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Conversations With Prostate Cancer Experts


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Prostate Cancer Dormancy + Disseminated Tumor Cells

Dr. Julio Aguirre Ghiso is a Professor of Medicine, Hematology and Medical Oncology and Oncological Sciences at Ichan School of Medicine at Mount Sinai in New York City. His research explores why and how in some patients disseminated tumor cells can remain dormant for years after initial treatment before reactivating to form incurable metastases.

Prostatepedia spoke with him about his research and about a clinical trial testing his findings that is currently looking for prostate cancer patients.

To  learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us or download the issue.

Why did you become involved in cancer research? What is it about cancer research that has kept you interested?

Dr. Julio Aguirre-Ghiso: When I was an undergraduate student, I was looking for challenging problems to solve in biology. Serendipitously, I started working and volunteering for a cancer biology team in Argentina, where I trained. I became very interested. I was working on tumor immunology. Then I became very interested in the cell biology of cancer cells. At some point, I realized that it didn’t really matter if it was cancer or Alzheimer’s or some other basic biological questions on other organisms; what I really was curious about was solving tough problems and answering questions. This was a good mix where, if I were able to do it, I would also be helping people with cancer in the future.

Focusing on cancer would give me an opportunity to apply my curiosity to something that is relevant for people. That was the original intention. Since I was not an MD, my curiosity was about mostly biological questions. This was a fitting problem to go after.

Let’s talk about the concept of disseminated tumor cells. Can you explain to us how that works and how it is related to the development of metastasis?

Dr. Aguirre-Ghiso: Patients usually present with what’s called a primary tumor. That’s the first cancer lesion ever found in that patient. At that time, doctors will do certain tests on that primary tumor to understand if it had gone through certain changes that would make it able to spread. When cancer cells grow, they may acquire certain abilities that allow them to spread from that primary site—from, let’s say, the prostrate or the breast—to other parts of the body.

The disseminated tumor cells are these cells that have spread throughout the body. They have disseminated from the primary tumor to other organs in the body. Those could be the bones; the liver; the brain; or the lung. When they arrive to those organs, they’re not immediately able to grow. Since they’re usually solitary cells–that’s how we find them in the patient samples and in the mouse models that we’ve used—we call them disseminated tumor cells. They’re not yet metastases, but they’re not in the primary tumor. They’ve left and arrived to other organs. That’s the definition of these disseminated tumor cells.

Why are they important? We and others have provided compelling evidence that these cells are the source of the metastases. Those are the cells, not all of them, but some of them, that are able to eventually grow into metastases that affect the functioning of the organ, and sometimes systemically, the functioning of the patient. That’s what leads to death. That’s why these cells are important.

Do all disseminated tumor cells eventually grow into metastases?

Dr. Aguirre-Ghiso: No.

How do you know which disseminated tumor cells are going to grow into metastases and which are not?

Dr. Aguirre-Ghiso: Well, that’s been a major challenge and a major push from my program: to try to get in early and identify those disseminated tumor cells so that we have some idea if a patient carries disseminated tumor cells that are not going to do anything and the patient doesn’t have to worry, or if the patient carries some cells that look like they’re switching and they’re going to form metastases.

That has been our goal. It’s not yet a clinical test, but that’s why we have pushed the boundaries of our research to get to that point as fast as possible because we think that instead of waiting and not doing anything or treating blindly and then waiting until those metastases grow, we can intervene earlier. We would like to be able to say that this patient has only dormant cells and they don’t look like they’re going to reactivate based on certain markers or gene signatures.

That patient would then only need to be monitored, but new treatments may allow eliminating even those cells. If another patient has a mixture of cells some of which are fully dormant and some of which look like proliferative cells, we would treat him in a different way.

We have provided data for this from our mouse models and from clinical patient samples in prostate cancer. We published two papers in 2014 and in 2015 on this.

Not all cells are going to grow.

In fact, if you look at early lesions in breast cancer, for example, disseminated tumor cells are found in the bone marrow of 13-15% of women with ductal carcinoma in situ but only a small fraction of that 13-15% will develop metastases. It’s not a given that if these cells are there they’re going to grow, but if they are there, there is a higher risk of metastases. That has been proven by large population studies that have been published in The New England Journal of Medicine. This is true for not only breast cancer but for other cancers as well. The goal and the challenge is to have enough information to be able to predict accurately what those cells are going to do when you detect them.

Where we are in the timeline of being able to predict which patient is carrying potentially dangerous disseminated cancer cells and which is carrying dormant disseminated cancer cells?

Dr. Aguirre-Ghiso: We have different areas of research into these disseminated tumor cells. Why they are dormant? Why do they sleep in the body for a long time and then awaken? We discovered a marker in 2015 that could distinguish these deep-sleeping cells in both prostate cancer and breast cancer models. If the cells had this marker, they would behave in this dormant way, and if they didn’t have this marker, they would look more like a proliferative or an about-to-reactivate cancer cell.

At that time, it was correlative between just two groups of patients. Last year, we published a paper on breast cancer where we used the same marker detected in tumor cells disseminated to the bone marrow of breast cancer patients. We were able to show that if patients had this marker they were much less likely to relapse with bone metastases than if they didn’t have this marker. In 2015, we’ve published the original finding where we just said this is probably a good marker; we understand how it works in mouse models. In 2018, we showed that the presence of the markers can distinguish retrospectively how patients behaved. Now the challenge is for people to start using the markers prospectively to see if it helps them make decisions on how to treat or monitor patients. We are very much at the early stages of applying the information that we have generated and bringing it into the clinic.

On the other hand, in that same 2015 paper, we were able to show that if we use two drugs that are FDA-approved and combine them in sequence, we can turn on these dormancy mechanisms in different types of cancer cells—i.e. breast, prostate, and head and neck cancer cells. Because these drugs were available—and there are independent studies showing that when prostate cancer patients are treated with hormonal therapy and anti-androgens, they turn on this marker of dormancy that tells you the cancer is deciding to go into sleeping mode— we wondered if we could repurpose those drugs and treat prostate cancer patients at risk of developing metastases to see if we could delay the onset of metastasis and keep the disseminated tumor cells in a dormant state.

To read the rest of our conversation and to learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us. Or download the issue.


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Clinical Trial: Combining Erleada (apalutamide) with Zytiga (abiraterone)

Dr. Eleni Efstathiou is an Associate Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas.

She spoke with Prostatepedia about her clinical trial combining Erleada (apalutamide) with Zytiga (abiraterone).

What is the thinking behind your trial combining Erleada (apalutamide) with Zytiga (abiraterone) in men with metastatic castrate-resistant prostate cancer? Why this combination as opposed to another?

Dr. Efstathiou: Here is the idea. There is a large trial on combining Zytiga (abiraterone) and Erleada (apalutamide) for all patients who have failed original Lupron (leuprolide) injections or standard androgen deprivation therapy. This trial is for men with metastatic castrate-resistant disease; it compares that combination to just one of the agents alone. I’m part of the steering committee for that international trial.

The trial that I just initiated here at MD Anderson is a smaller trial. This trial is trying to identify and confirm a subset of men who harbor cancers that are going to be exquisitely sensitive to the combination and may need no further treatment for years and not just an average of about a year

This all started with my first trial, now 11 years old. That specific trial was characterized by the fact that the men who received Zytiga (abiraterone) underwent biopsies of their bones while on treatment so I could study what was going on in the cancer realtime. It showed me that 70% of the men would respond. There was a reaction in the cancer cell while the androgens were dropping and they were undetectable. Their androgen receptors were going up. The next trial that I did used a drug that is very close to Erleada (apalutamide) called Xtandi (enzalutamide). That trial showed exactly the inverse, that as you gave that drug the receptor was switched off, but the androgens went up. All of this is in the tumor cells. This means there is some feedback happening, but does this feedback contribute to resistance? Could the combination actually help these men who get both drugs survive longer and get better responses?

But there is a caveat. I looked more carefully to find the characteristics in the tumor samples taken prior to treatment and found that there were specific molecules that, if expressed, were associated with a benefit. It made sense to me to focus on those specific characteristics in the cancer and try to combine.

I then did another trial where I combined Zytiga (abiraterone) and Xtandi (enzalutamide) and looked to see if my theory made sense. It did. It looked like the men who had these molecular characteristics responded better on the combination than those who didn’t.

But that was all hypothesis. The next thing you need to do when you discover something is test it. Then you need to confirm it to validate it. I used a 180-patient trial to test it. The next step would be the validation if testing looked promising. A validation means you have preset the parameter of the research trial; you’re trying to become agnostic to the outcome so you’re not biased in any way.

The testing also panned out. The trial we’re now discussing is the validation. Patients who come in the door accept to undergo a biopsy. We don’t need to do the old-school bone marrow biopsies anymore. We have great radiologists who go in with very fine needles and take several samples so the patient has no pain, just the discomfort of the process. Then we look at the cancer cells to see if they have these characteristics. I would tell you that about 30% of the cases have these characteristics that would make them eligible for the trial. The men who do have these characteristics in their cancers start treatment. If my hypothesis is correct, the validation will be that 90% of these men should respond in an outstanding and protracted fashion. I’m trying to hone in on who would be the ideal candidate for a combinatorial trial. The way the field is going, we’re throwing all the drugs at all patients; that helps a lot of people to a degree, but on the other hand, it causes a lot of toxicity, especially if you combine two rather than one agent. That is the main gist of this trial.

What can men expect to happen step by- step?

Dr. Efstathiou: You get a biopsy. In about a week, we tell you if you area candidate or not. You start the treatment. Then it’s quite straightforward: we follow you just as you would be followed in your doctor’s office. You come once a month to see me. This may go on for years, if all goes well. I have some patients who have been on treatments like this for years. Sometimes after six months of treatment, apart from seeing us to evaluate toxicity, we also perform imaging again to see what is going on with the cancer.

What images studies will you be using?

Dr. Efstathiou: CT scans and bone scans. We have not included, unless it’s needed for this trial, more advanced imaging such as PET scans. As we monitor these imaging studies, we see how the cancer cells seem to be more quiescent. The lesions become smaller. If, God forbid, the disease tries to progress again, then we would repeat a biopsy Remember, as I’m sure you’ve discussed with a lot of other specialists in prostate cancer, one of the main concerns is prostate cancer’s heterogeneity. When I’m doing biopsies, I’m actually looking at a snapshot of a specific subset of cancer cells. What if there is a cohort of cancer cells in there that is very resistant and expresses completely different molecules?

This clinical experiment gives me the opportunity to see if the way I am assessing things is actually capturing well what is happening with regard to the prostate cancer activity. There are a lot of investigators out there who are huge advocates of liquid biopsies without having done the basics of assessing what is going on in the actual tumor that has grown in the bone, lymph nodes, or liver. I understand that the dilemma for most people is the difficulty of doing biopsies, but if we want to be honest in all other malignancies, that’s how the development of all the targeted agents started. At the end of the day, it is going to be important to not ignore the actual tumor samples and to try and characteristics those well. Above and beyond this specific trial, one of my main efforts is to hone in on a classification of the disease that allows you to appropriately designate specific treatments to specific patients. There was some nice work recently presented in a meeting that supports that idea. Some of the mutations or alterations can be found early on.

If we know which these are, then we can pursue them. If we know that others change over time, then we can do real-time biopsies.

Which tumor biomarkers are you looking at?

Dr. Efstathiou: One of the most important parameters is androgen signaling. I was the one who reported for the first time the association of AR-V7 in the tumor sample with lack of response to these drugs. Right after that came the liquid sample data from the Johns Hopkins and Memorial Sloan Kettering groups who were doing it in the circulating tumor cells.

One of the markers is related to AR-V7, but I went a step further. The androgen receptor needs to be intact. I’m looking at the two ends of the androgen receptor. The one end is the end where the androgens go and attach themselves. The other end is the stable end, the one that never changes. The end to which the androgens attach themselves is the one that is affected by mutations and variants. I measure both ends and then I look at the difference in the ratio between the two. That’s another important marker.

I also look at PTEN, which is a very known marker. I look at RB loss, p53 mutation, and the proliferation index of the cancer.

What are the eligibility criteria?

Dr. Efstathiou: It’s very simple. Patients must have not received previous new agents such as Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide). They must have failed standard hormonal approaches, such as androgen deprivation therapy or bicalutamide. They also have to have metastatic disease. These are the main criteria. It’s very straightforward.

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Dr. Ken Pienta: Chemo For Prostate Cancer

Dr. Kenneth J. Pienta, of the Johns Hopkins University School of Medicine, is an international expert in the development of novel chemotherapeutic agents for prostate cancer. He was the recipient of the first annual American Association for Cancer Research Team Science Award and is the author of more than 300 peer-reviewed articles. He frames this month’s conversations about chemotherapy for us.

Pienta_lab_Background

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In 2018, chemotherapy for prostate cancer continues to be one of the many options we have to lengthen the lives of patients suffering from metastatic prostate cancer. There are still multiple other therapies that we don’t consider chemotherapy. Second-generation anti-androgen therapies like Zytiga (abiraterone), Erleada (apalutamide), and Xtandi (enzalutamide) are all now standards of care in castrate-resistant prostate cancer. We also have Xofigo (radium-223) as an option for patients with bony metastases.

There are two chemotherapies that have been approved for prostate cancer: Taxotere (docetaxel) and Jevtana (cabazitaxel). Now, the real challenge for patients and providers is when to use those chemotherapies.

Multiple studies have demonstrated that, when you’re newly diagnosed with metastatic prostate cancer, it may be beneficial to receive a limited number of doses of Taxotere (docetaxel) at the start of hormone therapy. That’s especially true if you have multiple places where the cancer has spread. That’s not correct for all people, but for some patients, it is a good option. More and more physicians are prescribing Taxotere (docetaxel) with a luteinizing hormone-releasing hormone (LHRH) antagonist at the start of therapy.

However, that doesn’t mean you cannot use Taxotere (docetaxel) after other things have failed. If you failed second-line hormone therapy or have failed radium therapy, Taxotere (docetaxel) is still a good option that helps people live longer.

Jevtana (cabazitaxel) continues to be a good chemotherapy option if patients have failed Taxotere (docetaxel).

Thank goodness we’ve seen over the last several years an increase in the number of drugs available to treat metastatic prostate cancer in addition to chemotherapy. Chemotherapy has been around for quite a while now, but there is still a role for it.

Again, the challenge for all of us is: when do we slot them in for you? The chemotherapy we use for prostate cancer is really a single agent chemotherapy, either Taxotere (docetaxel) or Jevtana (cabazitaxel). This is not the multi-agent therapy we use for other cancers, so the idea of major side effects is a bit overblown. For example, nobody vomits from chemotherapy for prostate cancer. The drugs we use to prevent that are too good.

We also have gotten much smarter about limiting the number of doses we use. We don’t necessarily give chemotherapy until it doesn’t work anymore. Often, we just give several doses and then take a break. If you get more than a couple doses of chemotherapy, you will still lose your hair temporarily.

Chemotherapy can make you feel more tired when it lowers your blood count, and it can make you more susceptible to infections, but people are very rarely hospitalized now for an infection from chemotherapy. It’s virtually unheard of that somebody would die as a side effect of chemotherapy.

The major side effect of Jevtana (cabazitaxel) tends to be diarrhea, but again, as we’ve learned about the dosing of that drug, that has become more manageable.

Another side effect of both drugs can be peripheral neuropathy, which is tingling in the fingers and toes. But we watch for that too. If you start to develop that, we tend to stop the drug. These are very tolerable medicines.

The word chemotherapy always evokes images of horror, but chemotherapy in 2018 is a lot different than it was even five years ago. We just know how to give chemotherapy much better. When I started in the field 30 years ago, if you had metastatic castrate resistant prostate cancer, survival was 6 months. Now, with the advent of all these newer therapies, we’ve gotten much better. The landscape of how to treat prostate cancer has changed completely in the last five years. It will change completely again in the next five years. The challenge is in what order are we going to use all these powerfully good drugs rather than having only one drug to give or none at all.

For us as physicians, it’s an exciting time to take care of men with prostate cancer.

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Genomics + Prostate Cancer Care

Dr. David J. VanderWeele is an Assistant Clinical Investigator in the Laboratory of Genitourinary Cancer Pathogenesis at the National Cancer Institute. He is particularly interested in investigating the progression of clinically significant prostate cancer.

Prostatepedia spoke with him about how genomics impacts patient care.

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What is genomics, and how does it differ from genetics?

Dr. VanderWeele: Typically if you’re talking about genetics, you’re talking about an individual gene or a small set of genes. When you refer to genomics, you’re referring to all the genes or a very large set of genes. Genomics usually refers to the genes–the DNA sequence. But sometimes genomics is also used to refer to when those genes get expressed (as RNA), or to other changes to the DNA that don’t change the DNA sequence (also called epigenetics).

What do and don’t we know about why some men develop curable or indolent prostate cancers while some develop widely lethal diseases?

Dr. VanderWeele: A lot of effort has been put into trying to learn more about the genes you inherit from your parents and how that influences the likelihood that you’re diagnosed with cancer. Most of that effort has been unable to identify which alterations in your genes make it more likely that you will get an aggressive versus an indolent cancer.

As many of your readers probably know, many people get indolent prostate cancers. In fact, many autopsy studies have looked at patients who have died of other reasons and have never been diagnosed with prostate cancer. Once men reach their 70s or 80s, it looks like more than half of men develop prostate cancer. Of course, those are relatively slow-growing cancers.

The most information that we have now is that men who come from families with breast and ovarian cancer syndrome appear to be more likely to get cancer and more likely to get aggressive cancer. These involve BRCA1, BRCA2, and other DNA repair genes in a similar pathway. Though there aren’t FDA-approved therapies yet, there are trials suggesting that these patients are also more likely to respond to certain therapies approved for breast and ovarian cancer.

This is a pretty small subset of all the men with prostate cancer, but the percentages increase with any kind of measurement of aggressiveness. If you look at people with localized cancer, that percentage increases if you have high-grade cancer versus low-grade cancer. The percentage increases if you compare people with advanced castrate-resistant prostate cancer to those with localized cancer.

If you look at the length of time between a man’s diagnosis and when he dies, that rate increases significantly the shorter that time is. That is just looking at three of these genes, BRCA1, BRCA2, and ATM. If you look at a broader number of these DNA repair related genes, it looks like ten to twelve percent of all patients with castrate-resistant prostate cancer harbor a mutation that they inherited from their parents. It seems likely that for most of those patients, that inherited gene contributed to their prostate cancer.

That has led to some debate about how often we should test for mutations in these genes. Is that a high enough number that we should test everyone with castrate-resistant prostate cancer? Should we still rely on family history to provide guidance for which people should be tested?

Is it really expensive to test those men? Why wouldn’t you just go ahead and test?

Dr. VanderWeele: Depending on how you do it, testing costs have come down quite a bit.

But when you’re testing for genes that could potentially be passed on to your offspring, or that siblings or other family members may have inherited, there are implications for your other family members, not just for you.

Some members of your family may definitely want to know that information and think that more information is better. Others may feel that if they find out that they harbor that gene mutation, they will just feel like they’re waiting for the other shoe to drop. It’s not information that they’d want to know.

Generally, we advise people to get counseling to help them think through some of these issues before getting tested for genes they’ve inherited from their parents.

Do we know why some men respond to certain drugs and therapies and others don’t?

Dr. VanderWeele: There’s a lot of interest in that. There has been some progress made in terms of identifying the biomarkers that might suggest which patients are more likely to respond to which types of therapies. At this point, however, most patients still get treated with most therapies.

There are some genetic biomarker-driven therapies that look like they’re on the horizon. Patients with mutations in BRCA2, ATM, and related genes are more likely to respond to a type of therapy called PARP inhibitors, which are currently approved for patients with ovarian or breast cancer, but not yet for prostate cancer.

There was a single Phase II study that showed that patients who had loss of a specific tumor-suppressor gene called

PTEN are more likely to respond to a certain type of targeted therapy. There are larger ongoing trials to demonstrate that these are indeed predictive biomarkers for response to these therapies.

There are companies like FoundationOne and GenomeDX that look at the molecular features of a man’s cancer. Are those tests useful? What do they tell a patient?

Dr. VanderWeele: The FoundationOne test looks for mutations, deletions, or amplifications of specific genes that are relevant for a wide array of cancers. There are a lot of companies offering this type of sequencing.

Many hospitals offer their own version of it. A FoundationOne type of test can tell you if you have a mutation in BRCA2 or ATM. They should also be able to tell you if you have a deletion in PTEN. When they detect a mutation is present, however, generally they are not looking to determine if you inherited those changes from your parents versus the mutation being present only in the tumor cells.

These genetic tests are more popular in other types of cancers, because for prostate cancer there aren’t yet any FDA-approved therapies that would be given based on the results of these tests. These tests will become more popular as we make progress in demonstrating the benefit of these specific therapies and in our ability to predict which patients are most likely to respond.

If a patient reading this gets one of those tests, is it likely that his doctor is going to know what to do with the results? Will the results actually impact his treatment?

Dr. VanderWeele: There are probably a small number of patients who will have a result that will directly impact their therapy. At this point, the way that it would impact therapy is that it might suggest that they should find a clinical trial testing a specific type of drug.

I see.

Dr. VanderWeele: There are also other commercially available prostate specific genetic tests, like the one performed by GenomeDX, that are mostly aimed at men with localized prostate cancer who are trying to decide how aggressive their therapy should be. Typically, this means whether they should pursue active surveillance or get surgery or radiation.

Sometimes these tests are also used to determine if a patient should get radiation after undergoing a prostatectomy or if he should just continue to follow PSA numbers. The prostate specific gene expression tests are RNA-based tests, which are a little different.

They measure the levels of expression of a few specific genes. Tests like FoundationOne look for mutations, amplifications, or deletions of genes—which means they are DNA-based tests.

Tests like Decipher are more widely used now, right?

Dr. VanderWeele: Yes. They’re probably used mostly by urologists. My sense is that how often urologists order those tests and how heavily they rely on them versus other ways to predict the risk level of the prostate cancer varies quite a bit from urology practice to urology practice.

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Can Decipher Change Your Prostate Cancer Treatment Plan?

Dr. John Gore is a clinician, surgeon, researcher, and educator specializing in urologic oncology and general urology at the University of Washington.

Prostatepedia spoke with him about how Decipher changes the way doctors treat men with prostate cancer.

What is Decipher?

Dr. Gore: Decipher is from a family of genomic tests. In general, it tries to look at some of the alterations in people’s genes associated with cancer or its progression. Decipher attempts to create a panel of genes associated with the likelihood of a cancer coming back. It takes that panel of genes and integrates it with clinical information to calculate the risk of developing spread of cancer to sites that could be detected clinically, like the bones or the lymph nodes, within five years after prostate cancer surgery.

When is a man likely to encounter this test? After that initial biopsy when he is first diagnosed? After his prostatectomy?

Dr. Gore: The most common scenario would be after surgery. If a man has his prostate removed and the pathology shows that he has a cancer that by all accounts seems to have been successfully treated with the surgery, Decipher may not be the right test for him.

If he has some high-risk features— his cancer is potentially encroaching on the shell of his prostate, he has a positive surgical margin, or there is involvement of the seminal vesicles that sit behind the prostate—then he might benefit from Decipher.

That way we can ask if—in addition to knowing that he had some high-risk pathology features—he appears genomically to have a high-risk cancer?

What do the results look like? Do they change how a man is going to be treated post-surgery? How?

Dr. Gore: The actual report that a patient or doctor gets tells them the probability, or percent risk, that he will have clinical metastases within five years of having his prostate removed for prostate cancer. In general, those numbers tend to be in the single digits to low teens. It’s not a common event.

For most people, prostate cancer surgery successfully treats their cancer. That is why this is best used on higher-risk individuals.

In our study, we looked at a cadre of patients who were either found to have high-risk features at the time of their prostate cancer surgery, or now their PSA is subtly rising after going to zero after surgery. Those patients should potentially have more aggressive treatment.

We showed that if a patient had the Decipher test, physicians’ recommendations changed. If your Decipher results showed a lower risk score, your doctor was more likely to recommend observation.

Patients with a higher risk Decipher score were more aggressively treated. They were recommended to go ahead and get additional radiation to the area where their prostate was removed, rather than just active surveillance.

The bottom line is that Decipher changes how men are treated?

Dr. Gore: Yes. We have some follow-up data we just presented at the American Society of Clinical Oncology, Genitourinary meeting in February that showed that those treatment recommendations were actually followed 80% of the time.

You said only men who are high-risk should really be tested. Not everyone getting prostate cancer surgery needs a Decipher Test?

Dr. Gore: That’s right.

Is Decipher widely accepted in the medical community? If a man in rural Minnesota goes to his local urologist or local community oncologist, will he likely be offered the Decipher Test? If not, should he ask his doctor to order it?

Dr. Gore: I think it’s definitely worth requesting it. One thing that has come up is insurance payer coverage, not just for the Decipher Test, but also for other tests like it. The bar that some of these companies have to cross to get their test approved is fairly high.

Some insurance companies are asking if the test not only changes treatment for patients. The trial they’re looking for will compare patients who got the Decipher Test with patients who didn’t to see if the decisions that were made impacted cancer outcomes. If, for example, your Decipher results say you’re high-risk, and you get radiation based on that information, was that the correct decision? The challenge is that prostate cancer is immensely slow-growing. Even when it’s high-risk, even when it’s aggressive, we’re talking about clinical outcomes that take years and years to manifest. It imposes an irrationally onerous burden to prove that these tests are the right thing.

You could wait 10 years to find out if the treatment decisions were correct. Meanwhile, time is passing and these men need to make choices…

Dr. Gore: Absolutely.

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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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