Pharmacogenomics: Genes, Cancer Drug Response & Personalized Dosing

•45:20 SUMMARY KEYWORDS patient, medications, drug, gene, dose, pharmacogenomics, testing, question, impact, interactions, metabolizer, poor metabolizer, ultra rapid, evidence, drug metabolizing, guidelines, cytochrome, pharmacogenetics, cancer, prostate cancer SPEAKERS Kristine Aschcraft, Marty Tenenbaum, Ally Perlina, Brian McCloskey, Rick Stanton, Brad Power Brian McCloskey 00:06 Kristine Ashcraft is with us today from Invitae, and she is going to be talking about pharmacogenomics. Kristine Aschcraft 00:51 The focus of my presentation is on pharmacogenomics. Invitae offers diagnostic testing as well, like hereditary cancer screening, that clearly would also be applicable. Pharmacogenomics is germline genetic testing that helps us understand when our genes would dictate that for a growing list of medications, whether we need a higher dose, a lower dose, or a different medication altogether. In terms of the problem this helps us address, non-optimized medications are a major public health problem. We lose a life every two minutes in the United States due to non-optimized medications. In 2016, the last time it was measured, we spent $528 billion nationally on non- optimized medications, which is more than we spent on the drugs themselves or on any major chronic disease, including cancer. Regarding cancer care, greater than 99% of patients will have a pharmacogenetic variation that impacts their response to on average more than 10 commonly prescribed medications. And the more medications you're taking, the more likely you are to have a problem. Although this may not impact a prostate cancer medication per se, it can impact the overall medication regimen and have an impact on the overall health of a patient. About half of the medications that are prescribed to patients do not work as intended, ranging from about 38% of antidepressants, up to three-quarters of cancer medications. Genetic variability is not the only thing at a play here, but it is a major contributor to treatment failure. There's a very interesting analysis that came out of the UK last year. They looked at just shy of 500,000 patients in the UK Biobank and again confirmed that greater than 99% of individuals have an atypical response to at least one medication, but on average 10 drugs. The other thing that was interesting, they have longitudinal data in primary care of the medications that were prescribed for these patients over time, and they found that one in five new prescriptions in primary care was impacted by pharmacogenomics, and one in 11 would have specific drug or dose change guidance associated with them. This is a snapshot of some, and not all, of the medications that are impacted by high evidence drug/gene interactions, meaning that if testing is done, there is specific guidance if a variation is found on how you would consider modifying the drug or dose selection based on that information. I bolded the medications that I think you may come across in prostate cancer care. I know statins sometimes are utilized. They're certainly pain management, some antiemetics. But the thing to keep in mind over here on the right in the pie chart, is that the same genes impact drug response across all sorts of different clinical areas for life. I think of pharmacogenetic profiling as something like a seatbelt for medication management that really needs to be used every time a medication decision is made the rest of the patient's life to understand if they need different archetypes. We're working on a study about the impact in cancer care right now, but these are broader. I'm just showing that this can be very helpful for patient care. This was a study that was done in patients 65 and older, taking at least three medications, one of which was known to have high evidence drug/gene interactions at minimum and what was seen in just four months. 71% fewer emergency department visits. 39% fewer hospitalizations. Saving $1132 per patient prior to the cost of testing. Here's a follow up study. This was done in patients that were flagged as being at high risk of readmission. This was a program that was already doing an exceptionally good job. They were in the top 10th percentile for lowest readmission rates in the country. That's because they had a very proactive program, where a pharmacist would visit the patients in the home and review their medications because medication-related issues are one of the main reasons patients end up back in the hospital. These pharmacists were either randomized to give the patient's treatment as usual or high touch pharmacy care where they were given access to pharmacogenetic testing and improved clinical decision support that didn't just look at drug/drug, but also drug/gene interactions and cumulative interaction risks. What was seen in just 60 days was 42% fewer emergency department visits and 52% fewer readmissions. It was not an endpoint of the study, but 85% fewer deaths, saving $4380 to a patient in just two months. Kristine Aschcraft 06:05 Here's a quick lesson in pharmacogenetics. Generally, when we do testing, we're looking at these drug metabolizing enzymes, mainly cytochromes, that mainly express in the liver. We place people into different categories or phenotypes, based on the genetic information. Generally, when we prescribe medications, we assume all patients are normal metabolizers, also called “extensive metabolizers” in the literature. I think of this like a two-lane highway. You take medications, and they must go through these enzymes to be converted to something the body can then flush out and get rid of. Your normal metabolizer has two lanes of this highway that processes medications. You have intermediate metabolizers with one active and one inactive gene, or down to one lane of this highway. Poor metabolizers have no, or very, very reduced activity, or no lanes. The ultra-rapid metabolizers have duplications or upregulation, or additional lanes of these drug metabolizing highways. Here's the difference between active drugs and prodrugs. We take most medications in an active form. They often hit the cytochromes or sips in the liver, these drug metabolizing highways, to be converted to something we then flush out and get rid of. ogenomics and Dosing” Here's the difference between active drugs and prodrugs. We take most medications in an active form. They often hit the cytochromes or sips in the liver, these drug metabolizing highways, to be converted to something we then flush out and get rid of. Prodrugs are different. Tamoxifen, for example, is commonly given to prevent breast cancer recurrence. It is a prodrug. It is taken in an inactive form. It hits these drug metabolizing enzymes in the liver, specifically Cytochrome P450 2D6 (CYP2D6) to be converted to Endoxifen in this instance, and then that must go through again to be converted to something the body can then flush out and get rid of. I bring that up because you're going to have a different response if it's an active drug versus a prodrug if you have a pharmacogenetic variation. Poor metabolizers, those with no lanes of this drug metabolizing highway, are at risk of toxicity over time. They're not able to process the medication. They keep taking the dose every day over time, and it's going to build up in their body, and they can have adverse effects. Intermediate and normal metabolizers tend to be in range, and then your ultra-rapid metabolizers process the medication out so quickly that they are at risk of treatment failure. You can see these little dotted lines here: we've got a toxic and therapeutic levels sign. This is your therapeutic range. Some drugs have a very narrow therapeutic range, and some have a very wide therapeutic range. These variants can be impactful even for intermediate metabolizers. For example, it's a narrow range drug. It's the exact flip for prodrugs. An example here you may be quite familiar with, Tramadol and codeine, are very commonly prescribed pain medications. They are prodrugs taken in an inactive form. They do not give any pain relief until they're converted. If you're an ultra-rapid metabolizer, codeine, for example, is converted to morphine by CYP286. If you're an ultra-rapid metabolizer you convert so much to morphine, you're at risk of toxicity. They've put a black box warning encoding on Tramadol recommending that it not be given to children or nursing mothers because of cases of severe toxicity including death. On the opposite end, poor metabolizers are not going to make that conversion, so they will get zero pain relief from these medications. Kristine Aschcraft 06:34 Nomenclature - I've been tossing about the term “CYP”, or cytochrome family, which are the most important pharmaco genes. You'll see that cytochrome is reduced to CYP and then 2C19 2D6, 2C9 etc. Unlike some other things you may be familiar with, we categorize different variants into alleles. You will see this come out as *1/*2. There are three main sources for PGx information, led by CPIC (the Clinical Pharmacogenetics Implementation Consortium). If you remember nothing else, I tell you, this is a great, great reference. If you go to Google and type in CPIC, CPIC and drug and genes, it pulls up a great table. You can key in any medication that is being offered to you and see whether there is a CPIC guideline for drug or dose change guidance or FDA guidance on how that medication would be modified and which gene is impacted. A great resource they update all the time, PharmGKb aggregates data on genetic variant drug response. It feeds into CPIC. Then, of course, the FDA s is an important resource because more and more newly approved drugs have pharmacogenetic guidance in the drug approval on the label. For CPIC, the key thing to keep in mind is the assigned levels. Level A or B is really the one that a lot of laboratories focus on including Invitae. Level A or B means that when we have that information, we can provide guidance on how to act on it. There's going to be drug or dose change information associated with that guideline. CRD usually means developing evidence or the evidence is weak. Again, focus on the AB CPIC levels. These are the medications that currently have high evidence drug gene applications in oncology. Again, I don't see prostate cancer. I know sometimes drugs are used depending on the type of cancer that isn't necessarily in that area. I'm not sure if any of these are ever used in prostate care, but these are the drug gene pairs that currently have high evidence. You can see very specific guidance, and often if it says dose reduction, there's very specific guidance on what that dose reduction should be. This is just a summary when patients are tested and found to have this genetic type thing. One of the biggest examples we hear about quite often is DPYD for Fluorouracil or Capecitabine metabolism. This is a sad story about Lynn Stevens. She was a former machinist who was in a landmark strike for equal pay for women. In late 2018, she was diagnosed with early-stage bowel cancer following routine screening, had a successful bowel resection surgery, and her doctors recommended chemo to knock out any residual cells. She and her husband agreed that this was the best approach. In March 2019, she had her first and last dose of 5-Fu. She died less than four weeks later, but not from cancer. Her husband said her last weeks were agony.