Paul Mathew, MD, a Genitourinary Oncologist at Tufts Medical Center in Boston, talks about using genomic profiling to find better treatment plans for those with prostate cancer.
Interview conducted by Ivanhoe Broadcast News in August 2019.
How are most prostate cancers diagnosed?
MATHEW: In the United States, most prostate cancers are diagnosed by screening. In other words, men receive a PSA test and/or a digital rectal examination to examine the prostate gland, usually in the primary care physician’s office. This is what leads to the diagnosis. An elevated PSA will prompt a referral to a urologist, a surgeon who will then perform a biopsy, which is when the diagnosis is formally rendered.
What is the traditional path for prostate cancer being diagnosed?
MATHEW: The treatment of all cancers is stage and risk adapted. So, the first effort of the oncologist is to determine the stage and risk category of the cancer. And that will determine the treatment. If you have a localized form of prostate cancer, it’s potentially curable – but not all localized prostate cancers require a cure. In other words, you may be very low-risk and the cancer could be safely left alone. We may choose to simply watch and wait or monitor the progress of such a cancer over time rather than intervene. When intervention is judged to be necessary, the major tools are surgical, or radiation based. The most common interventions are radical prostatectomy – nowadays, they are being done by laparoscopic and robotic approaches – or external beam radiation therapy.
At what point is genetic testing appropriate?
MATHEW: It’s important to understand what you mean by genetic testing because in one sense it refers to whether this patient has inherited a risk for prostate cancer. That refers to testing the “germ line,” meaning what you’re born with. In another context, genomics of the tumor that has now been diagnosed may be of value clinically. Those are two different things.
What kind of screening for that type of cancer is available?
MATHEW: There are currently some specific contexts in which the genomics of the tumor can be valuable to the managing clinician. I did mention that in low-risk cancers, the choice might be to simply watch a patient if the risk is judged to be low. However, it isn’t always obvious under the microscope whether this is indeed a low-risk cancer. Some additional tools may be valuable in stratifying that risk further. One such set of these tools are tests that analyze expression levels of sets of genes in tumors in order to provide a refined estimate of the risk of this cancer beyond what is apparent under the microscope. This can add to the decision-making process between the patient and the physician on whether such a cancer can be left alone. For example, something that looks like a low-risk cancer under the microscope but has a high and adverse score on these genomic studies might shift the management decision towards treatment rather than observation. Another context has to do with much more advanced disease. When the tumor is beyond cure and the efforts are to control it, there’s emerging knowledge on how the genomics of such a tumor might deliver novel approaches to treating the cancer beyond beyond the current standard of care.
How new is genomic testing for these advanced cancers?
MATHEW: We have seen the early iterations of genomic testing of these tumors that are delivering ideas about novel investigational therapies for a good number of patients. I cannot say in prostate cancer, for example, that more than a minority will have an FDA-approved therapy matched to a genomic lesion. We have not yet reached that stage. The standard of care in advanced prostate cancer has long been hormone therapy and there have been several advances with newer and more effective hormone therapies that are now available; but there are other treatments that can add to disease control, such as a vaccine, chemotherapy and a bone-homing radio isotope. All of these treatments have been developed without reference to tumor genomic studies. Things are changing now. Genomic tests that detect defective DNA repair mechanisms in tumors or specific druggable pathways related to loss of what are called tumor suppressor genes may bring new treatment strategies in advanced disease in the near future. Furthermore, there are rare forms of tumors that have what are called high-mutation burdens, i.e. tumors loaded up with mutations. They can be recognized by the body’s immune system as foreign. By using a new class of immunotherapeutic agents called immune checkpoint inhibitors, you can treat such tumors. So, genomic testing allows us to identify that relatively small group of tumors in prostate cancer that have that signature.
Who do you offer this testing to?
MATHEW: Right now, for advanced disease, we don’t have any tools to decide between one patient and the next, why one person has a higher probability of finding one of those mutations that we can do something about, versus not. We must decide that we’re going to test everyone that we can, or not. Right now, we don’t have a stratified approach towards that decision.
Do you try to test your advanced cancer patients?
MATHEW: The guidelines reflect the uncertainty of just how many patients this is going to benefit. Some of the defects that we are identifying on genomic testing are still under investigation in relevant clinical trials. This is partly why there’s some hesitancy in a categorical endorsement of this for everybody. Patients shouldn’t be under the assumption that just by testing the tumor they’re going to get that magic bullet that’s going to change everything. There’s a chance that you could find something that could make a difference. Science needs to progress much more before we can say that’s most of our patients. My personal approach is to consider it in every patient with advanced disease, particularly those in whom hormonal treatments are not controlling the disease.
Why did you do this testing in John?
MATHEW: John was a young man who didn’t have a particularly high PSA and he had advanced disease locally. The tumor was very large in his prostate and had already spread to lymph nodes in the abdomen. We tried combination therapies with hormone therapy and chemotherapy which his tumor very quickly became resistant to within a matter of weeks to a few months. We took him to surgery, got his large prostate out because we thought this was where the large burden of the disease was, but his metastatic disease came back quickly. At this point, we did the studies on his tumor anticipating his life was in danger and looking for an opportunity to change the paradigm with his treatment beyond what we’d already done.
Could you walk me in layman’s terms through what doctors are looking for at that point?
MATHEW: We’re looking for a wide variety of possibilities. There are two main categories of lesions that I know I can do something about, because I have therapeutic agents at hand, even though they are not yet FDA approved. I can look for that opportunity to treat the patient outside of a trial. There are defects in DNA damage repair involving something called double-strand break in the DNA. There are different types of damage that our DNA can suffer. One type is called double-strand, meaning our DNA has two strands. When that is affected, there’s a class of drugs called PARP inhibitors. Those drugs are currently under investigation but could make a difference based on published data in patients whose tumors have this defect. So, that’s one class. That frequency has been estimated in an advanced prostate cancer around 20-25%. That’s not a small number, but that is not FDA approved, and you won’t find it in the guidelines quite yet. The second group of tumors which are much less common are those that have a high-mutation burden from DNA mismatch repair, but that frequency is much lower at 2-3%. In John’s case, he had a very rare mutation found in perhaps 0.1% of all prostate cancers. This was a DNA proofreading enzyme that was defective. As a copy editor in a newspaper must check for errors, so, too, this enzyme must check the DNA and make sure there’s no errors. If that enzyme is mutated, the tumor can accumulate hordes of mutations. This is exactly what John’s tumor had. What that meant was this hyper-mutated tumor was likely to be vulnerable to a new class of anti-cancer therapy that had just emerged in recent years called immune checkpoint inhibitors. I was able to obtain such an immune checkpoint inhibitor for him. It is not yet FDA approved for his indication and he’s been on it for the last three years and he is now in a complete remission.
What stage was he, how much time did he have, and what other options did he have?
MATHEW: He had metastatic disease – Stage 4. After the hormone therapy and chemotherapy had failed, there was little else credible to control his disease. His life was in danger. I would have estimated the life expectancy under a year, if not six months with the natural progression of such an aggressive disease. It became clear that the immune checkpoint inhibitor treatment was working extraordinarily well for his disease with the first set of re-staging studies; it had essentially, regressed dramatically. And, he’s off all hormonal treatment now. He has normal testosterone and virtually no side effects from the treatment. He did have some minor drop in his blood sugar, but we just gave him a touch of prednisone to bolster the function of his adrenal gland to replace that function. He’s done remarkably well.
Are you looking at that advanced, aggressive cancer where nothing is working, and there might be some answers here?
MATHEW: We’re in that inflection where many oncologists can guess where things are going to go. Nobody is cured with hormonal therapy, but some patients have very long responses, lasting many years. So perhaps where they sense the advanced hormonal therapies are not working, that might be an opportunity to look for profiling such a tumor. And admittedly, even though the FDA-approved therapies in existence to match with that are few, nevertheless, there may be opportunities for investigational studies because they may list a genomic alteration that is matched with an investigational trial. The vendors that offer these studies will often issue a report that matches the identified mutation or mutations with classes of therapy or investigational therapy that might be available. It can trigger the physician to refer the patient for such an investigational trial. That could be an additional value.
Is there anything I didn’t ask you about genetic profiling that you would want to make sure our viewers understand?
MATHEW: I’m going to come back to the idea of genetics. John for example, had a father with prostate cancer, two siblings with prostate cancer, and a sister who died early of breast cancer. So, he had a powerful family history of cancer. It suggested that he may have an inherited risk for cancer development. That’s something important for your viewers to know is that a patient diagnosed with prostate cancer may be carrying an inherited risk. Sometimes that knowledge influences the treatment of that individual patient using for example, the PARP inhibitor strategy for patients who have inherited a mutant BRCA-1 or the BRCA-2. That strategy is well-established for ovarian and breast cancer and is likely to emerge for prostate cancer soon. It’s been estimated that men who have metastatic disease at diagnosis, the prevalence of these inherited germline mutations runs around 12%. For patients who have high-risk, localized prostate cancer, that runs about 6 to 7%. If they have low to intermediate risk, that runs lower at about 2%. So, there are some other triggers. If you have a family history of prostate cancer, father or brother particularly under the age of 60 or someone in your family died of prostate cancer, or maybe a sister has been diagnosed with ovarian cancer and knows that she’s BRCA-1 or 2 mutant. There is a type of prostate cancer under the microscope called intraductal carcinoma that we know may be associated with inherited forms of prostate cancer. Referral to a clinical genetics expert armed based on the risk profile of a patient is a good idea to consider even if they have localized disease. Now, we’re thinking that all men who are diagnosed with metastatic disease or localized high-risk disease should consider a clinical genetics referral and a discussion as to whether they should be tested for an inherited risk for cancer susceptibility gene such as BRCA-1 or 2.
How is John now?
MATHEW: He is fit as a fiddle. He works out regularly. He works. He has no symptoms of his cancer and no side effects of his treatment. He’s very fortunate. The dilemma that we have now is, is he cured or not? Should we continue his treatment? If so, for how long and at what frequency? We have these discussions between us and the clinic. I emphasize the uncertainty of the situation. There are no markers for me to specifically assure him that he’s cured such that if we stop the immunotherapy, there would be no prejudice to him. We have sort of decided together to reduce the frequency, not abandon it altogether, but do it every three months for the foreseeable future. How long we will do this is unclear. We will probably stumble into that decision together at some point.
At some point, do these inhibitors stop working? And if so, is there a next step on the horizon for John?
MATHEW: Most of the experience with this class of drug in cancer in general has been that if you attain a complete remission, the chances are it’s going to last a long time, if not forever. It’s rare for someone to have a prolonged complete remission as much as he’s had for a relapse to be observed if the therapy has stopped. So based on precedent, he’s in good shape. Is that precedent enough for us? In prostate cancer, his case is a very well-documented outlier in the literature, so there isn’t any precedent to refer to and say here’s what someone else did and had the same mutation as you did in prostate cancer. He’s sort of ahead of the pack in that sense. For that reason, it’s hard to change what’s working well.
The immune checkpoint inhibitor that he is on is not FDA approved for prostate cancer? Are they for other types of cancer?
MATHEW: Let me be very clear on the approval. It’s not approved for his particular mutation, the polymerase eta mutation. But there is another form of DNA damage repair defect called mismatch repair deficiency. It’s associated with a phenomenon called microsatellite instability. That group of tumors has received blanket approval for immune checkpoint inhibitor therapy across all tumor types, so it includes prostate cancer. So, it is available and is FDA approved for that indication. I think the FDA should approve it for this indication too i.e. polymerase eta mutated tumors with high-mutation burdens.
I always ask how long it could take, and doctors throw up their hands and say, it’s the FDA…
MATHEW: I think the rationale is quite strong. Maybe because it’s more rare, it hasn’t reached their attention as much, but it probably should. So maybe if somebody is listening, they should take some action.
Is there anything you’d like to add?
MATHEW: If you’ve been diagnosed with prostate cancer, it’s important to understand it’s a frightening and unsettling situation, but try to take the time to educate yourself about the illness. Try to form a partnership with a physician who helps educate you and communicates well and understands your fears and anxieties and worries about the future, assists you with second opinions if needed to clarify your understanding and to help you make good decisions. Don’t rush into a decision unless, of course, it’s an urgent situation as delays in treatment for weeks and months can be harmful. If you’ve been diagnosed with localized prostate cancer through a PSA screening test, you usually have some time to make a very good decision in consultation with a broad range of doctors who are involved in the multidisciplinary care of prostate cancer.
And just because we have viewers all over the country and large cities and small towns, when you hear a term like clinical geneticist, is this something they would have to travel for, could they find this kind of comprehensive care in larger cities, or is it pretty much across the board?
MATHEW: Access to clinical geneticists for pre-test counselling can be challenging in certain locations. In such a situation, the physician might choose independently to send a specimen for testing. I’m talking about a germline testing and then refer afterwards. That is not an approach I prefer, but sometimes circumstances are such that it can be difficult for a physician. Every physician should learn how to counsel patients on the implications of genetic testing. It can cause a lot of fear and anxiety about the impact on, for example, health insurance or life insurance and so forth. So, those are the questions that people would have in their mind. That’s why clinical geneticists play such an important role. It would be my preference if they could get access to a clinical geneticist to use even if it meant some travel.
END OF INTERVIEW
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