your doctor prescribes something in the future, then it may be worth it. But talk to your doctors. They can order the test.

Again, it’s a small list and the drugs aren’t common, but a lot of prostate cancer patients are on Coumadin (warfarin). If you’re already on a standard dose and you’re regulated, then it’s perfectly fine. You don’t need to know your genotyping.

But if you’re just starting on Coumadin (warfarin), it can really help find the right dose for you.

What are some of the barriers to global adoption of genomics to guide treatment? (That is a pretty ambitious goal: to have everybody genotyped at birth.)

 

Dr. Figg: We need a full appreciation of the potential side effects of drugs and how we can limit those side effects with genotyping. That appreciation has to come from the medical community. Once they fully understand that they can guide therapy more specifically, or pick the right dose or right drug for an individual, they will be more inclined to do this for their patients.

What implications do genomics and pharmacogenomics have for rising health care costs?

Dr. Figg: For pharmacogenomics to impact health care costs, we need studies that show we’ve prevented hospitalization by genotyping. We need studies that show we’ve prevented serious complications associated with drugs. And studies that show we had to put fewer patients on a clinical trial in order to get the activity level we’re seeking.

On the other hand, we can select patients who will have the best response to therapy by genotyping. Instead of doing a 1,000-patient study, we may only have to do a 300-patient study to show that a specific drug is more effective than standard of care. We’re trying to select the population that will have the best response to treatment. This can reduce clinical trial costs and make it faster for drugs to gain FDA-approval.

Download the March issue.

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Author: Prostatepedia

Conversations about prostate cancer.

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