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Conversations With Prostate Cancer Experts


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Health/Tech Collaborations For Prostate Cancer

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles, has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with him about collaborations between healthcare and tech industries for prostate cancer.

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Have you had any particular patients or cases that changed how you view your role as a doctor or how you practice medicine?

Dr. Paul Nguyen: Several years after treating him, I heard from a patient who recounted for me what it was like to meet with me when he had first been diagnosed with recurrent disease. He said he’d had a lot of uncertainty and anxiety about his future. He said that the way I spoke with him had changed it entirely for him. He said I had a plan for him, knew exactly what we were going to need to do, and that we were going to do it.

I didn’t do anything particularly different in that encounter than I normally do, but hearing that made me realize how patients really hang on our every word, our every facial expression, our every cadence, and the emotion that we project when we speak. This made me so aware and conscious of making sure that, at all times, in every encounter, I have that combination of being sure about what I need to do and maintaining hope and optimism in every part of our discussions.

That was a good learning cycle for me. I hadn’t thought of it that way when I was with a patient. You just don’t think that every intonation, every gesture has such a huge impact. But it does. That was a very valuable learning experience for me that has really shaped how I think about every patient encounter before I walk into the room.

What are your current research projects? Which are you most excited about?

Dr. Nguyen: I have spent my entire career using information from the medical record about patients’ health status and tumor characteristics to figure out which men should get hormone therapy and for how long. Now, I’m incredibly excited about the opportunity to unleash the power of genetic testing of tumors. This will help us understand, on a genetic and molecular level, which patients should be given hormone therapy and for exactly how long. This will be a lot more precise than the clinical information by itself. I’m working with Dr. Felix Feng and others, which has been a wonderful collaboration.

How do you see evolving technologies impacting prostate cancer research? Dr. Nguyen: Technology gives us opportunities to do the kinds of studies we never dreamed possible, which is amazing.

I’ll give you an example. Dr. Feng and I are about to take prostate cancer samples from biopsy tissues taken 25 years ago from men who had cancer, samples stored without a clear purpose in mind. I give a huge amount of credit to the people who designed these studies in the early 1990s. They had no way to analyze this tissue, but they knew that someday, this tissue would be important to humanity. There wasn’t a specific test that they were storing these samples for, but they knew some kind of technology could decode what was going on in those tumors, to study how the tumors work, and who should get which treatment.

I feel so fortunate to come along 25 years later, when we do have the technology to analyze this tissue, and research it. This is the research I’m about to do now, which would never have been possible without new technologies.

Do you see technology impacting how we design clinical trials from the get-go?

Dr. Nguyen: Absolutely, because now people are designing trials with technology. There’s a trial being led by Dr. Feng from UCSF and Dr. Dan Spratt at the University of Michigan that incorporates genetic technology.

All the patients are tested upfront with this new technology to help decide which arm the patient goes into, which is really cool. This new scientific technology is being worked into clinical trial design.

Which innovations or technologies have the biggest impact?

Dr. Nguyen: There are two kinds of impacts. One is the ability to do large-scale genomic studies for a relatively low price. That has been a game-changer because it used to be so expensive to sequence the DNA of patients, but now you can approximate that rather cheaply and then do studies on thousands of patients. This way, we can pick up very small signals, which are very valuable.

The other invaluable impact is the ability to detect very minute amounts of tumor in the blood, very tiny traces that can tell us a lot.

In the circulating tumor cell?

Dr. Nguyen: Exactly.

Do you think artificial intelligence will play a role?

Dr. Nguyen: For sure. I’ve spent most of my career working on simple, clinical data. You can see the patterns of simple data yourself by doing simple statistical analyses. But now, the patterns are much more complex. Instead of five datapoints, you might have two million datapoints per patient. So we need AI. We need sophisticated machine learning to help us discern some kind of pattern out of that huge amount of data, to help us make sense of it.

Are there any specific collaborations, other than the ones we’ve already discussed, that you think look promising?

Dr. Nguyen: We’re seeing a lot more collaborations across specialties and disciplines to get research done. So much of what we’re seeing now is team science whereas people used to do studies with their own group.

Now, if you look at a paper, it’s not just one group or one discipline. At each institution, it’s five disciplines, and then you might have ten institutions on a paper, each contributing something different because that’s just what it takes now.

Every group has its own, little special expertise that gets put together to get a big paper or a big trial done. That’s what has really exploded. We’ve all recognized that, in order to get good science done, we have to team up.

Is just it easier to collaborate with people now via email and sharing of data? Or is there something about the way cancer research has been funded that has fostered that collaboration?

Dr. Nguyen: Yes. Those factors definitely contribute. It is definitely easier to share data now with the internet. Efforts to fund team science have definitely led teams to be created that might not have been created organically before.

There’s something fundamental about the increasing use of technology in studies and trials where only certain groups have this kind of technology expertise. You might have one group that knows a lot about the technology and another group that has a large number of patients and ideas. And you have to reach outside of your little sphere in order to get these kinds of exciting studies done.

It seems like before everything was pretty much siloed: you had tech, you had healthcare, and then, within healthcare, you had prostate cancer versus pancreatic cancer versus breast cancer. But now, the walls are coming down between those silos, with things like increased genetic testing. Would you say that’s true?

Dr. Nguyen: Absolutely. For example, some of the cool studies done in prostate cancer genetics were modeled on similar research done in breast cancer genetics several years before. Breast cancer had the Oncotype study, and then prostate cancer developed the Oncotype test many years later. We’ve seen molecular subtypes of breast cancer (luminal A, luminal B, and basal), and now there’s a study led by Dr. Feng suggesting that you’ve got similar kinds of subtypes in prostate cancer. We have to be knowledgeable about other fields. You can’t just be in your own silo now.

Last week, I spoke with engineers at University of Pennsylvania who are working with microchip-based technologies and machine learning to increase liquid biopsy’s usefulness in pancreatic cancer. They said this allows them to process much more data than they could before. They hope this has potential in other cancers. I know that’s more along the lines of diagnostics than what you’re doing, but do you have any thoughts about that?

Dr. Nguyen: We are all trying to take those same kinds of approaches with the folks who do machine learning. We need them desperately now because we’ve got so much data, and we just can’t figure it out on our own.

That’s exactly where we’re all headed.

Join us to read the rest of Dr. Nguyen’s comments on collaborations between the health and tech fields for prostate cancer.


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Clinical Trial Eligibility + Black Men

Ms. Marie Vastola is a Clinical Research Assistant in Radiation Oncology at Dana-Farber/Brigham and Women’s Cancer Center. She works on Dana-Farber-led and international clinical trials that accrue men with multiple stages of prostate cancer. She is an author on six research articles focusing on prostate cancer and has presented her research at a national conference.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles and has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with them about how eligibility requirements for prostate cancer clinical trials may unfairly exclude African American men.

How have black men been underrepresented historically in prostate clinical trials? What are some of the prevailing theories or ideas about why that might be?

Dr. Nguyen: It’s multifactorial, and that was something that our research aimed to get at. Because of the historical experiences like the Tuskegee experiment, some African- Americans may have been more leery of engaging in clinical trials. Because trials require certain costs and extra time away from work, this can be more difficult on certain populations. Or it could be from the doctor side. Some doctors may not be as willing to engage African-American patients to enroll them on trials. There are multiple factors, so it’s hard to know exactly what is the main driver.

Ms. Vastola: We have patients come from long distances to Dana-Farber, and they do that because they know that Dana-Farber is a good place for them to get treated. Many patients, especially ones who travel long distances, either have connections in the medical field and that’s how they found out about this, or they’re highly educated and they have the resources to look into research and potential treatments themselves. These are tools that only people who are a little more privileged have.

Why did you zero in on eligibility criteria? What were you looking at?

Ms. Vastola: Actually, a patient is what started this research project. I had been screening an African-American patient for one of our open trials, and filling out the paperwork to determine if he was eligible. Most of this paperwork is related to the cancer, to make sure that patients have the type of cancer that we’re studying. But other sections of the checklist establish that the patient is otherwise healthy. We wouldn’t want to give an experimental treatment to a patient who wasn’t healthy for their sake and for the research’s integrity. He didn’t meet the criteria for one of those health checks.

One of the ways we determine that a patient is otherwise healthy is to look at their immune function, and his white blood cell count was too low. I hadn’t seen that before, and we ran his blood test again. His medical oncologist said the patient had benign ethnic neutropenia, which I had never heard of it until then. Because of that he couldn’t go on the trial that we had. It wasn’t a trial that we were running out of this hospital, but we talked to the sponsors. And as with many big trials, they don’t allow exceptions, no matter what.

He didn’t get the opportunity to be on a trial that was designed for men just like him, and that was really frustrating. Everyone involved with his treatment was frustrated with that, and so we looked into if that could be happening to other men. We also looked at creatinine. It’s well known in the medical field that black patients have a higher serum creatinine, and so you have to use a special formula that accounts for race when you’re looking at their kidney function. We looked at benign ethnic neutropenia because that’s what started it, and it was something that people seemed unaware of.

Dr. Nguyen: In a research group, the ideas usually come from the lab principal investigator (PI), and then the junior people carry it out. In this case, Marie actually came up with this idea herself because of a patient experience that she had, seeing an African-American patient not be able to get on one of our trials. It’s what led to this Journal of the American Medical Association Oncology paper, which is impressive.

That is. What did you look at?

Ms. Vastola: We wanted to know how often this happens. Was this a fluke, or does this happen to other African-American men? The best way to find out was to look at the eligibility criteria of other trials. Every trial records when people don’t meet the criteria. They don’t often record why though, so we couldn’t just look at the internal records of our trials. The website clinicaltrials.gov lists all trials available to patients in the United States and also a lot of international trials, and it usually lists the eligibility criteria. Not all the trials go into detailed criteria, but many do. We went through 401 trials that had endpoints that we thought meant that they had the potential to reach large audiences and change practice. We looked at all of them and pulled the eligibility criteria to see how many of them had this white blood cell criterion.

We expected some would have it. We did not expect that almost 50% of trials would have either of these two criteria. We were also surprised that the serum creatinine criterion was so common that a quarter of the trials have it.

People are aware of this, and they know to calculate kidney function accounting for race. A lot of trials would use serum creatinine, which is just the blood test, but then they would also say that if a patient meets formula criteria (based on race), then they’re okay, which is what we want to see. Not all trials do that, and that’s the issue. Every single lab result you look at that measures creatinine says at the bottom that if the patient is African-American, apply this formula. But over 25% of these trials weren’t including that formula.

What else did you find?

Ms. Vastola: Those were the two criteria that we looked at. We also broke it down by year, size of the trial, the phase, and toxicity of the therapy. We were glad to see that, over time, people are using the serum creatinine eligibility criteria less and less, which may mean that more people are aware of it. That’s not the case for the white blood cell criterion though.

Dr. Nguyen: We looked only at trials that have survival as an endpoint, so these are trials looking to make people live longer. We think it’s especially important that all patients have equal access to these kinds of trials. There are a few consequences of not having African-Americans on these trials. Patients who go on trials can sometimes get access to new drugs, so it’s a problem if African-American patients aren’t getting on trials. We also don’t get to learn enough about whether certain drugs perform particularly well in African-Americans, and so we don’t get to learn about the specific benefits or lack of benefit of certain agents for African-American patients. We wind up extrapolating from the larger patient pool, which probably works most of the time, but perhaps there’s something special that we can learn from having African-American patients on trials so that we could find better cures that can be tailored for African-American patients.

Ms. Vastola: Exactly. Not having access to these clinical trials hurts the individual because they don’t have access to treatment that could potentially help them. But the lack of access also hurts the whole population.

It also skews your results, so that what you’re learning about isn’t really prostate cancer in all men, just prostate cancer in a subset of men.

Ms. Vastola: Exactly.

What do you hope this will mean for clinical trial design and eligibility recruitments?

Ms. Vastola: We presented this research letter at the Prostate Cancer Symposium of the American Society for Clinical Oncology in poster form. We got a lot of feedback from academic investigators, people who devote their lives to this. Their papers define the field. They said they’d never thought of this, and that some didn’t know benign ethnic neutropenia existed. This section of the eligibility criteria—the part that defines whether a patient is healthy—is just carried over from trial to trial because it’s so standard. It’s not something people think about when they design trials because it’s so standard.

It’s textbook. We hope that, as more people understand this, they will consider it when they design their trials.

Dr. Nguyen: We were guilty of it in our own trials, and that’s how this all came about. We just used standard entry criteria copied over from previous studies. We were surprised to learn that this could disproportionally disadvantage African-American patients from being able to enroll in our trials. Given all the barriers that African-American patients face in getting on clinical trials in the first place, the last thing that we need is yet another barrier.

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Clinical Trials + You

In May, Prostatepedia asks doctors, advocates, and patients why men with prostate cancer should consider joining clinical trials. Chances are you’ve never thought about entering a clinical trial. You and your doctor have hammered out a prostate cancer treatment plan that takes into account your particular cancer and which side effects you’re willing to live with and which you’re not. But a clinical trial? Most men never really think about joining a trial unless their own doctor brings it up—if he or she does at all.

But there are clinical trials available to men at every stage of the prostate cancer journey from new diagnosis to active surveillance to monitoring for potential recurrence to advanced disease. Some trials offer men access to a drug or therapy that they might not otherwise be able to get. Other trials help scientists learn about prostate cancer biology or genomics. All are important and all advance our understanding of prostate cancer with the aim of eventually eradicating the disease all together.

Understanding clinical trial terminology will be important as you evaluate whether or not you’re interested in joining a particular trial. A Phase I clinical trial generally looks at drug safety and includes a smaller number of patients. A Phase II trial collects preliminary data on whether a given drug works in men with prostate cancer. A Phase III trial collects further information about drug safety and effectiveness—usually in different populations, different dosages, and in combination with other drugs. Phase III trials can lead to a drug’s FDA-approval.

Reading–and then forwarding the issue of Prostatepedia to your doctor–is a great way to start a discussion about clinical trials. Be sure to take notes and do your own research afterwards until you’re sure you understand the pros and cons of each trial you’re considering.

Support groups—online and in-person—can be wonderful resources as you evaluate your options.

The bottom line is that it’s worth investigating if there is a clinical trial available for you at this time whether or not you decide to join one in the end. You’ll learn a lot about your options moving forward and may just find one that’s a fit.

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Dr. David VanderWeele: Why Prostate Cancer?

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 why he became a doctor.

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Why did you become a doctor?

Dr. VanderWeele: Physicians come to the job through a number of ways. For me, it was both an interest in biology in general and in cancer biology specifically. I really enjoyed learning in undergraduate school, and later on in training, how cancer represents a normal biological process gone awry.

Of course, many people also have a family member who helped inspire their choice, either directly or subconsciously. My mother had breast cancer; I’m sure that was part of my internal motivation and interest in oncology.

How did you end up specializing in prostate cancer?

Dr. VanderWeele: I was interested in genitourinary oncology—prostate cancer, bladder cancer, kidney cancer, and testicular cancer—because there is a wide range in the natural history of those diseases and how we treat them. I became especially interested in prostate cancer in part because some prostate cancers are very aggressive and others are more indolent. The first step of managing prostate cancer is assessing the risk of the disease and not just treating all cancers the same way.

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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.

Join us to read the rest of Dr. Gore’s thoughts on the Decipher test for prostate cancer.


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Dr. John Gore: Why Medicine?

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.

Why did you become a doctor?

Dr. John Gore: My initial vision for my life was that I was going to be a lawyer. Then I found that I really enjoyed my experiences while interning at the hospital. That brought about an application to medical school. I think being a doctor offers a chance to have a daily meaningful impact, which is a unique part of the job.

How did you end up working in urology?

Dr. Gore: Urology is a specialty that very few people enter medical school thinking that they want to do. In part, most people are like I was and don’t even know about the specialty. I don’t have any doctors in my family. The only doctor I knew was my own pediatrician. I just assumed I was going to be a pediatrician.

But I really enjoyed surgery. I enjoyed being in the operating room. I just really enjoy the generic construct that someone has a problem and I have the tools to fix it.

Urology is an interesting hybrid. Most surgeries have a homolog in internal medicine. For example, there’s cardiothoracic surgery and cardiology. There’s colorectal surgery and gastroenterology. We don’t really have that in urology. We do a lot of chronic disease management. We do a lot of long-term follow-up of our own patients. It is, in many ways, a hybrid of internal medicine and surgery, which is really cool.

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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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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.

Join us to read Dr. Feng’s thoughts on genomics + prostate cancer.

 


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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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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.

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