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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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Genomics + Personal Medicine For Prostate Cancer

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer.

His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about how genomics is personalizing medicine for patients.

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How is genomics changing how doctors decide who needs treatment for prostate cancer and who doesn’t?

Dr. Felix Feng: Our field is in an exciting time in terms of advances in genomics and prostate cancer. For the vast majority of the past few decades, prostate cancer treatment has been selected and optimized outside of genomics. We’ve had a number of breakthroughs in the last few years that have suggested that a large part of prostate cancer treatment in the future may rely on genomics.

The most important example of this is the use of PARP inhibitors in men with prostate cancer that have DNA repair alterations, and most commonly, alterations in the genes BRCA1, BRCA2, and ATM. Including this example, we have three examples in the context of metastatic prostate cancer where genomics is actively being used to personalize therapy.

A study from Dr. Johann de Bono’s group at the Royal Marsden in the United Kingdom first demonstrated that patients who have DNA repair alterations have responded particularly well to the PARP inhibitor Lynparza (olaparib). In a follow-up study, which was run out of the University of Michigan, Drs. Maha Hussain, Arul Chinnaiyan, and I confirmed these findings in the context of a randomized trial. It’s clear that using PARP inhibitors for patients with DNA repair alterations is one example of using genomics for personalized medicine. There are a number of different companies now exploring a variety of trials trying to get PARP inhibitors FDA approved as a therapy for patients with metastatic castration-resistant prostate cancers.

A study reported by Dr. Johann de Bono at the European Society for Medical Oncology Conference about two years ago demonstrated that patients with prostate cancers in which a gene called PTEN is inactivated responded well in a randomized trial to an AKT inhibitor. That is now being evaluated in a Phase III trial.

Another use of genomics to advance medicine is in cancers with alternations in a class of genes called mismatch repair genes, which have been shown to confer sensitivity to various immunotherapies. That represents an approved syndication across all cancers, not just prostate cancer.

In the localized prostate cancer setting, there are two genomic classifiers based on RNA expression that help identify patients with low-risk prostate cancer who are more likely to progress to more aggressive disease. This may be used to determine which patients should be followed with active surveillance. The two classifiers that are most commonly utilized in this setting are Oncotype DX by Genomic Health and Prolaris by Myriad.

In the context of higher risk patients treated with surgery, there’s a classifier called Decipher made by GenomeDX Biosciences. That has been shown across very large numbers of patients to be a prognostic of metastatic progression after radical prostatectomy. Already, that classifier has been incorporated into ongoing clinical trials to select which patients with aggressive disease should be candidates for treatment intensification.

Can genomic classifiers be used to select specific patients for specific therapies?

Dr. Feng: My team has helped develop two of the first clinical grade classifiers predictive of their responses to specific therapies. One is a biomarker panel called PORTOS, which stands for Post- Operative Radiation Therapy Outcomes Score, and may be useful in predicting response to post-operative radiation therapy—those treated with radiation therapy after radical prostatectomy. PORTOS predicts specifically which men will benefit from radiation therapy. We validated its performance in a manuscript published in Lancet Oncology two years ago.

More recently, we’ve applied a genomic classifier utilized in breast cancer to prostate cancer. It’s called PAM50 and is used to determine which women with breast cancer should get hormone therapy after surgery. It turns out that these molecular subtypes of breast cancer also exist in prostate cancer. Specifically, we found that there are luminal A, luminal B, and basal subtypes of prostate cancer.

When we look at which patients are most likely to hormone therapy, our initial data suggests that it’s the luminal B patients who have the most aggressive disease and who also benefit from hormone therapy. We did all of these studies in large retrospective cohorts, but because we wanted to validate this prospectively, we are about to initiate a trial in the context of a national clinical trial called NRGGU006, run by the NRG Oncology Clinical Trials Group.

With NRG-GU006, we stratify patients by their PAM50 molecular subtype. These are patients who have been treated with radical prostatectomy and have had biochemical PSA recurrence.

These patients are stratified by PAM50 status, and then they are randomized to standard therapy—which is salvage radiation alone—or salvage radiation plus short-course Erleada (apalutamide), which is a next generation anti-androgen.

From all of these examples, you can see that, across different contexts— from active surveillance to the more aggressive, locally advanced prostate cancer to metastatic prostate cancer, there are now a number of strategies that use genomics to personalize medicine.

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Dr. Felix Feng: Why I Became A Doctor

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer. His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about why he became a doctor who cares for men with prostate cancer.

Why did you become a doctor?

Dr. Felix Feng: I became a doctor because my family has a strong history of cancer. Unfortunately, I learned the repercussions of cancer at an early age. All four of my grandparents passed away from some form of cancer. My father has successfully overcome three different cancers. Just last year, my sister, unfortunately, passed away in her 40s from cancer.

Before ever becoming a doctor, I was part of many patients’ families. I saw it strongly from the patient side and decided that if I was going to commit my life to studying something, it was going to be cancer.

So then your journey is really personal.

Dr. Feng: Very personal.

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Genetic Testing + Counseling

Ms. Merel Nissenberg is the President of the National Alliance of State Prostate Cancer Coalitions, a nation-wide organization comprised of state prostate cancer coalitions dedicated to saving men’s lives and enhancing the quality of life of prostate cancer patients and their families through awareness, education, and the development of a public policy network.

She talks to Prostatepedia about guidelines for genetic testing in men with prostate cancer.

Much has been written or suggested about the genetic component of some prostate cancers. For example, a family history of prostate cancer can increase a man’s risk of such a diagnosis. There have also been articles about the genetic component of certain breast cancers: BRCA1 and BRCA2 have historically been strongly implicated in the familial pathway for that diagnosis. What is more recent is the now more-firmly established connection between certain mutations like BRCA1 and BRCA2 and prostate cancer. However, guidelines for genetic testing in men with prostate cancer have been limited.

Recently, the Journal of Clinical Oncology published a special article entitled “Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017” following the Prostate Cancer Consensus Conference held in Philadelphia on March 3-4, 2017. Members of the panel strongly agreed that men should engage in shared or informed decision-making on the issue of genetic testing.

Panel members emphasized the strength of the inherited predisposition of prostate cancer, noting higher risks with BRCA1, BRCA2, and HOXB13 genes. The panel noted that prostate cancer patients with BRCA2 mutations have poor prostate cancer-specific outcomes. We now consider the link between prostate cancer and DNA mismatch repair (MMR) gene mutations to be stronger than we suspected, adding a specific opportunity for treatment. In fact, up to 12% of men with metastatic prostate cancer have inherited genetic mutations, mostly with BRCA1, BRCA2, and ATM. And targeted agents for these specific mutations confer better outcomes for these patients.

The panel concluded that: “Identifying genetic mutations of inherited prostate cancer… has implications for cancer risk assessment for men and their families, for precision treatment of metastatic disease, and is being incorporated into guidelines for individualizing prostate cancer screening strategies specifically for male BRCA1 and BRCA2 mutation carriers.”

Unfortunately there are no generally accepted standard guidelines for genetic counseling and genetic testing in prostate cancer, or standards on how to fully interpret results of current panels with multiple gene testing. The information discovered through genetic testing not only informs treatment for the prostate cancer patient himself, but is also an aid to other members of his family, including women who may have a genetic disposition for developing breast cancer. As for the patient, not only does the information potentially help guide prostate cancer treatment, but it also makes both him and his clinician aware of the potential for additional cancers.

The results of the Philadelphia Prostate Cancer Consensus Conference can be read in detail in the Journal of Clinical Oncology 36, no. 4 (February 2018), 414-424. Their considerations included the following:

  • which men should undergo genetic testing for prostate cancer;
  • which genes should be tested based upon clinical or family scenarios;
  • how the testing results should be used to inform screening for prostate cancer; and
  • how results should be used to inform treatment of early stage (localized), advanced stage (high-risk), and metastatic prostate cancer. Genetic testing done thoroughly and properly can help guide screening and treatment decisions.

The National Alliance of State Prostate Cancer Coalitions strongly endorses the use of genetic testing and genetic counseling for prostate cancer, and urges clinicians to read, consider, and follow the scientifically sound suggestions of the 2017 Philadelphia Prostate Cancer Consensus Statement on the Role of Inherited Prostate Cancer Risk. NASPCC will be presenting a Webinar on Genetic Testing and Genetic Counseling in Prostate Cancer on May 9, 2018. It is supported by Myriad Genetics. (Visit https://naspcc.org/index.php/may-9-2018-naspccwebinar to register.)


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Patients Help Shape Prostate Cancer Genomics Study

Joel Nowak is a prostate cancer patient and well-known prostate cancer activist.

Prostatepedia spoke with him about his involvement with the Metastatic Prostate Cancer Project.

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What is the Metastatic Prostate Cancer Project?

Mr. Nowak: This is a joint project between the Broad Institute and the Dana-Farber Cancer Institute. But what is really more important to me is the researchers who are involved: Dr. Corrie Painter and Dr. Eliezer Van Allen are really committed to what they’re doing. They’ve modeled this project off of a metastatic breast cancer project that they also started.

One of the researchers is a cancer survivor, so they understand what it means to have cancer. Their understanding motivates what they’re doing. They’re carrying it forward; they’re not just doing it because they have a grant.

How did you come onboard with the Metastatic Prostate Cancer Project?

Mr. Nowak: My friend Jack Whelan, who I’d worked with at the American Association of Cancer Research Scientist↔Survivor Program, had a very rare blood cancer. Then one day he surprised me by saying he’d been diagnosed with prostate cancer. I thought he was joking at first.

Unfortunately, his cancer progressed really quickly, probably related to all the treatments he had for his blood cancer. The project staff brought me, Jack, and Jan Manarite in to work on the project. They asked me to look at their materials and give a patient’s perspective. They wanted to know if I found value in the project

They asked me to give them specific feedback and suggestions for improvement. Jack, Jan, and I have also brought in two others. Dr. Van Allen’s team has taken all of our suggestions and made the changes.

They also asked us to spread the word, let people know about it, reach out within the prostate cancer community, and help recruit.

What is it about the project that makes it patient-friendly?

Mr. Nowak: The project is patient friendly because once someone consents and says, “Count me in,” the project team does all the work. They send out a package, which we advocates helped redesign, and you just contribute your spit. Then you bring your sample back to the post office or FedEx; it’s all prepaid. Spit it and ship it. That’s the effort.

We also send out blood vials that are also prepaid. Theoretically, you can walk into a lab and they’ll draw your blood for free. Or you can bring the vials to your next doctor’s appointment. You don’t even have to make a special appointment; just ask them to draw an extra tube.

It’s easy.

Mr. Nowak: Yes. It’s easy, and it’s all prepackaged. Either you or the phlebotomist can just put it into the prepaid package and send it off. You don’t have to do much.

Part of the consenting process is the release of the medical records. The project does the sequencing of the blood and saliva, and if applicable, we ask for tissue. There’s not a lot of tissue in prostate cancer, generally, so that was one of the issues I brought up. I wanted to ensure that no one’s tissue is used up and withheld from them for the purposes of this research, because you never know when we’ll need your own tissue for treatment decisions. We advocates said this was a big issue, so the project will only use a small piece and return it. You need to get it back: you just never know when you’ll need it yourself.

You need to look out for yourself.

Mr. Nowak: Yes. It’s appropriate to be selfish in this particular situation. The only thing you have to do as a patient is read the consent, discuss it with the appropriate people at the project, sign the paperwork, spit, and bleed. That’s all we have to do. Everything else is handled by the project. You don’t even know it’s happening; it’s all behind the scenes.

This is a research project, not a clinical trial, but even with clinical trials everything gets de-identified. That means that your personal information is safe, but you also get no follow-up information. As a patient advocate, I asked what they could do to give some feedback to patients. They were very open to having this conversation, but they are sensitive about overpromising anything. We don’t want to mislead anyone.

If we start seeing trends in the data, we will give some feedback. We can’t tell individuals that they have gene mutations or not, for example, because their sample was de-identified. But if, hypothetically, we see samples from 300 people with a combination of at least three gene mutations and that 285 people with a particular mutational sequence respond to Xtandi (enzalutamide) but not to Zytiga (abiraterone), then we will give feedback.

But this is exciting. When we start seeing trends or possible trends, the project will release information to people who participate. There will be aggregate data feedback. We’ll be able to publish relationships. It doesn’t of course stop me as a patient from going to my doctor and getting sequenced. Probably all of us should be sequenced anyway.

The patient can follow up as he chooses…

Mr. Nowak: Exactly. Then they could say, “I’ve been sequenced, and I have this mutation.” That is just an additional talking point with your doctor from the aggregate data. I’m excited about that. That’s going to give some people another thing to consider when deciding between treatments.

Why should men participate? Did you participate?

Mr. Nowak: I did. Jack and I fought over who would be Patient 1. I had respect for Jack, so I told him he could be Patient 0, and I’d be Patient 1. Technically, I’m Patient 2. Men should participate for a number of reasons. First of all, we have to think about the next generation. My prostate cancer is genetically linked. My father had it. His brother died from it, and his only child, who’s older than I, who had been treated. My grandfather had prostate and breast cancers, and my great-grandfather died of prostate problems. Many of us have or are going to have kids, so we should make it a little better for them if we can.

I spend a lot of time working with people and helping them figure out how to have a conversation with their doctor about treatment. Anything that can give us more information and more points of conversation is important. Aggregate data might help us have better conversations that may help make better decisions going forward.

This is one of those rare research projects where I could possibly benefit directly. As I start going through treatment protocols and so forth, I have no idea where they may find something that works better for me. It’s just going to guide my decision-making. Maybe it’ll extend my life because I made a better decision thanks to the project.

We also need to understand cancer more generally in terms of genetics and its microenvironments. We need to understand cancer not only as separate diseases. Prostate cancer only describes the organ from which the cancer originates. It doesn’t really describe my disease or another’s. We need to drill down and understand the type of prostate cancer that one has and how it relates to cancer generally. That is going to guide us in making better decisions.

This type of research is invaluable. There are no risks. There is nothing invasive. The more we understand, the better future research will be, whether for specific treatments or a better understanding of biomarkers, which we have a terrible dearth of knowledge about. To me, it’s a no-brainer for us who are going to benefit at no cost.

I hope men sign up.

Mr. Nowak: Yes. That’s our goal. Now that we have IRB (Internal Review Board) approval, our next step is to get men signed up.

To participate visit https://mpcproject.org/home

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The Making of A Cancer Activist

Joel Nowak is a prostate cancer patient and well-known cancer activist.

Tell us about your own prostate cancer journey and how you came to cancer activism.

Mr. Joel Nowak: Part of my journey to being an advocate pertains not only to having prostate cancer and recurrence but also to the fact that I had multiple primary cancers. I currently have five different primary cancer diagnoses.

I was treated initially for prostate cancer at the end of 2001. I had a Gleason 3 + 4 with a PSA of only 4. I had surgery. I went back in five years and my PSA went crazy, up into the 80s.

At that point, it was a recurrence. We did a bunch of scans. We identified a couple of lymph nodes in the prostate bed, as well as a very significant and large tumor in my kidney. At that moment, the assumption was that I had a prostate cancer tumor in the kidney and that the kidney had stopped functioning and was basically dead. I had a nephrectomy, which is the removal of the kidney. We found out that it was a different diagnosis: clear cell renal cancer.

Looking back, I see that prostate cancer recurrence saved my life because that’s how I found out that I had renal cancer. If it weren’t for my prostate cancer recurring, I would not be here today.

I was in my early 50s, so I was fairly young at the time. I knew I was metastatic with prostate cancer and had been diagnosed with another primary cancer. Knowing that I was metastatic weighed very heavily on me. There was no way to use that C-word—cure—which I don’t like to use. I looked desperately for people in a similar situation. I refer to it as looking like me, but I don’t mean physically. I mean people in their 50s, with a kid in high school, a kid in college, and metastatic prostate cancer that was incurable and possibly terminal.

I found myself becoming angrier and angrier.

Not only did I have metastatic cancer, but also I felt very alone in the sense that I couldn’t find anybody in a similar situation. I went from one cancer support group to another. Though I lived in metropolitan New York where there are options, I still could never find anybody I could relate to directly, someone with a similar experience. I found plenty of older men who were worried about whether or not they would make it to their grandchild’s wedding and things like that, but for me, that had no relevance. I became more isolated, lonelier, and angry.

One night, I was inappropriate with the group leader of one support group. I was overly aggressive and blamed that person for what I perceived as my situation. Instead of reacting to my aggression, the person just sat back in their chair, looked at me, and said, “Why don’t you do something about it?” I went home and discussed it with my wife who tried to stabilize me. “Why don’t you,” she said. I got angrier at first and just stewed for a while.

It has been 10 years, but when I went to bed that night I thought I was going to die within a few years. It’s common for many men with recurrence or metastatic cancer to wonder if they’re going to die in a year or two. I felt terrible and angry. I’m not really an angry person, but I had become a very hostile person.

When I woke up the next morning, I decided that I didn’t want to live my life feeling that way. I was going to find a way to let go of that anger and do something about it. That’s how I got involved with activism.

You decided to channel all the fear, anger, and anxiety into something positive.

Mr. Nowak: Yes. I think that’s what it was. I’m not saying that I still don’t have moments; I do. And since then, I’ve had two additional primary cancer diagnoses. One of them was a rare cancer. But the prostate cancer was the only one that caused that kind of emotional response, probably because that is the only one, so far, that is metastatic.

I spend a lot of time with prostate cancer, but I also work with other cancers—metastatic, advanced, and progressed prostate cancer.

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