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.)

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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The Metastatic Prostate Cancer Project

Dr. Eliezer Van Allen, Assistant Professor of Medicine at Harvard Medical School, a clinician at Dana-Farber/Partners Cancer Care, and an Associate Member at the Broad Institute of MIT and Harvard, focuses on computational cancer genomics, using new technology in precision medicine, and resistance to targeted prostate cancer therapies.

Prostatepedia spoke with him about the Metastatic Prostate Cancer Project, a nationwide genomic research study for men with advanced or metastatic prostate cancer.

What is the Metastatic Prostate Cancer Project?

Dr. Van Allen: The Metastatic Prostate Cancer Project is a patient-driven research initiative whereby we researchers partner directly with patients to dramatically expand the scope of our understanding prostate cancer genetics. We try to fill in all of the missing gaps that are currently a challenge in our field. Hopefully, we’ll learn what drives advanced prostate cancer, how to treat it more effectively, come up with new drugs, and understand the differences between more indolent cancers and those that progress in the metastatic setting. Essentially, I want to answer the questions I had during my initial clinical observations way back when.

You say you want to partner directly with the patients. How does that disrupt the normal clinical trial process? Normally, patients would access trials through their doctors?

Dr. Van Allen: Exactly. That’s what I’ve done during my postdoctoral training and in my junior faculty stage. That’s what we all do: we devise the research project, write a bunch of protocols and consent forms, and get them approved in our hospitals. Then we rely on the doctors and research teams to approach patients. They consent their patients to the studies that are already defined and set in stone. We use that to research. That’s obviously been a driving force for many modern discoveries. It’s a remarkable thing.

And that’s how we have to lay the first genetic maps of prostate cancer and cancers in general. This project flips genomics on its head. We’ve been working with prostate cancer patients to build a project with, by, and for men with advanced prostate cancer, their families, caregivers, and loved ones in order to resonate with patients. We are creating a mechanism such that patients can consent without leaving their home and participate without necessarily living near an academic medical center. This helps expand the scope of what we were able to learn in new ways.

A couple of years ago, while trying to define the genetic maps of local and advanced prostate cancer, we launched the first of these patient-driven projects at the Broad Institute in metastatic breast cancer. Using social media, patient outreach, advocacy partners, and patients themselves describing what it means to participate in these projects, that study enrolled over 4,000 women and men with metastatic breast cancer. Given that we’re thrilled when the average study to define the genetic maps of prostate cancer enrolls 100 patients over the course of years, if not decades, that number in such short time is remarkable. As we developed that project, I immediately thought of prostate cancer.

Rather than doing a top-down research project whereby we start with an idea in a researcher’s head, we go through the hospital and the doctors, and eventually, the patients, we’re starting with the patients. They’re talking directly to the researchers and building up. That is the ethos of this project.

This is not a traditional, academic project whereby we generate all the data, sit on it in our own little groups while we try to make sense of it, and eventually make it available to the larger community. Rather, as soon as we have a nominal amount of data, we make it immediately available to any researcher around the world who wants to use it. We’re trying to create a resource that anyone could use. The first 100 patients with genetic and clinical data have been made available for researchers pre-competitively. We don’t wait and publish these results in an academic journal or any other medium first.

Publishing in a traditional academic journal can restrict access for patients. If they want to read to read the results, they have to pay $30 to download the article.

Dr. Van Allen: Exactly.

If someone reading this wants to participate, what do they do?

Dr. Van Allen: If you have advanced prostate cancer, simply go to mpcproject.org. There, the homepage describes what’s involved. When you click the “count me in” button, it sends you on what we hope is a very quick journey through a few basic questions. Then, it asks for your permission or consent to participate in this project. There are a few more simple questions after that.

Soon after you register, you’ll receive a box that contains a saliva kit that the patient will spit in and return to get their inherited DNA information. Additionally, there’s a liquid biopsy kit, which is a vial that you bring to your doctor’s appointment to collect a liquid biopsy of your tumor. Then you return the sample to us.

When we receive those materials, we perform genetic profiling and access the medical record data. We de-identify everything to make sure it’s private, so nothing is exposed. We build a cohort and learn as we go.

Each step of the process has been vetted, scrutinized, criticized, and modified based on patient feedback such that we hope it resonates with this group. Part of this is actually iterating as we go. This is a research project. We’re not a clinical lab, so at the moment at least, we do not return results to individuals. But we do regularly engage with patients to share aggregate results of anything we learn in real time.

Patients won’t have access to the results of their tests?

Dr. Van Allen: Right. Unfortunately, we can’t provide individualized results, at the moment at least, because it’s beyond the scope of this project. It’s something we’re very interested in trying to explore. It creates many additional complexities. There is a holy patient/doctor relationship that we want to respect. That being said, often men will ask what’s in it for them and ask why would I want to do this?

We try to share aggregate results as regularly as possible. Patients can take those aggregate results, or any sort of interesting findings, to their doctor to consider if it’s relevant to them. Also, it’s a beautiful thing to see how patients themselves get when it comes to helping others: This is for the brothers, the sons, the patients that come after me, and I want to contribute. I want to help solve this puzzle, even if I may not see it in my lifetime. That altruistic aspect is genuinely great.

They do get to participate.

Dr. Van Allen: Yes. They’re just surprised that folks like myself, or anyone in the research world, is even talking to them. But patients are the most powerful people in this world. They have the power to really make these kinds of change

I think most people would want to participate if it’s easy to do. Are you providing detailed information about the kinds of tests you’re running so that if patients wanted to repeat them with their own doctor they could?

Dr. Van Allen: We’re doing whole exome sequencing, which looks at all the coding region of the genome on the tumor and the inherited DNA.

We are also piloting sending in liquid biopsies. One emerging technology that’s arrived over the last couple of years is the ability to detect circulating DNA that has shed from the tumor into the blood. That is an important advance for this project because most men with metastatic prostate cancer will not have had a biopsy of their tumor at the time of metastatic disease. They may have had a prostate biopsy years, if not decades, before but that tumor from way back when isn’t an accurate snapshot of what the tumor is like in the metastatic setting. Detecting a tumor in relative real time using blood is something we’re pretty excited to explore as part of this project.

For the men we sequence, we do our best effort to track down their tumor block. We go through every precaution to ensure that we don’t exhaust the tumor biopsy and that clinical care comes first. If there’s ever a need for it down the road, that’s the number one priority. We’re exploring how to use these liquid biopsies to help us in this project.

Do you handle the liquid biopsies?

Dr. Van Allen: Yes, it’s the Broad Institute.

Can anyone participate? Can non-Americans participate?

Dr. Van Allen: At the moment, we are approved so that anyone from the United States and Canada can participate. Anyone in other parts of the world can complete the survey and provide some of the patient-reported data, but we don’t currently have permission to do the subsequent genomic profiling for them. In our soft launch, we’ve scanned through self-reported information from almost 200 patients. That has already initiated some ideas for research projects we never would have imagined.

This patient-reported data is quite valuable. Anyone who, at the moment, may not be eligible by virtue of not qualifying from a regulatory perspective for our institutional review board can still contribute to this project in a meaningful way.

A fair number of people travel for medical procedures. If someone travels to the United States for radiation, for example, could they have the samples collected at a United States institution and therefore participate in that way?

Dr. Van Allen: For now, the study can only collect samples and medical records from residents of the United States and Canada. We are actively investigating methods for including international patients.

Is there a fee to participate, or is this free for men?

Dr. Van Allen: Free.

Is there anything else you think men should know about the project?

Dr. Van Allen: We’ve been concerned about patient interest and openness. In our first project for breast cancer, the social media footprint was quite high. The social media chatter is noticeable and folks feel pretty comfortable expressing their thoughts, feelings, and opinions about their disease. Even though incidents of disease is roughly the same in the United States for breast and prostate cancer, the social media footprint for prostate cancer is the complete opposite.

As we geared up for our soft launch, we were curious to see if we’d end up with the same number of participants, even if we weren’t seeing any social media chatter. People don’t talk about this disease. Indeed, on the first version of the saliva kit that we mail out to the patients, metastatic prostate cancer project was printed on the box. Men asked us to take that off the box. We didn’t understand why. One guy explained: “I don’t want the mailman to know I have prostate cancer.”

It’s that kind of challenge we’d like to help overcome. We want to make men feel more comfortable talking about this disease amongst friends, families, and coworkers. We hope this project can be the mechanism to help men open up about it. It’s encouraging that in the first ten days we’ve accrued an almost identical number of patients as we did with the breast cancer soft launch a couple of years ago. Nobody talks about prostate cancer on Twitter and Facebook, at least in open settings. We’re very curious to learn how patients become comfortable talking about this disease and about this project.

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Dr. Eliezer Van Allen: Why Medicine?

Dr. Eliezer Van Allen, Assistant Professor of Medicine at Harvard Medical School, a clinician at Dana-Farber/Partners Cancer Care, and an Associate Member at the Broad Institute of MIT and Harvard, focuses on computational cancer genomics, using new technology in precision medicine, and resistance to targeted prostate cancer therapies.

Prostatepedia spoke with him about why he became a prostate cancer doctor.

Dr. Eliezer Van Allen: An engineer probably would’ve been closer to what I had imagined. Medicine was, in some sense, an accident. When I went out to college at Stanford University in the late 90s, I studied something called Symbolic Systems, which is a mix of computer science and a bunch of other coursework. Many of my friends from that era, who studied the same things, stayed in Silicon Valley and are now software engineers, computer scientists, and whatnot.

While I was pursuing this degree of study, some of my friends worked on creating Camp Kesem, a camp for kids who have or had a parent with cancer. (It seemed like a cool thing to do, I’d do some good, and learn something.) We had the first camp in 2001 with 37 kids. I was lucky to be a counselor.

I say, very genuinely, that that was a life-changing experience. It really exposed me to a humanistic side of medicine, which I really hadn’t seen up to that point. It also exposed me to the world of cancer and how cancer touches not just patients but their whole families. That pushed me to pursue medicine, and cancer medicine in particular. It was a seminal life experience. It’s cool to see how that program has grown both locally and nationally. There must be hundreds of Camp Kesems at this point.

How did you get involved with prostate cancer?

Dr. Van Allen: While in medical school and residency, I met patients who had prostate cancer. I was really struck by them. I’d meet them in the hospital, some when they were very sick and often times with advanced cancers. A lot of the prostate cancer patients appeared to be very different from each other and from all the other cancer patients I saw. In part, this was because the treatments were so different than those given for other cancer patients across the board. It was just so striking.

Even back then, when I didn’t understand the details and nuances, I noticed that some men seemed to bounce back from any kind of cancer-related illness and live for many years. Others, who were often on the younger side, would have catastrophic advanced disease, terrible side effects to the treatments, and would die quickly. That puzzled me.

I got to know a lot of these guys while working at the Veterans Administration Hospital in San Francisco. I just felt a very symbiotic bond. I don’t know how to explain it. There’s some sort of unwritten connection with these men that resonated with me.

I took that with me into my continued training as an oncologist, both clinically and as a computational biologist. As a person with a computer science background who started to build a career at the intersection of cancer genomics, prostate cancer, clinical medicine, and the emerging space of cancer data sciences, this particular puzzle became very exciting to explore for both humanistic reasons and the emerging scientific reasons.

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The Genomic Revolution Comes To Prostate Cancer

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Genomics + Prostate Cancer

In April, Prostatepedia is talking about how genomics is impacting prostate cancer treatment.

Dr. Snuffy Myers offers his thoughts on genomics and on this month’s conversations.

I am especially excited about our April issue. Genomics offers multiple ways to improve prostate cancer treatment. We are only at the beginning of the genomics revolution.

I am well aware, though, that many of our readers may not have a sufficient scientific background to fully understand the power of this way of looking at cancer.

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The key insight is that gene expression determines a cancer cell’s behavior. Before the genomics revolution, we tried to predict cancer behavior based on appearance under the microscope—i.e. Gleason grade or imaging techniques. This approach has had its successes but is far from perfect. Instead of inferring behavior from appearances, genomics looks directly at the genes that drive behavior.

Genomics for prostate cancer is most advanced for newly diagnosed low to intermediate risk disease. We have several competing commercial products; the three most widely used are Decipher, Oncotype, and Prolaris. All three look at the expression of multiple genes. The pattern of expression of these genes has been shown to correlate with a cancer’s future behavior.

I have been particularly interested in a next generation test called the Decipher Grid. It dramatically expands the number of potentially important genes tested. This includes genes that may predict responsiveness to radiation, hormonal therapy, and some chemotherapy agents. Time will show Decipher’s Grid’s usefulness.

When a specific gene mutation is known to drive the growth of a cancer, it is possible to develop drugs that selectively kill cancer cells that have that mutation. This process has already revolutionized lung cancer treatment. For prostate cancer, we now have only a few examples. In several conversations this month, doctors mention DNA repair mutations BRCA2 and ATM. These mutations are commonly linked to breast and ovarian cancer. A class of drugs called the PARP inhibitors are effective treatments for ovarian and (to a lesser extent) breast cancers containing these mutations. When these mutations are inherited, they are associated also with an increased risk of aggressive prostate cancer.

While the frequency of BRCA2 mutations is low at diagnosis, the incidence increases as prostate cancer advances. Several studies show that 25-35% of advanced prostate cancers contain mutant BRCA2 or ATM. One Phase II clinical trial reported a greater than 80% response to a PARP inhibitor. Other genes important in aggressive prostate cancer include TP53, PTEN, and RB1. However, no drugs are clinically available to target cells where the function of these genes has been altered or eliminated. TP53 and PTEN have selective drugs in preclinical and clinical testing. The take-home message is that genomics is already improving the treatment of newly diagnosed prostate cancer and offers hope for better treatments for advanced disease.

Subscribe to read our April issue on genomics.

(Subscribers, you can read all conversations about genomics in your April issue of Prostatepedia.)