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Conversations With Prostate Cancer Experts


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Differences Between Prostate Cancer Genomic Tests

Eric A. Klein, MD, is an international leader in the biology and management of prostate cancer. Dr. Klein serves as Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.

Prostatepedia spoke with him about the differences between the various genomic tests available to prostate cancer patients.

Dr. Eric Klein: These tests measure the expression of genes in prostate cancer. That’s what they’re designed to do. They predict the likelihood of your having higher-grade cancer or cancer that penetrates the rind around the prostate (called extraprostatic extension), or cancer in the lymph nodes or seminal vesicles. These tests predict that better than biopsy or plain old Gleason grading. This gives us a leg up in deciding who is a good candidate for surveillance.

If your biopsy only shows Gleason 6, but you actually have higher-grade cancer in the prostate, or you have some cancer that’s through the rind or in the seminal vesicles, you’re not a good candidate for surveillance. We know that from decades of doing radical prostatectomies. These patients are at highest risk for progression and that’s what these tests measure.

They also tell us whether a pure Gleason 6 cancer is one of the 5-10% that has molecular features of high-grade cancer.

These are biopsy-based tests. For example, if a patient has a biopsy that shows Gleason 6 cancer and otherwise favorable features, such as a PSA below 10, and a PSA density below 0.15, we wonder whether he’s a candidate for surveillance. We always do a confirmatory test after a first biopsy. Decipher can also be used after the prostate has been removed to help decide on the need for additional treatment.

A genomic test like this is appropriate in some patients. An MRI of the prostate is appropriate in others. Sometimes it’s appropriate to get both. We don’t have enough experience to know which is the best test for which scenario, although I have some ideas about that. Then, once we confirm that the patient has a low-grade cancer that lacks molecular features of high-grade cancer, we feel confident in putting him on surveillance.

The results can do two things. They can confirm that the patient is a candidate for surveillance. Sometimes they can convince a reluctant patient that surveillance is the right thing. We don’t want to over-treat people who have low-grade cancers that aren’t going to kill them because the side effects of treatment are worse than the likelihood of his dying of cancer. Sometimes, the results can convince a physician that surveillance is the right thing. If you look at the criteria for putting people on surveillance, it’s mostly patients who have just a minimal amount of cancer–low-grade cancer, a Gleason 6 on a biopsy.

We published a study in the Journal of Urology recently that showed that even among patients with high-volume

Gleason 6 cancer in multiple cores— four or five remove cores—many have no molecular features of high-grade cancer. In the past, they haven’t traditionally been considered good candidates for surveillance, but based on the biology of their tumor, they are good candidates for surveillance.

You may have someone who has a couple of cores of low-grade cancer, maybe a PI-RADS 4 lesion on MRI.

You’re not sure if they’re a good candidate for surveillance or not. If a genomic test confirms the absence of molecular features of high-grade cancer, you can put the patient on surveillance. That is the kind of information that genomic tests provide. They have their nuances.

Oncotype and Decipher are good for patients with very low, low, and favorable intermediate-risk disease. Prolaris is best validated for patients who have intermediate risk disease. It doesn’t have good discriminatory value for low-grade cancers. Generally, they all measure gene expression and they’re all are used in the same way.

These tests help determine whether or not someone is a candidate for surveillance. At the moment, we don’t use these tests based on biopsy to determine which treatment to give a patient, but that’s coming. Post-prostatectomy, Decipher can help tell us that.

There are challenges to active surveillance. Say we put someone on surveillance and he starts out with 1 core of Gleason 6 cancer. A year later, he is re-biopsed and has 3 cores of Gleason 6 cancer. We don’t know whether that’s true biologic progression that requires treatment, if all that Gleason 6 cancer was there in the beginning and was just not sampled by biopsy, or if the patient grew some new Gleason 6 cancer that doesn’t have any biologic potential.

This isn’t established yet, but I believe we can use these tests for what I call serial biologic monitoring, meaning you biopsy patients a year or three apart. These tests, for the very first time, allow us to measure true changes in biology as opposed to just changes in what we see on biopsy, which may underestimate what’s going on in the prostate. This is a new paradigm.

Another common scenario is a man who has a low-grade cancer on initial biopsy (1 core, Gleason 6) and a year later has a little bit of Gleason 3+4 with 5% pattern 4 and 95% pattern 3. In the past, that would always trigger treatment. But it’s my belief, based on what we’ve learned from these tests, that this is probably not correct. Many of those men can still stay on surveillance.

Join us to read the rest of Dr. Klein’s thoughts on genomic tests for prostate cancer.

 


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Dr. Eric Klein: Why Medicine?

Eric A. Klein, MD, is an international leader in the biology and management of prostate cancer. Dr. Klein serves as Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.

Prostatepedia spoke with him about why he became a doctor.

Why did you become a doctor?

Dr. Klein: I don’t really know. I never remember wanting to do anything else.

Even when you were a little kid?

Dr. Klein: When I was in first grade, I missed a month of school because I had what they thought was rheumatic fever. My pediatrician came to see me a couple times a week. That doesn’t happen so much now.

No. It doesn’t.

Dr. Klein: I suspect that’s had some influence because my parents really respected him. But I can’t articulate it for you. I never wanted to do anything else. It was not an intellectual decision. It’s just what I wanted to do. I was born wanting to be a doctor.

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The Genomic Revolution Comes To Prostate Cancer

Dr. Oliver Sartor, the Laborde Professor of Cancer Research in the Medicine and Urology Departments of the Tulane School of Medicine, is one of the leading researchers in advanced prostate cancer today. He is also the editor-in-chief of Clinical Genitourinary Cancer and the author of more than 300 scientific papers.

Dr. Sartor puts this month’s conversations about prostate cancer genomics into context for us.

“We can divide genomics into two different categories. The first category is germline genomics, which is the DNA with which you’re born. It’s clear that about 12% of people with advanced prostate cancer will have alterations in their inherited DNA, in particular in genes involved with DNA repair. Most common of these alterations are BRCA2. There are a variety of others that are somewhat prevalent, including ATM, CHEK2, and BRCA1. There are others that are more rare.

The implications of these germline mutations are significant for the patient: in certain configurations they may predispose a cancer to be sensitive to certain therapies, such as PARP inhibitors or platinum-based chemotherapy or (rarely) immunotherapy. There is more complexity, but knowing the germline mutation helps the informed clinician make decisions. In my practice, we test all patients with advanced prostate cancer for these germline mutations. (A National Comprehensive Cancer Network guideline suggests the same approach.)

These germline mutations represent the DNA with which you’re born. That DNA is going to have repercussions if also mutated in your family members. Men who have some of these DNA repair mutations have an increased risk of prostate cancer. In addition, there is a small increased risk of pancreatic cancer and male breast cancer for those with some of the germline mutations. Around 30% of men with BRCA2 will be diagnosed with prostate cancer in their lifetime, but that cancer is more likely to be aggressive if diagnosed. With regards to females, it’s particularly important. Females with DNA repair defects are more likely to have breast and ovarian cancer. Female with DNA repair mutations, in particular BRCA1/

BRCA2, ought to consider having their breasts or ovaries removed at an appropriate time. Prophylactic surgery has been demonstrated to be potentially life-saving for those individuals. The risk of breast cancer may be as high as 70% and the risk of ovarian cancer may be as high as 40%.

Thus, for these germline mutations there are implications for treatment and implications for the patient’s family.

We should be doing prostate cancer screening earlier in men with these DNA repair defects for prostate cancer; we should be doing biopsies at a PSA of 3 or higher, and perhaps even lower, for younger men known to be at risk. Starting screening at age 45 has been suggested by some. In addition to germline genomics, we need to also talk about somatic genomics. Data indicates that about 60% of individuals who have a DNA repair germline mutation are likely to have another second genetic mutation occur within their tumor. In addition, many of the tumors can acquire an alteration in their tumor DNA even when the germline is normal.

Taken together, about 20 to 25% of men may have DNA repair mutations in their tumor’s DNA. That makes them particularly sensitive to certain therapies such as the PARP inhibitors, as I mentioned earlier, or platinum chemotherapy. When you have two DNA repair mutations in the same cell, the likelihood of response to these agents appears fairly high.

There are also other DNA defects of considerable interest, such as alterations of the mismatch repair genes MSH-2 and MSH-6. When these alterations do occur, there is a potentially increased probability of responding to immunotherapy such as the new PD-1 inhibitors.

Overall, the guiding light today in genetics in my practice is to look at both the germline DNA and the tumor DNA. I choose to look at the tumor DNA circulating free DNA (cfDNA) tests, in particular the Guardant Health assay. The ability of other assays to corroborate the Guardant Health findings is not yet clear. There is clear data to indicate that different assays give different results, but nevertheless, I think in the early exploratory phase we’re in now, it’s important to begin to test patients in order to better understand their genomics and hopefully guide us towards better therapies. This will happen part of the time but certainly not all of the time.

There is more to the story of prostate cancer genetics. We’ve looked at androgen receptor mutations that can have implications for a response to Androgen Receptor directed therapy, such as Xtandi (enzalutamide), Zytiga (abiraterone), and Erleada (apalutamide). We’re dissecting a number of permutations that occur. It’s a complex scenario, because very few men have only one mutation. Most have multiple mutations. And in most cases, these mutations are not targetable with current therapies. This is very important for people to know.

Everybody thinks if they get a genomics test that means they’ve got a treatment. It’s not the case. Many times we get the genomics results and find that there are no known treatments we can use for that man’s particular alteration. That said, there is a subset of men who will have informative genomics while many more people will have non-informative genomics.

There is a final issue I’d like to discuss. There is currently a bit of a debate amongst physicians over the utility of PARP inhibitors such as Lynparza (olaparib) as compared to platinum chemotherapy. But it is noteworthy that platinum-based chemotherapies are inexpensive compared to PARP inhibitors. This does not require a clinical trial. (Most men will access PARP inhibitors through a clinical trial, although sometimes insurance companies are willing to try.)

As it turns out, neither the platinum-based chemotherapies nor the PARP inhibitors will be effective forever, so we do need strategies to manage patients after PARP inhibitors or platinum-based chemotherapies fail. Currently, that space is unexplored. We have to gather much more data before we can make conclusions about those with underlying DNA repair defects who have failed platinum-based chemotherapy or PARP inhibitors.

This is an area of active and important investigation that represents a conundrum for many patients today. I’ve got a patient right now going through this. We’re debating what to do next. I’ve tried to be as honest as I can when I say, “I don’t know what to do, but we’ve got to try something.”

We are in the middle of a revolution, but the parts and pieces are not yet clear. For some, understanding tumor genetics at the current level is helpful. For others, it is perplexing and expensive.

Join us to read this month’s conversations about prostate cancer genomics.

(Already a member? You can read all conversations in your copy of April’s Prostatepedia.)


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Meditation + Active Surveillance

Dr. David E. Victorson is a clinical psychologist and Associate Professor at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois.

Prostatepedia spoke with him about a trial he’s running on mindfulness meditation and active surveillance for prostate cancer.

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Why did you become a clinical psychologist? How did you end up working with cancer patients?

Dr. David E. Victorson: My training was in clinical health psychology and behavioral medicine. A lot of my early training experiences were in cancer, and in some of those, I had the opportunity to work with men with prostate cancer and their spouses in a clinical capacity.

The reasons why I went into this area are multifaceted, but I would say one of the primary reasons is that there is so much that we can do with our own behaviors and lifestyle practices. There is so much good that we can do for our own health by ourselves without needing any heavy equipment or extreme intervention. A lot of times, it just takes a little nudge in a different direction to get people going on a path that will be incrementally better for them.

How do you usually work with patients?

Dr. Victorson: I don’t work with patients in a clinical therapeutic capacity today. I do 100% research. In 85-95% of our research studies, however, we deliver psychosocial and behavioral clinical interventions. Sometimes you might call them self-management interventions. A lot of them are prostate cancer-focused.

Usually, we involve spouses. We help men and their spouses learn skills that can support their health and well-being in different ways.

Most of those studies are group-based, bringing groups of men and their spouses together for classroom skills.

I’m sure that the skills you teach are useful beyond a cancer diagnosis.

Dr. Victorson: They are. A lot of the things we do are applicable across a whole range of different diseases and conditions. People who don’t have a disease can still benefit. But when you get a prostate cancer diagnosis, modifiable health behavior comes into the picture quickly in terms of diet and exercise.

What we’re trying to do with our meditation study is along the lines of mood management, which can be really important in the context of cancer. There’s nothing like a cancer diagnosis to motivate a person to make that kind of lifestyle change. I’ve heard that before, especially when it comes to exercise and prostate cancer.

Dr. Rob Newton told me that cancer patients tend to be more motivated than cardiovascular disease patients, for example. (See Prostatepedia December 2017.)

Dr. Victorson: Right.

What will you be doing in this particular trial? Why mindfulness education in an active surveillance population?

Dr. Victorson: We are comparing our eight-week mindfulness intervention with a matched attention control program. We anticipate that the attention control program is also going to lead to positive health changes, but we hypothesize it will be different than the mindfulness program.

This is a blinded trial, and men and their partners won’t know what group they’ll be put into outside of the fact that it’s a health promotion intervention. This can be challenging for recruitment when you don’t know what you’re signing up for.

All the men will know is that we are testing two different health promotion and wellness interventions that have been shown to be good for men with prostate cancer. That’s about as far as we go.

Most people who sign up really like it, but they don’t even know that they’re signing up for a mindfulness intervention. We’re not trying to deceive anyone, but we need it to be blinded like this to increase the rigor of our results.

Why mindfulness? As we’re doing a better job of prostate cancer screening, we’re finding more indolent or lower grade prostate cancers. Many of these cancers don’t need to be surgically removed or radiated. Active surveillance is becoming a more possible management paradigm. We know that trend is only going to continue.

Many patients are happy with active surveillance. But there are others who, because of how they grew up or because of what cancer means to them, equate cancer with death. When they’re told they have a tumor, they just want it out.

We’re dealing a specific demographic. Older men might be used to the idea of just wanting to get the situation fixed. That’s how they may cope. We’re also dealing with a treatment culture in which active surveillance hasn’t totally caught on. There are still quite a few urologists who recommend what they were trained to recommend: surgery or radiation even for a very low-grade tumor.

There is a certain type of man who will leave active surveillance after one to three years for definitive therapy even when it may not be medically warranted. This shift may be more connected to them wanting peace of mind and just wanting the cancer out.

I always try to say to patients, “If that’s what it’s going to take for you to get peace of mind, more power to you. You know better than me. I don’t have prostate cancer.” But at the same time, as a health psychologist involved in behavioral medicine, I know that there are other ways to help men manage their anxiety than through surgery.

Therefore, we’re exploring which behavioral approaches can be delivered to keep men on active surveillance longer when it is medically warranted. If their physicians say that they can stay on active surveillance longer, we try to support that. You’re hoping that with mindfulness meditation you’ll be able to help men stay on active surveillance longer.

Could mindfulness ultimately be a routine part of active surveillance programs?

Dr. Victorson: Yes. That is the 30-year career goal. We’re not going to be able to answer that question from this five-year trial, though. One of the biggest indicators of peace-of-mind-related departure from active surveillance is uncertainty intolerance and fear of progression. Those two things can form a powerful cocktail that might drive a man to leave active surveillance prematurely. Some men are able to tolerate uncertainty and fear of progression more than others.

We know that mindfulness training can be very useful in helping someone learn to tolerate uncertainty to a greater extent. We can help build that muscle, if you will, in tolerating uncertainties and with sitting with the discomfort of not having your tumor taken out. We are looking at mindfulness training to help reduce fear of progression and increase tolerance to uncertainty. We think those are two important mechanisms toward this goal.

The psycho-educational health promotion group of men and their partners will learn how to integrate positive health behaviors into their lifestyles—things like eating more vegetables, getting more physical activity, and being more aware of their patterns and behaviors. The program doesn’t have anything to do with mindfulness, regulating emotion, or tolerating uncertainty.

Learn more about Dr. Victorson’s clinical trial.