Dr. Neal Shore talks about how anti-androgens work for prostate cancer.
Mr. Philip Steward is on the Steering Committee for two San Francisco Bay area support groups
Prostatepedia spoke with him recently about his experiences with prostate cancer molecular profiling.How did you find out that you had prostate cancer?
Mr. Philip Steward: I had a rising PSA for several years at my annual physical. The doctor kept saying we won’t worry about this until your PSA gets to 10.
In 2001, I told my general practitioner that I wanted to have a urologist take a look. The urologist did a DRE and immediately said I should have a biopsy.
I was then diagnosed with Gleason Grade score 8 prostate cancer. Sixty percent of my biopsy cores were positive. My PSA was 3.85. If I had waited until that PSA got to 10, I might not be talking to you right now.
The urologist, of course, was a surgeon. He recommended surgery and said that guys like me—with my numbers—typically live seven years.
I asked him what the chances were that the cancer had already escaped the prostate. He said about 60%.
I asked then why would you do a local therapy? He said you either beat this stuff or you don’t.
Of course, it was devastating.
But that’s when I decided to get educated.
How did you find your support group?
Mr. Steward: Two good friends of mine had had prostate cancer earlier. I called them both two days after I got the pathology report. One suggested a support group in Mountain View, California, near where I live.
How did you come to use molecular profiling for your prostate cancer?
Mr. Steward: My first approach was to make an appointment with Dr. Leibowitz and his associate Dr. Tucker. They prescribed hormonal therapy and concurrent low dose chemotherapy. The chemotherapy consisted of five cycles. Each cycle included chemotherapy infusions every week for three weeks followed by a week off.
After this series of chemotherapy and hormonal therapy, I had no treatment for the following five years during which time my PSA slowly returned. I then went on hormonal therapy again for nine months. I was treatment free for two years. Once again, the PSA slowly returned.
When the PSA came back again, I saw Dr. Mac Roach at the University of California, San Francisco (UCSF) to have IMRT radiation to my pelvic area and high-dose radiation to my prostate gland itself.
After the radiation treatments, another five years passed without any treatment, but my PSA slowly rose again. At that point I had a multiparametic MRI at UCSF along with a biopsy of my prostate.
They didn’t find any cancer.
A little over a year ago, I went to Phoenix Molecular Imaging in Phoenix, Arizona for a C11- acetate PET/CT scan. They found that my pelvic area and abdomen were clear. The radiation treatments had been successful. But now I had metastasized cancer in my lungs— 20 nodules.
I wanted to make sure that the nodules were really prostate cancer, so Dr. Steven Schwartz at Good Samaritan Hospital in San Jose, California was able to obtain tissue samples of the nodules using a videoassisted thoracoscopic surgery (VATS) procedure. The pathology of the lung nodules proved it was really prostate cancer.
I requested the tissue samples be sent to Foundation Medicine (https://www.foundationmedicine.com/), hoping to find out if I would be taxane-sensitive. Foundation Medicine was not able to tell me if my cancer was taxane-sensitive.
I then learned that GenomeDX (https://genomedx.com/) in San Diego could test to determine taxane sensitivity. I contacted them and submitted a sample of my lung tissue for evaluation. They sent the results to Dr. Tanya Dorff at the University of Southern California-Norris Cancer Center who thought the metastasized cancer would be sensitive to Taxotere (docetaxel) and that I didn’t need Paraplatin (carboplatin) as a part of my infusion treatment. She thought there was an overexpression of two genes for which existing drugs might be effective if the chemotherapy didn’t work.
You took the initiative to contact GenomeDX? Your doctor didn’t suggest it?
Mr. Steward: Right. My doctor really didn’t know that they could do that kind of testing.
A representative of GenomeDx, Jason Alter, spoke to our San Jose, California support group. He said they could test for taxane-sensitivity. The test isn’t FDA-approved, so it would cost money. I emailed the company and they said it would cost $3100 to test a sample of my lung tissue.
Is it normally covered by insurance?
Mr. Steward: No. It is not covered by insurance.
Did you talk to other patients in your support group about your experiences?
Mr. Steward: I talked to everyone in my support group. No one has used this kind of testing.
Because their doctors hadn’t suggested it? Or they’re reluctant?
Mr. Steward: Probably because their current circumstances don’t present a need for this information.
You have taken a proactive approach, haven’t you?
Mr. Steward: I felt I had to. Gleason grade score 8 is not trivial.
Are you still an active member of the Mountain View support group?
Mr. Steward: I’m on the Steering Committees for both the Mountain View, California group and the San Jose, California group.
I suppose you would never have known about GenomeDX without the support group.
Mr. Steward: I went to a support group meeting two days after being diagnosed and found the level of knowledge possessed by the members impressive. There are several men in the group who probably know more about prostate cancer than my general practitioner did at the time of my diagnosis.
Do you have any advice for men considering this kind of testing?
Mr. Steward: If you were considering chemotherapy, it would be nice to know if your tumor is going to be sensitive to it, because the side effects are really harsh. I have been told that about half of men with prostate cancer don’t have a form of cancer that is sensitive to taxane-based chemotherapy.
Since 100% of men have the side effects, half the men suffer for no benefit. A series of chemotherapy infusions is expensive. It would be more cost-effective for your insurance company to pay $3100 to test for chemotherapy sensitivity than to pay for chemotherapy that doesn’t work.
If I were facing chemotherapy and had the money, I would get my tumor tested to make sure it was Taxotere (docetaxel)-sensitive.
Dr. Daniel Petrylak talks about how doctors may begin to use biomarkers to help guide treatment.
Dr. Joshi Alumkal is a medical oncologist and Co-Leader of the Prostate Cancer Research Program at the Knight Cancer Institute at Oregon Health & Science University (OHSU) in Portland, Oregon. His lab at OHSU focuses on identifying ways by which prostate cancer evolves into the lethal form of the disease.
Prostatepedia spoke with him about how doctors hope to use genomics to guide treatment.
When and how do we molecularly profile tumors?
Dr. Joshi Alumkal: For patients with newly diagnosed localized prostate cancer, we have fairly standard therapies: radiation, surgery, hormonal therapy with radiation for higher grade cancers, hormonal therapy after surgery in patients who have lymph nodes involved, etc.
Otherwise, there isn’t good data to suggest that the use of molecularly targeted therapy or any other forms of adjuvant therapy are useful to patients.
Molecular profiling is primarily limited to metastatic disease. In that scenario, we’re thinking more about how an abnormality may guide therapy. We think about using investigational agents, which are associated with risks and side effects. These investigational agents may be worthwhile because we think the benefit of treatment outweighs the risks. For someone with localized prostate cancer, we don’t know if finding specific molecular abnormalities will impact their care—particularly because local treatment with surgery or radiation may be sufficient to cure them. If we found a molecular abnormality in a localized prostate cancer, it would be a stretch to recommend an adjuvant molecularly targeted therapy.
Molecular profiling of a tumor certainly offers an opportunity to identify patients for clinical trials, but a lot of those efforts are focused on patients with advanced metastatic prostate cancer.
Would it make sense for men with metastatic disease to get their tumors molecularly profiled?
Dr. Alumkal: It’s at least worth having a discussion with your physician about determining whether or not molecular testing is something that makes sense and if it could be done safely. Ideally, one would biopsy a new metastatic lesion rather than use an old, archived sample. That way you can get as much information as possible about what is going on at that point in time in a man’s tumor.
AT OHSU, we have been involved with a Prostate Cancer Foundation and Stand Up to Cancer-funded Dream Team Award over the past three years. We routinely perform metastatic research biopsies in patients. We have an internal 124-gene mutation panel that we commonly perform in patients.
That includes many gene alterations that are potentially targetable with specific drugs. In our practice, the most common use of molecular testing is in patients who have advanced disease and whose cancers have progressed despite one or two approved therapies—when we’re starting to run out of options.
We want to know if there are other things going on in the tumor that may be targetable with specific medications approved for diseases other than prostate cancer. There has been a lot of excitement recently because a variety of groups have shown that approximately 20% of patients with metastatic prostate cancer resistant to most approved treatments have mutations in gene involved in DNA repair in their cancer.
These mutations involve genes like BRCA1 or BRCA2, which are genes historically associated with hereditary forms of breast and ovarian cancers.
Preliminary data from a small clinical trial in the United Kingdom suggest that a class of medicines called PARP inhibitors—they specifically tested a drug approved for ovarian cancer called Lynparza (olaparib)—can work quite well in patients with mutations in these DNA repair genes. (See Prostatepedia June 2016 for a conversation with Dr. Joaquin Mateo about that study.)
That is one example of how a mutation found in molecular testing could lead us to recommend that certain patients join a clinical trial focused on PARP inhibitor treatment. A variety of companies that have developed PARP inhibitors have initiated, or will very soon initiate, clinical trials in men with advanced prostate cancer whose tumors have these abnormal genes. That is an exciting new avenue of research—looking at tumors and finding abnormalities that seem to correlate well with response to a class of medicines. We have some sense of who may benefit from these drugs. But by no means do we know for certain all the patients who are likely to respond. There is some refinement needed in understanding which genes are really important and which patients may be best suited for that type of therapy.
This is one of the first examples of a molecular assay for prostate cancer that is being used to make treatment decisions for prospective clinical trials. It’s a really exciting time, particularly since the frequency of these alterations is around 20% and quite common.
If you do molecular profiling on one lesion in a man with multiple lesions, does that testing give you information about all of his lesions? Or does each individual lesion have its own molecular profile?
Dr. Alumkal: The verdict is still out on that. There are a variety of groups trying to tackle this question. Most of these studies have been done through what are called through rapid autopsies, in which patients donated their bodies to science to allow researchers to evaluate tumors from multiple sites. There are certainly unique things that you will find in different metastases within a patient. In many cases, there are many features that are the same from metastasis to metastasis within the same patient. There have been a small numbers of studies done in this area. Some work was done by Dr. Steven Bova in Finland and more recently in Dr. Peter Nelson’s laboratory at Fred Hutchinson Cancer Research Center in Seattle, Washington.
Those studies have had some differing results. It is clear is that many of the alterations present within a patient are conserved across all their metastases. It’s not uncommon when we treat patients with therapeutic drugs to see a fairly uniform response or progression in patients. Clinically, that does suggest that many drugs’ behavior may be similar in different cancer lesions within a patient.
I think one way around what we call heterogeneity, or differences between tumor lesions within a patient, is to have tests that sample all of those tumors. That is where a lot of groups are developing bloodbased sequencing or liquid biopsies. Tumors shed DNA into the circulatory system. You may be able to sample DNA and measure DNA from a variety of different tumor sites in a blood sample. This is another set of tests being developed by several companies.
If those assays prove to be more helpful than a single biopsy of a single metastatic lesion, they may be useful in helping guide therapy.
Are liquid biopsies currently available?
Dr. Alumkal: There is at least one major company called Guardant Health (http://www.guardanthealth. com/), which has a blood-based assay for mutational profiling, including many of the genes relevant to prostate cancer involved in DNA repair. It is by no means a comprehensive set of genes, but that is probably the best known and most commonly used blood-based test on the market. There are several other companies developing tests similar to the Guardant assay that will soon be in this space. There has really been an explosion in interest in trying to find non-invasive ways to sample tumors from patients and to provide molecular or genomic information. It’s really hard to get sufficient material from metastatic biopsies to do genomic testing.
At OHSU, we have been fortunate enough to work with an excellent team of interventional radiologists who have honed their technique over the past several years. We’re now at the point where the vast majority of biopsies we’re performing provide sufficient tumor and DNA for informative molecular testing. This is not something easily done at most centers. Having an expert radiology infrastructure is really critical. That is really why, hopefully, bloodbased tests that can be done anywhere will be shown to be as effective, if not more so, than a single-site biopsy.
Are community oncologists and urologists interpreting and using this data effectively?
Dr. Alumkal: There are a variety of different companies that provide mutational testing. As I mentioned, we have our own diagnostic lab here at OHSU. Foundation Medicine (https://www.foundationmedicine.com/) is another company that provides these types of data. It is critical that the output of those tests and those reports be digestible, both by physicians who are at academic centers and by those in community practice. In many cases, patients themselves want these reports for their own records.
We need companies that can provide that information in a digestible fashion and provide recommendations on how those alterations may impact care and clinical trials. We need information that makes those genomic results most informative and actionable.
What are the barriers to genomics becoming more widely used to guide treatment?
Dr. Alumkal: Certainly cost, and whether payers will cover these tests, is critically important. It will be important for the companies that develop these tests to demonstrate that mutational testing can have a significant impact on patient care and decision making. Those are open questions—whether or not the technology will provide better information than clinical information alone. If they can demonstrate impact that could certainly increase the usefulness of this information.
I think we need prospective cohorts of patients to demonstrate what these tests’ characteristics are, what their false positives are, what their false negatives are, and how reliable they are. We want to know that if we were to order these tests, we’re likely to find things that will impact how we care for patients.
Does it make any sense for a man five years after surgery to have tissue banked after biopsy or prostatectomy molecularly profiled?
Dr. Alumkal: If there isn’t a new lesion that can be biopsied, one could consider using an old, archived sample from the same patient. Particularly if the patient has undergone multiple rounds of therapy that could dramatically alter the DNA of their tumor, then it’s probably preferable to get a fresh biopsy and test that new tissue for gene alterations.
If that isn’t possible, then I think there is value in going back and looking at that archived or prior specimen to see if something that was present then could be targetable or actionable. The hope would be that that abnormality is still present and that targeting it now with a specific medicine might make sense.
Those are obviously unknowns, particularly if five years have passed. We may have eradicated the tumor cell that was present to begin with in the original tumor sample and what has grown and emerged is an entirely different cell with a different set of alterations. That is why getting a fresh sample gives a better sense of what may be going on at this moment in time. We’ve certainly had patients interested in getting more information about their tumor, particularly if they wanted to have as much information as possible to guide certain therapies. In those cases, we have gone back to those archive samples and tried to determine if there are abnormalities that were present that suggest a certain medication might make sense.
In those cases, we refer patients for clinical trials, or in some cases prescribe medicines approved for other cancers to treat their disease.
Would it make sense to periodically redo molecular profiling as part of a monitoring plan or is that excessive?
Dr. Alumkal: Anything that doesn’t kill a cancer makes it stronger. We know cancers continually evolve. My hope is that in the future, we’ll get to the point where we can serially monitor patients with non-invasive blood tests to get a better sense of whether or not their treatment is working. If their treatment stops working: why?
How has the cancer changed? To the extent that we can determine that that is safe and useful and can guide decision-making and treatment choices, then I think we’ll see more widespread implementation of those sorts of tests.
It will take linking finding those abnormalities with knowing that if certain abnormalities are present certain medications may target those abnormalities. That will be paradigm-changing.
My hope is that in the very near future, we’ll approach advanced prostate cancer the way oncologists approach localized breast cancer. Oncologists evaluate the estrogen receptor status, progesterone receptor status, and the HER2/NEU status to get a better sense of whether or not certain targets are present to guide whether certain therapies may work.
We’ve seen similar changes in lung cancer. If you have certain alterations in a gene called ALK or in a gene called the EGFR, then specific medications that target those abnormalities make sense for those patients.
We don’t yet have those types of tests in prostate cancer, but I’m hopeful that through a variety of different research and commercial efforts we’ll develop testing that can guide how we treat patients rather than the shot-in-the-dark approach we take now. Today, we just take existing drugs off the shelf and hope they’ll work well in that specific patient sitting in front of us.
Don’t you waste time and money in that approach?
Dr. Alumkal: Yes, because in many cases what we prescribe doesn’t work and it takes time to figure that out. That is lost time for that patient who could have been on a more effective therapy or who could have avoided side effects.
Getting more information about what is going on in the tumor and coupling that with therapies that can target the abnormalities present is a major unmet need in advanced prostate cancer specifically and in oncology in general.
Is there anything else you think prostate cancer patients should know?
Dr. Alumkal: We’ve never known more about prostate cancer than we do now in 2017. That will only improve. As we understand more about what makes each individual patient’s cancer tick and as we find abnormalities that we can do something about, we’ll really be able to make a significant difference in the lives of patients. I don’t believe we’re many years away from that.
Dr. Alicia Morgans is a medical oncologist at Vanderbilt-Ingram Cancer Center in Nashville, TN.
She specializes in treating advanced prostate cancer. She is particularly interested in addressing treatment side effects and in how men with advanced prostate cancer make treatment decisions.
Prostatepedia spoke with her recently about how genomics is—and isn’t—being used in the clinic.
What is genomics versus genetics?
Dr. Morgans: Genetics looks at different genes that can be passed on and inherited through different generations to give you certain traits or different features, like eye or hair color. Genomics for oncology is the study of the genes that alter a cancer’s behavior or growth. It involves our understanding of what is driving a cancer’s growth in a particular person.
Are we currently using genomics for screening prostate cancer?
Dr. Morgans: We use genetics in that we think about men with a first-degree relative with prostate cancer as being at higher risk. Some organizations suggest that men with a first-degree relative should start screening for prostate cancer at an earlier age, though with the United States Preventive Services Task Force (USPSTF) recommendations, things are a little bit murky right now.
We think about people with a family history of breast and ovarian cancer who have BRCA1 and BRAC2 mutations as being an additional group who may think earlier about screening for prostate cancer.
But we’re not necessarily using genomics in the screening setting yet. We use genomics after we have screened someone and taken a biopsy. Genomics can help us predict who may have an aggressive cancer and who may have a less aggressive cancer that can be followed with surveillance instead of treated immediately with surgery or radiation.
How are we using genomics to select initial treatments?
Dr. Morgans: There are some tests that men can use at the time of prostate cancer biopsy or after a prostatectomy that help them and their doctors think about how likely their cancer is to come back, to become metastatic, or to cause them to dieof prostate cancer. Those are tests urologists most commonly use.
Some are used when men get a biopsy and some, like the Decipher test, are used on a prostatectomy specimen. GenomeDX, the company that makes Decipher, just announced a biopsy product to predict the risk of metastatic disease, as well.
There is the Prolaris test which is done on a biopsy specimen. Prolaris uses genomics to risk stratify who is likely to have their cancer come back in an aggressive form and who will have low-risk disease and not necessarily need to have surgery.
How do we use genomics to predict who will or will not respond to certain drugs? For example, looking at AR-V7 mutations to predict resistance to drugs like Xtandi (enzalutamide) and Zytiga (abiraterone)?
Dr. Morgans: AR-V7 testing, which would potentially help us predict who would respond to drugs like Xtandi (enzalutamide) or Zytiga (abiraterone), is not in clinical practice yet. We do not yet have a Clinical Laboratory Improvement Amendments (CLIA)-certified test that can identify AR-V7 mutations in circulating tumor cells or in prostate tissue that will tell us whether or not a patient will respond to Zytiga (abiraterone) or Xtandi (enzalutamide). At some point, a test like that will likely be commercially available.
There are clinical trials that are attempting to use the presence or absence of AR-V7 to either enroll people, risk stratify them, or statistically stratify them in the analysis, but it is not a commercially-available and clinically-used test at this point.
Do you think that is the path genomics will take in the future?
Dr. Morgans: We would love to have a test that could tell us which drugs will work for a particular patient’s cancer and which drugs won’t. We don’t have those tests now, but if and when that information becomes available to clinicians, it will dramatically impact how we treat prostate cancer.
Do you think genomics will change how we design clinical trials?
Dr. Morgans: It already has to some extent. There are clinical trials that focus around certain mutations or alterations. There are studies that include only patients with AR-V7. There are PARP inhibitor studies that use the presence or absence of DNA repair defects to include or exclude patients. These advances in our understanding of genomics are definitely being integrated into clinical trial design.
If those clinical trials demonstrate a benefit, it will be another step forward for genomics. Genomics will then have to be incorporated into our practice over time.
So it’s just a matter of time before we demonstrate genomics’ usefulness and then it will quickly become integrated into patient care?
Dr. Morgans: I don’t know how quickly, but we’re trying. Changing practices in medicine doesn’t always move quickly enough for many of us for important safety reasons in place to protect patients. I would say that genomics has already demonstrated utility. Now we need to finish the clinical trials to really prove that it has a role in clinical practice to help men live longer and better lives. If the studies don’t show this, it won’t be integrated into patient care. I think we are all hopeful that genomics will provide meaningful direction for clinicians as we choose among treatments for men with prostate cancer.
To this point, there is a great New England Journal of Medicine paper by Dr. Joaquin Mateo and colleagues that performed biopsies on men with advanced disease who had had one or two lines of chemotherapy. (See Prostatepedia June 2016 for a conversation with Dr. Mateo about that study.)
The men in the study underwent biopsies and were then treated with Lynparza (olaparib), which is a PARP inhibitor. Those men who had DNA repair defect mutations appeared to have a very high response rate to Lynparza (olaparib) by the criteria included in that study.
I would say that genomics is already demonstrating the possibility of effectiveness. It just needs to be demonstrated on a larger scale. Mateo’s study only included 50 or so people, not hundreds, as we would have in a definitive, practice changing study. But early signs of clinical utility are definitely there.
Couldn’t a medical oncologist take that study by Dr. Mateo and his colleagues and apply the same principles to his or her own patient?
Dr. Morgans: Medical oncologists are doing that, but sometimes we’re limited by insurance. I have patients on Lynparza (olaparib) right now, and we are hopeful that all will go well. We commonly use genomic testing to look at mutations in patients’ prostate cancers, but whether or not an insurance company will pay for us to use an off-label treatment is another question.
It’s easier in a clinical trial setting, because pharmaceutical companies pay for the cost of the drug. It can be more challenging if you’re not in a clinical trial setting.
Are those drugs very expensive?
Dr. Morgans: One of my patients paid out-of-pocket for a week for Lynparza (olaparib), and I believe it was in the thousands.
What about genomic tests? Are they expensive?
Dr. Morgans: That varies by state, by medical institution, and by patient insurance. I have not had trouble getting genomic testing for my patients.
What if a patient has already been treated years ago. Is the biopsy tissue usually preserved or does a patient have to request it?
Dr. Morgans: The patient doesn’t have to request it if a biopsy or surgery was already done. The patient can talk to his doctor or his family could talk to his doctor and say, “We want to have genomic testing.” The doctor just has to request the test and identify the tissue sample that should be used. Sometimes the patient has preserved samples. If that patient has had a prostatectomy, for example, there may be a recently preserved sample that could be sent.
However, I would say the most useful genomic testing is done on a metastatic site at the time that a patient is progressing after first line treatment. The reason is that over time, after being treated with multiple medications, prostate cancers acquire new mutations that allow them to become resistant to different treatments.
If you sample the initial prostate tumor, you may find a set of mutations that don’t include the ones currently driving that cancer and allowing it to get around the treatments used at that particular time. If there is a way for patients to undergo a biopsy of a metastatic site, that tissue would give them a clearer picture of the mutational or genomic profile of his cancer at that time. There can also be some difference, or heterogeneity, between the genomic profile of different metastatic sites. The genomic profile of one metastatic site may not be exactly the same as another metastatic site. There are stronger driver mutations that we think really help that cancer grow and spread and are driving the growth of that cancer. We hope those mutations would be the same across different metastatic sites, but different sites do acquire different mutations. That has been demonstrated in multiple studies at this point.
If you get multiple biopsies over a number of years, should you have all of those tissue samples tested?
Dr. Morgans: You could. But I don’t know how many times an individual insurance company will pay for genomic testing. I have had some patients tested multiple times, usually separated by at least a year to two years because they were on one therapy and then another. These are not inexpensive tests. Sometimes an insurance company may say, “We just won’t pay for that.” But I have not had a problem getting a genomic test at least once for patients.
Is there anything else patients should know about genomics?
Dr. Morgans: Genomics is where we’re going. Being able to predict who will respond to which treatment is our goal. We want to prevent people from being exposed to treatments that aren’t going to help them and stop them from wasting time on therapies that are not going to help them to live longer and better lives.
I would say that, right now, while genomic testing is happening in the clinic, sometimes it takes a patient asking, “Can I have genomic testing on my tissue?” If you are really interested in getting cutting edge prostate cancer treatments, at least understanding which mutations are present in your personal cancer is the place to start.
Dr. Snuffy Myers talks about statins and prostate cancer.
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.
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.
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.
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.
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.
Dr. Laurence Klotz talks about using molecular biomarkers to predict if your prostate cancer is too aggressive for active surveillance.
In March, Prostatepedia is talking about how we’re using (or not using) genomics to guide prostate cancer treatment.
Dr. Snuffy Myers says in his introduction to the issue:
This month, we’re talking about our understanding of the genetic and molecular mechanisms driving prostate cancer. If we can understand how cancer differs from your body’s normal tissues, we can selectively kill cancer while minimizing damage to normal tissue. As it turns out, this type of research is very difficult.
How can genetic changes cause cancer? How do they determine the biology of the resulting cancer?
Genetic information is stored in DNA. The DNA molecule is like a library filled with instructions for a cell to accomplish various tasks. At any one point, only a small set of the instructions are activated and followed.
In normal biology, the instructions activated are appropriate to the task at hand: liver cells activate instructions for liver structure and function; muscle cells activate instructions for muscle structure and function.
Normally, these cells’ growth and spread are tightly controlled. If you remove half a liver, the liver regrows to its normal size and then stops. Cancers cells’ growth and spread are no longer controlled. Liver cancer cells grow and spread beyond the liver and, if untreated, kill the patient.
How does your body read those DNA instructions?
Your body first creates a RNA molecule that is a copy of the instruction. You use this RNA molecule to produce a protein that makes cells change their structure or behavior. Cancer behavior comes from a set of proteins that promotes inappropriate growth and spread. Several mechanisms cause the production of these protein sets.
The DNA instruction set itself can change, or mutate. We can detect these mutations in DNA instruction sets through DNA sequencing.
DNA sequencing technology has advanced rapidly and costs less then $1,000/sample. If you can get a sufficiently large biopsy of your cancer, we can sequence the DNA. Foundation Medicine is the largest commercial firm offering this service today.
Unfortunately, mechanisms not involved in DNA mutation, and therefore not detectable by DNA sequencing, can change that RNA copy. Adding the methyl group to DNA commonly alters RNA copy production and plays an important role in prostate cancer. One approach measures RNA copy production of genes important to prostate cancer biology. Tests like Prolaris and Decipher used in early, organ-confined prostate cancer use this approach.
Another approach measures proteins that control prostate cancer behavior or response to treatment. Caris Life Sciences measures the presence or absence of proteins that determine responsiveness to two major prostate cancer chemotherapy drugs called Taxotere (docetaxel) and Paraplatin (carboplatin).
All of these tests require a biopsy. It is often difficult to biopsy prostate cancer and especially bone metastases.
In advanced prostate cancer, we find cancer DNA in the blood. We can isolate and sequence these cancer DNA fragments to identify mutations in a liquid biopsy.
Guardant Health is the most established company in this area. At my clinic, we’ve used the Guardant360 liquid biopsy extensively to identify hormone-resistance mutations, as well as DNA repair mutations that predict for PARP inhibitor response.
We are only beginning to apply molecular biology to prostate cancer treatment, but the approach has great promise.