Practical Applications of Pharmacogenomics To Improve Patient Outcomes

TRANSCRIPT for Webinar with the title: Practical applications of pharmacogenomics to improve patient outcomes

 

0:00
These are our speakers for today.

0:01
Unfortunately, Kathy O'Brien could not be with us so her section is pre recorded and Kathy is a board certified genetic counselor who has been with Quest Diagnostics since 2005.

0:14
She received her Masters of Science in Genetic Counseling from the University of Colorado Health Sciences Center.

0:19
Before joining Quest Diagnostics.

0:21
She works as a as a clinical genetic counselor at Stony Brook University Hospital, Winthrop University Hospital, and NYS Institute for Basic Research.

0:32
Her special interests include hereditary oncology and pharmacogenomic testing.

0:38
Next is doctor Mark Kruzel.

0:40
Mark Kruzel is an MD, MB, DA and is the Medical Director for Oncology and Consumer Initiated testing here at Quest Diagnostics where he leads the efforts to expand access to high quality diagnostics and advanced precision medicine.

0:54
He focuses on creating patient centered testing models that integrate with clinical care and also partners with national pairs on reimbursement strategy.

1:02
Doctor Kruzel is passionate about improving health outcomes by expanding diagnostic access for underserved populations and advancing precise, efficient testing pathways.

1:14
He is an active member of the American Society of Clinical Oncology, the Association of Molecular Pathology, and the American College of Healthcare Executives.

1:22
Doctor Kruzel earned his medical degree for McGovern Medical School at the University of Texas Health Science Center at Houston and holds a master's of business administration from Cox School of Business at Southern Methodist University.

1:36
Since Kathy couldn't be here today, we have another subject matter expert who has shared in helping create this presentation today and will be here for the Q&A.

1:43
Michelle Vasilier is a genomic science specialist at Quest Diagnostics.

1:47
She specializes in patient and client support for hereditary oncology and pharmacogenomic testing.

1:54
She's a board certified genetic counselor with an Ms.

1:56
from Brandeis University.

1:58
She brings over 25 years of clinical laboratory experience across prenatal, Women's Health and oncology.

2:04
She's passionate about healthcare provider education and advancing patient care in hereditary cancer genetics.

2:10
Also joining us as a special guest is Karen Merritt, who will be speaking about a patient advocacy story.

2:20
All right, these are our disclosures for anyone's review.

2:29
And just to review the objectives before we jump into today's talk.

2:32
We're going to review clinical importance of pharmacogenomics, which we like to call PGX testing and how it can improve patient care.

2:40
Discuss the importance of genetic testing using specific examples of high impact gene drug associations including DPYD testing for flora permitting toxicity.

2:50
We're going to illustrate the patient journey and the transformative impact of pharmacogenomics on care and identify appropriate candidates for PGX testing and discuss polypharmacy panel and single gene testing approaches in clinical practice.

3:06
To kick us off as Kathy, I don't think the sound is working.

3:29
Hold on, let me fix the sound issue.

3:31
See here.

3:51
2nd, 2nd.

3:55
So I thought I'd start off by looking at some statistics, and these statistics illustrate the need for a more personalized approach to prescribing.

4:02
So first, if you think about it, many people are taking medications and over 20% of patients in the United States take multiple medications and many of them are taking 5 or more.

4:13
There are approximately 2 million adverse drug reactions each year in the United States, and these are between the 3rd and 4th leading cause of death.

4:20
And so it's really critical that we use all the tools that are available to us to reduce these risks.

4:28
Most medications are developed for the average person in a specific population, and sometimes that's the average person in a given ethnic group.

4:36
Frequently it's Europeans, but we know that not everyone is the same.

4:40
So this slide is really illustrating a concept that people in the audience here are very familiar with.

4:46
You can have a group of people with the same diagnosis on the same prescription who don't all respond the same, and there are many reasons for that.

4:54
There may be differences in their medical histories and underlying medical conditions.

4:58
You can have environmental factors, sometimes there are compliance issues, but there may also be genetic factors that come into play.

5:05
So the more that we can do to understand all the reasons impacting medication response and variability, the better we can tailor treatment to the individual patient.

5:14
So ultimately we want everyone to be in the group where the drug is beneficial and not toxic.

5:22
The pharmacogenetic testing can really provide important information that can help drive treatment choices and actually improve patient outcome.

5:29
There are multiple studies that have shown that testing can reduce the risk of adverse drug reactions.

5:34
In fact, there was a study that was conducted in Europe, the PREPARE study, and that showed a 30% reduction in adverse drug reactions just by using a 12 gene panel.

5:44
Multiple studies also show that greater than 90% of patients will have at least one clinically actionable pharmacogenomic variant.

5:51
About 18% of approved therapies have clinically actionable pharmacogenetic associations.

5:56
And so the likelihood that we're going to take a medication that's impacted by a variant we carry is actually quite high, especially when you think about it over the course of a lifetime.

6:07
So what is pharmacogenetics, pharmacogenomics, PGX?

6:10
These are terms that are often used interchangeably, but basically they're referring to how genetic variation impacts medication response.

6:19
It is a very important piece of the patient's clinical picture.

6:22
But I do want to point out that it's a companion to and not a replacement for evidence based medicine.

6:30
So why pharmacogenetics?

6:32
It can help complete the clinical picture.

6:35
It can help decrease toxicity and increase efficacy.

6:38
There can be cost savings to patients, to healthcare systems and insurers and drug companies also find pharmacogenetic testing helpful because it can help speed up the development of drugs and also can potentially help unsure medications that may have been removed because they have a high frequency of toxicity, even though they might be beneficial to the people who respond appropriately.

7:03
So now that I've explained why pharmacogenetic testing is important, it's also important to just level set expectations.

7:09
It's not a magic wand and it shouldn't be used in a vacuum.

7:12
And it's it's really a tool that can be used in combination with other patients and environmental factors to help choose medications based on the best information and the most complete information.

7:23
And so I think a pharmacogenetic testing really is a companion to and not a replacement for evidence based medicine.

7:32
So pharmacogenetics is a really important piece of the clinical picture, but it's not used in a vacuum and it's certainly not a match of Guam that's going to tell you what is definitely going to work.

7:43
It's a tool that's used in combination with other patient and environmental factors to help choose medications based on the best information.

7:53
And there are many things that influence drug responses.

7:55
Some of these things are intrinsic things like organ dysfunction and weight, and others are extrinsic, like drug drug interactions or environmental factors.

8:05
So genetic variation can influence drug response in different ways.

8:09
We have variations that can impact pharmacokinetics, which, Simply put, is what the body does to the drug.

8:15
So certain genetic changes can affect things like drug absorption or distribution and metabolism.

8:21
And genetic changes can also influence pharmacodynamics, which is what the drug does to the body.

8:27
Genetic variations can also impact immunogenicity.

8:30
So specific HLA alleles are associated with adverse drug reactions like hypersensitivity to things like a back of ear.

8:41
So types of pharmacogenes.

8:43
Let's do a deeper dive just in terms of how these genes impact proteins that in turn impact drug metabolism response.

8:50
And genetic changes can impact drug transporters.

8:53
They can impact drug metabolizing enzymes.

8:57
Genetic changes can also impact drug targets or receptors as well as the HLA alleles.

9:02
So if you have changes in transporter function, that can affect both drug efficacy and toxicity.

9:10
And examples of genes that code for transporters are SLCO 1B1 and ABCG 2.

9:16
And both of those genes are important in the risk of statin myopathy.

9:21
You can also have genes that code for drug metabolizing enzymes and those enzymes can either inactivate or activate compounds depending upon the metabolic pathways.

9:32
The majority of clinically actionable pharmacogenetic variation occurs in genes that code for drug metabolizing enzymes.

9:39
So examples of genes that code for important drug metabolizing enzymes are cytochrome P-452-C9 or SIP 2C9.

9:48
And SIP 2C9 is important for medications like non steroidal anti inflammatories and a number of other medications like phenytoin.

9:56
And then we have SIP 2D6, which is again important for a number of medications including things like tamoxifen.

10:07
We have Sip 2C-19 which is important for clopidogrel, Sip 3A5, UGT 1A1, DPYD, TPMT and UDT 15.

10:17
All of these genes code for drug metabolizing enzymes that are important for a number of very common medications.

10:25
Then we have the major histocompatibility complex for MHC genes and associations with immune mediated reactions.

10:31
So some HLA alleles are associated with increased risk for hypersensitivity reactions like Stevens Johnson syndrome or toxic epidermal necrolysis.

10:41
TEN.

10:43
And then we can have drug targets and drug targets are actually the molecules or pathways that a drug is designed to affect in order to deliver therapy.

10:52
So I'm not going to get into the details on reading a pharmacogenetic result, but basically reports usually list the genotype or diplotype as well as the phenotype.

11:01
So the genotype or diplotype is basically the genetic result.

11:05
So for instance, what variants, if any, were detected and then the phenotype is the expression of that genetic result.

11:12
So genes that code for drug metabolizing enzymes are codominant, meaning that the phenotype is really the result of the function of both alleles.

11:22
And then most reports should also list specific alleles or genetic variants that were tested.

11:28
And that's important because you want to be sure that the test includes all important variants.

11:35
So the majority of actionable pharmacogenes code for drug metabolizing enzymes and that includes the cytochrome genes along with other genes like DPYD and UGT.

11:44
1A1.

11:46
These genes are codominant, and that means that the phenotype is really a function of both alleles and medication.

11:53
Guidance is generally based on the phenotype, so you can have up to five metabolizer phenotypes, although some genes have fewer.

12:02
For some, but not all of the genes that code for enzymes, we use something called activity scores, and it's basically meant as a way to represent the amount of enzyme function.

12:13
And for those genes that use activity scores like SIP 2D6, SIP 2C9, or DPYD, the phenotype is based on the actual activity score.

12:23
So I eventually see activity scores being used for all genes that code for enzymes.

12:28
But right now there are some genes like SIP 2C-19 that don't use an activity scoring system.

12:34
Activity scoring is really a more precise way to characterize how much residual enzyme activity there is and then to provide a more precise way of giving medication guidance.

12:46
So if we look at these metabolizer phenotypes, poor metabolizers have variants that lead to little to no enzyme activity.

12:54
And that means that drugs that need this enzyme will be metabolized more slowly.

12:59
And the effect of that is going to depend on the medication.

13:03
So for instance, pro drugs that require the enzyme for activation may have decreased efficacy, whereas an active drug may be more likely to be toxic.

13:15
For intermediate metabolizers, they have some enzyme, but they do have less.

13:19
So again, metabolism would be slower, but there is some enzyme and that could mean a higher chance for side effects or in some cases reduced efficacy.

13:28
Normal metabolizers have enough enzyme that they should metabolize the drug normally.

13:33
Rapid, ultra rapid metabolizers have increased enzyme levels and they have faster than normal metabolism.

13:39
So again, that's going to mean different things for different drugs.

13:43
So in the case of something like codeine, codeine is a prodrug.

13:46
It is converted to morphine by the enzyme cytochrome P-452-D6.

13:52
So somebody who's an ultra rapid metabolizer for SIP 2D6 is going to convert codeine to morphine more quickly.

14:01
They're going to have higher levels of morphine in their circulation and that could translate to an increased risk for toxicity.

14:13
So changing gears a little bit, where do we go to get reliable pharmacogenetic information and how do you know what to trust?

14:20
There are a number of groups who put out guidelines.

14:22
We all know the FDA AMP often provides helpful information in terms of relevant variants that should be included for pharmacogenetic testing.

14:32
Here in the United States, probably the most influential of the pharmacogenetic practice guidelines come from CPIC, which is the Clinical Pharmacogenetics Implementation Consortium.

14:42
If we lived in the Netherlands, we would be following the Dutch Pharmacogenetics Working Group, abbreviated DPWG.

14:49
And while these groups don't always agree 100% in terms of the recommendation, there has been a lot of progress in terms of standardization.

15:00
So CPIC consists of a group of volunteers with extensive pharmacogenomic expertise.

15:04
And the goal is really to take pharmacogenetics from bench to bedside to really help clinicians take that genetic result and translate that into clinical action ability.

15:14
And there are currently 29 published guidelines and there are a number of others that are coming soon.

15:22
So Clin PGX is a comprehensive pharmacogenetic resource, and it was created to help support and expand pharmacogenetic knowledge, implementation, and education.

15:33
And if you go to this site, you'll see it contains a lot of information that can help you translate genetic results to actual patient care.

15:41
So Seepic and all these other awesome pharmacogenetic resources are now under this one umbrella.

15:46
And you could find information here on whether there's an important gene drug interaction that you should pay attention to.

15:52
It can tell you the level of scientific evidence behind various gene drug associations.

15:57
And that's important because not all gene drug associations are really ready for clinical actionability.

16:05
This is a screenshot of the Clinton PGX homepage.

16:08
And I just want to call your attention to some of the features on this site, specifically Farmdog.

16:13
And this Farmdog gives you a very transparent gene drug guidance tool.

16:19
And in fact, it provides detailed information from varied sources, including information from CPIC and the FDA as well as the Dutch Pharmacogenetics Working Group.

16:29
And you can either enter a particular genetic result and Farm Dog will give you information on medications that are impacted by that result, or you can just enter a specific medication and it will tell you if there's a gene that you might want to consider testing.

16:45
So if you entered clopidogrel, for example, it would prompt you for the SIP 2C-19 result.

16:53
So pharmacogenetic testing has relevance to medications that are used in virtually every specialty.

16:58
But here this particular slide is listing specialties where there are a number of commonly prescribed medications that have important pharmacogenetic associations.

17:07
So here I've lumped psychiatry, neurology and pain together just because there can be overlap in the medications that we use to treat these conditions.

17:16
But when we talk about psychiatry, 5 of the 29 seepa guidelines are for medications that have used in psychiatry.

17:24
There are important gene drug associations for a large number of antidepressants as well as anti seizure medications.

17:31
There are important gene drug associations for non steroidal anti-inflammatory drugs, opioids and so on.

17:37
And then the far right column kind of shows the genes that are most important for these types of drugs.

17:46
5 out of the 29 SEEPIC guidelines address medications with relevance to cardiology.

17:50
So for drugs like warfarin or clopidogrel, metoprolol as well as the statins, they all have important pharmacogenetic associations that can either impact efficacy or toxicity for GI, the thiopurines, proton pump inhibitors, anti nausea medications and so on.

18:09
For oncology, there are very important gene drug associations for the thiopurines, for tamoxifen, for fluoroprimidines and patients who carry variants in genes like TPMT or NUDT 15 or DPYD can be at increased risk for life threatening adverse drug reactions.

18:28
And so this testing provides information that's critical to have to prevent some of these adverse drug reactions.

18:37
So now that I've given you an overview of pharmacogenetics, our next speaker is going to talk to you about why pharmacogenetic testing for DPYD is so critical and the personal impact of fluoroprimidine toxicity.

18:50
So I'm going to turn the presentation over to Karen Merritt, and I'd like to thank you for your time and Karen will be joining us.

19:02
Thank you.

19:03
I finally made it.

19:04
Well, thank you for having me.

19:06
Good morning or good afternoon, depending on where you are.

19:09
I'm going to share about the human cost of ignoring DPYD testing.

19:15
I did not know what pharmacogenomics or PGX was in 2014 and I quickly learned how important pharmacogenomics is.

19:26
My mom, Linda, We like to think of her as so easy to live with and so hard to live without.

19:38
This is a picture of my mom and her kids.

19:40
We did a family reunion in Hawaii and on the far right side my mom and stepdad.

19:47
My mom had just had her port in.

19:48
You can't see it.

19:51
She looks healthy.

19:52
This was at a family reunion with her siblings and she would net will never see them again after this photo was taken.

20:02
So my mom is active, was active, 73 year old retired enjoying life.

20:09
I swear she was busier than us at the time.

20:13
She went in for a routine colonoscopy and turns out she had stage three **** cancer.

20:19
She made light of it.

20:20
She said.

20:21
Well, the good news is that this is curable.

20:25
The bad news is I have to stay in hot Arizona over the summer to get my treatment.

20:31
They prescribed 5 FU chemotherapy.

20:34
They told my mom it was fairly well tolerated and you know, warned about side effects of diarrhea and if your mouth gets irritated, call us for magic mouthwash.

20:45
Well, what happened was that she had was not given any information about DPD deficiency.

20:56
She was not informed of the risks.

20:58
If you are DPD deficient and are given 5 FU.

21:02
And how would you know if you're DPD deficient?

21:04
It's you're, it's not something that you're tested for as a child.

21:10
She started her chemotherapy on June 9th, 2014 and six days after she went to the emergency room for hydration.

21:20
She had been having continual diarrhea when she was at the emergency room.

21:26
This is where it would have been helpful for them to be aware of signs of toxicity by possibly looking at her.

21:33
Her mouth.

21:34
She had mouth sores that were pretty intense, keeping her from being able to eat.

21:40
She went home from the emergency room and a couple days later she collapsed.

21:44
Was taken to the hospital by ambulance.

21:47
Admitted at this point she she could not talk because her mouth hurt so bad, her low white blood cell count, she had low platelets, they'd started infusions.

21:59
She was basically at this time a sore from her mouth to her ****.

22:05
This began a 14 day vigil in the hospital.

22:09
We would wait every morning when that blood tests would come back to see what her white blood cell count was.

22:14
It was just so low and they told us when the white blood cell count starts going up, this is how it was sign that she's improving.

22:24
They also told us there was no way to know she was DPD deficient before starting her treatment and we know that to be incorrect.

22:33
She had round the clock specialist for this two week which was way more expensive than the DPYD test would have been.

22:42
We're shocked that DPYD testing was not standard of care.

22:46
These five FU has been around and known to be an issue with DPD deficient patient for 50 years.

22:54
6% of individuals have a DPD deficiency and it's an inherited condition.

23:00
I inherited the same genetic DPYD variant that my mom had on her death certificate.

23:07
It lists cardiac arrest as the cause of death and with we wish we had thought to have that be changed to read an adverse drug event because of toxicity to five FU due to DPD deficiency.

23:22
This would have required the hospital to report her death as an adverse drug event, which did not happen with others who have also lost a loved one due to not being tested for DPD deficiency before treatment with five FU or capesitamine chemotherapy.

23:45
We've come together and Co founded a nonprofit, Advocates for Universal DPDDPYD testing to improve the standard of care for cancer patients with the goal of making sure that no other family will suffer this horrific loss of a loved one who was taken from them from a preventable death because of toxicity.

24:09
Thank you and thank you for for the very powerful and important message you've provided our audience today.

24:22
This is, I know, very difficult for you to to talk about and, and have to speak to, but we're we're very grateful that you're willing to Share your story with us.

24:34
And in the next portion of this presentation, we'll talk about some of the clinical applications of of pharmacogenomic testing as it pertains to oncology.

24:47
And if you look at the the number of genes that are impacted, they're pretty significant and growing.

24:55
And so as we start to utilize our sequencing power within healthcare, I expect these two to grow.

25:06
And with the advent of precision medicine and the notion of really getting down to the core of treating the patient individually, their individual tumors, everything from screening to survivorship, we've got assays that are coming on market that are really focused on tailoring our approach not to the disease type, but to the individual.

25:30
And pharmacogenetics really falls and plays into that, into that paradigm.

25:36
And you can see here that fluoropyridines are a key component of that strategy.

25:42
And so if we dive in deeper and look at what is DPUID and how does it affect our metabolism, on the next slide, you'll see that DPYD really is a gene that codes for dihydropyramidine dehydrogenase.

26:03
And what that enzyme does is detoxify the metabolites of fluoropyramidines.

26:13
Patients who harbor alterations in this gene may not metabolize the the byproducts of this chemotherapy, and thereby those intermediaries can lead toxic and in some cases lethal, lethal levels.

26:30
It's become a such a hot topic recently and and tragically, it's taken this long for it to do so.

26:37
But see PIC, the consortium that Kathy alluded to earlier has issued guidance that when patients test for DPYD alterations, therapeutic intervention should take place with dose adjustments.

26:59
And this goes beyond just the the pharmacogenomic community and the pharmacy community.

27:05
If you look at NCCN guidelines, it's clearly stated in that on the next slide that DPYT testing is recommended prior to initiating therapy.

27:19
So much so it goes even further that the FDA has issued A guidance by placing warnings on the package inserts for certain medications that require this testing.

27:34
Here we can see the the capacitabine.

27:38
On the next slide you'll see the the, the guidance from the FDA on fluorouracil and really this has gained a lot of steam.

27:50
So how do we interpret this and how how does DPD phenotype and DPYD testing manifest in clinical applications?

28:01
Well, really it falls into 3 categories.

28:03
And Kathy alluded to this earlier as well in her discussion whereby patients are categorized into normal intermediate metabolizer or poor metabolizers.

28:13
And those categories correspond to whether or not patients should be treated with a particular medication and what that dosage should be.

28:27
So for normal metabolizers, those patients that have no alterations in their genetic code for DPD, they can be treated with medication as indicated at the dosage that has been deemed saved for their particular disease state and and them as an individual DPYD intermediate metabolizers.

28:51
However, those are the the category where patients have about a 70 to 30 to 70% of functionality or activity of the DPD enzyme.

29:05
And those patients based on C PIC guidance should have a 50% reduction in their therapeutic dose.

29:13
And you can titrate up for after that, after that initial reduction to really monitor the patient closely and identify when they might reach that threshold of toxicity.

29:25
So it is very much a nuanced tailored approach there.

29:30
And those patients who are poor metabolizers, they are completely deficient in, in DPD, they should obviously not receive this, this therapy, but this is kind of a, a, a fine tuning approach, right?

29:44
There's, there's a bit of an art associated to this.

29:47
So there's been a, a, a further development of how we can interpret these results.

29:52
And if you look at the next slide, it's really kind of a speedometer approach, right?

29:57
And you get an activity score.

30:00
And in each within each category that activity score corresponds to some guidance on what to do with doses.

30:09
Those that are normal to metabolizers or activity score two have no impact on their on their dosage.

30:17
For Fluori Uracel, those that fall into intermediate metabolizers fall into two categories, 1.5 and one.

30:28
And again these are kind of set points for how much dose reduction patients should have in the 1.5 category at least 25% reduction, potentially up to a 50% and one and the activity score of 1 should have a 50% reduction.

30:49
And then in those that are poor metabolizes, they might have some function remaining 0.5 being the activity score.

30:57
There really need to have a clinical discussion with the, with the physician to identify whether this patient may be considered for therapeutic intervention.

31:08
And those with 0 obviously should not receive the therapy.

31:13
So if you look at who should be tested and when they should be tested and how they should be tested, really there's a, a, a, a, a large opportunity here.

31:25
And on the next slide one perfect, we see that the use of pharmacogenomics really unlocks the value beyond just oncology, right?

31:38
You can think about this.

31:40
When patients are being treated, they're usually being treated with multiple medications and often times we're treating patients for their disease and then treat it and providing other interventions for some of the side effects associated with that disease.

31:57
So for example, Zofran, some patients might be getting SSRIs for depression during their their treatment course.

32:04
Those are things that really add to this polypharmacy approach.

32:09
We, we have and in many situations.

32:12
And so a polypharmacy or a large, broad pharmacogenomic panel offers insight to all of these categories, cardiology, neurology and psychiatry, oncology, GI interventions and even infectious disease and how patients metabolize antibiotics.

32:32
So you can see there's a, there's a true value here of, of going into the more broad approach.

32:39
And so when you look at who should be considered for PGX testing and, and how do we select those patients, it's not something that we want to do in the consumer space, right?

32:49
We're, we're not a one stop screening approach here.

32:54
This is really for patients that are on multiple medications, potentially have multiple health issues and are needing to make maximize their their treatment approach.

33:08
Oncology certainly falls into that category whereby ensuring that the chemotherapeutic agents were administering to patients are as efficacious as possible.

33:23
Some of those patients might be on anticoagulants.

33:25
You think about the cardiology segment there and we really want to minimize those drug to drug interactions, those drug interactions with our body, the metabolizers, right.

33:41
And so pharmacogenomics really helps with with that second category.

33:46
If we look at what flavors of a pharmacogenomic testing are available, it falls into 3 sub subgroups, the first being a single gene test, right?

33:59
We know we're going to give this patient five FU.

34:02
We want to make sure we're we're testing for DPID.

34:06
You can test for that that gene individually.

34:09
The other categories are targeted panels which are focused on sub categories of let's say all oncology drugs or all cardiology drugs and, and focus on that treatment window as it were.

34:25
And then finally in the middle we have the polypharmacy.

34:28
This is where we really get the most holistic approach and where it's important to understand that as we move into the age of precision medicine and we're continually moving into the a more precise setting, this is where we're going to get the most bang for your buck, so to speak and and have the most impact for patient care.

34:49
So we've talked about the implications, we've talked about what testing we have, what is the data show us and what studies have been done to really indicate the use of pharmacogenomic testing.

35:04
Well, there are two really prominent studies.

35:06
One is called the predict and the right study.

35:09
Both have very large cohorts and in both they looked at testing patients after treatment failure and before treatment initiation.

35:19
And the overwhelming result for both of these categories was that the earlier start, if you do pharmacogenomic testing prior to therapy initiation, the benefits are vastly outweigh the the risks there.

35:35
And, and really what we found is that most patients have at least one actionable genotypic alteration for the, the, the drugs that were looked at within the study and in the mayor, in the Mayor Baylor, Baylor Wright study, they had three actionable variants in that cohort.

35:58
So you can see that going the broader approach really has benefit.

36:04
So how are results provided to patients and and providers alike?

36:10
Well, there are two flavors that that are available.

36:14
One is purely the pharmacogenomics panel result where by the alterations are provided with minimal interpretation or guidance on therapeutic approach.

36:28
And the second one is a more integrated, much more user friendly, if you will, approach to pharmacogenomics whereby through Corielle Life Sciences, A curated database is introduced and provides patients and providers with the red, yellow, green stoplight approach of therapeutic indications whereby the alterations identified within the patient are associated with I.

37:02
I do not use, monitor or reduce the dose or, or, or go ahead and continue as intended.

37:12
The reason for this is there are multiple institutions that have their own pharmacogenomics monitoring and pharmacy program where they have their own interpretations.

37:28
And so they might not benefit from a choreal life sciences approach.

37:32
They have their own way to curate this data.

37:36
And on the next slide, this testing is so critical, particularly in oncology, but also in in neurology and psychiatry and and cardiology really across the gamut.

37:54
And it really aims to move away from this one-size-fits-all right.

37:58
We're no longer treating just the disease state, we're treating the individual.

38:02
And it's so imperative that we ensure that we're pulling in the the most appropriate data points so that we can make the right decisions and guide the strategy for treating patients and improving outcomes.

38:23
And that with that, I'll turn it over to Rebecca.

38:26
Thanks, Doctor Krozel, that was wonderful.

38:29
I also just wanted to add the other thing about the Coreal Life Sciences is that it's dynamic.

38:33
So as guidance and things change and update, you were getting there.

38:37
I just wanted to add that in that, that will continue to change.

38:42
So that's one of the benefits of being able to click over into Coreal is that as guidance changes, that document will also update.

38:50
But I just wanted to summarize.

38:51
Thank you so much to our speakers today and we're going to move into Q&A.

38:54
But just wanted to refresh everybody that today we reviewed our the clinical importance of PGX testing and how it can improve patient care.

39:02
We highlighted the importance of genetic testing using specific examples of high impact gene drug associations, including DPYD testing for fluoroperminine toxicity.

39:12
We described the patient experience and the transformative impact pharmacogenomics can have on care and identified appropriate candidates for PGX testing and discussed polypharmacy panel and single gene testing approaches and the clinical practice.

39:26
So feel free if there's any remaining questions to add them to the Q&A.

39:30
There is one in there.

39:31
I will add that this is recorded today.

39:34
It will be available on demand for rewatching or to share with those who weren't available today.

39:39
Anyone who registered will get a link to the recording so that they can do that if they got called into clinic or something else came up.

39:48
And then we also just wanted to highlight that tomorrow is World PGX Day.

39:53
So this is a very timely discussion and Karen's advocacy work is a big part of that day that is tomorrow.

40:00
So I'm gonna turn it over to our panel of experts.

40:05
Our one question that's in the chat is do the products?

40:09
Of specific drug metabolizing enzymes change with age, producing more or less of the metabolite with aging.

40:15
How how often is I'm guessing you're supposed to say how often is that measured?

40:21
Yeah, I can address that.

40:24
Thanks everyone for those great presentations.

40:27
So it's not necessarily that the metabolizing enzymes change with age, but our bodies change right, with age.

40:33
So, you know, there may be alterations in our digestive system, circulatory system, our liver, our kidneys, all the parts where we process all these enzymes.

40:45
So our ability to metabolize these drugs or clear them from our system may change with age.

40:52
So yes, it can actually absolutely change with age and should be considered and monitored.

40:57
How often they're measured.

40:59
You know, I would defer to the clinicians with regard to that.

41:03
I think that you, you know, like like a lot of these approaches, they're multi factorial multi, you know, lots of pieces of the puzzle, right?

41:11
So you have to take that into account if you're treating an older patient and you may want to do more monitoring that you would do, but I don't know that there's any necessary guidelines in terms of monitoring.

41:22
So, but yes, aging is another piece of the puzzle and factor to consider.

41:30
You have to remember that we're we're testing our genes here.

41:34
And so when you think about how your genetic code might change over time, there are multi factors for that, right?

41:45
And then we develop cancer from environmental exposures that cause alteration.

41:50
So is it possible that an alteration that wasn't present when you're 40 is present when you're 50?

41:55
It is possible.

41:57
Is it?

41:58
Is it likely that a germ line mutation may occur may be present from from birth?

42:04
It is possible as well.

42:05
So I think the message here should be let's get tested.

42:10
And and we're this is such a rapidly evolving field that you know, guidance about frequency will will come in time.

42:18
I think right now the message is get tested because it's, it's so vitally important.

42:27
Right?

42:27
Cuz your genes won't change.

42:29
Exactly.

42:31
The genotype isn't gonna change, the interpretation might.

42:34
Well said both of you.

42:36
There's one other question in the chat.

42:38
Feel free to put any more or the Q&A.

42:40
Just to note that you cannot come off mute.

42:42
So if anyone has anything to add, please make sure you're putting it in there.

42:45
You can reply to the thread if you have more information to add.

42:49
The next question is I saw that opioids were listed as having a gene drug interaction.

42:53
Is there any literature suggesting a genetic basis for addiction?

43:02
I mean, the general answer is yes, there is.

43:05
There are some studies that would suggest addiction, you know, especially for or opioid use is is definitely a thing.

43:15
And so, but I don't have, you know, more specific.

43:18
Are you wondering about genetic testing for addiction?

43:21
Is that not sure if you want to expand on the question at all, but certainly there are some variants in certain genes that you know, may predispose people to certain addictions that appears, but it's not something that I'm aware of routinely testing for.

43:38
So I don't know if you want to add anything.

43:40
Doctor Krizel Yeah, I think, you know, I think the jury on that is still out as far as clinical application as to that.

43:47
I think there's a lot of research in the space for that, but we we don't routinely do that clinically.

43:57
Great question.

43:58
And then the next one is for Karen.

44:00
So appreciate your story.

44:02
Karen, thank you for sharing something so difficult.

44:04
Is your group or others working on getting black box warnings added for some of these medications?

44:12
So we are solely focused on five FU and Cape Sidabine.

44:18
And yes, we have are so happy that in October of 2025, there's a black box warning on Cape Sidabine and the FDA followed up with that in February of this year, adding the black box warning to five FU.

44:36
And in October in 2025, even though 5 FU did not have the FDA black box warning, the NCCN colon cancer guideline, and then all the other panels have all followed up and aligned with the FDA that testing for DPYD variants should be done before treatment is started, unless in the rare cases that a patient needs to start right away.

45:04
And we have been told that that is rare.

45:10
Great work.

45:11
Thank you so much for your advocacy group really pushing for this.

45:14
It's going to have such a huge impact on patients lives and getting the right dosage for these meds.

45:20
Yeah, a lot of work, many years advocating.

45:24
So thank you.

45:26
Many years, I don't see any more questions in the chat, but I just think that one of the questions that we had chatted about that I thought maybe the panel can address when we have a few more minutes was just, you know, Karen's story is so compelling about this story of five FU.

45:41
So, you know, do you see any hurdles about implementing this genetic testing into the clinic?

45:46
And you know, what are different ways of approaching this screening for these drugs and identifying them?

45:56
Yeah.

45:56
So I think the elephant in the room is, is reimbursement, right.

46:00
And and that is, is definitely something that's evolving very rapidly.

46:07
Thankfully, DPYD it has coverage.

46:10
And so for that, that indication there is there is reimbursement.

46:14
But for some of the others, it's still an uphill battle to to get coverage for that.

46:22
Thankfully, you know, I think that there are programs in place at many of the laboratories, including including our own, where financial assistance is available.

46:34
And, and you know, these patients could get this testing with, with limited cost to them.

46:44
It's not free, but it is, it's something that that I think a lot of people are, are advocating for, including myself and, and, and speaking with payers on, on getting coverage for testing outside of the, the, the DPYD space.

47:00
I think I would also add, you know, turn around time, you know, like Karen was indicating, you know, how, how quickly do we need to start, you know, treating So, you know, is good turn around time.

47:13
And then also in terms of how to, you know, relay those results to the provider, you know, there's so many different electronic medical records and integration.

47:24
And so that can be complicated as well to complicate getting the results to the to the provider in a timely fashion.

47:31
So, yeah, there are some things to still address.

47:37
Absolutely.

47:37
Well, I'm not seeing any more questions popping up in the Q&A, so we will wrap up there.

47:41
But I just wanted to take time to thank everybody, Kathy O'Brien, who couldn't be here for, but also Doctor Krizel, Michelle and Karen for sharing your stories and expertise with everybody.

47:52
This has been so impactful.

47:54
And as mentioned, this is going to be recorded and available.

47:57
We also have a PJX podcast that you can find on our Healthier World podcast if you want to learn more, but feel free to reach out to any of us if you have any additional questions.

48:08
But thanks for everybody's time today.

48:11
Thank you, pleasure being here.

48:12
Thank you everyone.

48:14
Thank you.