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Prostate Cancer Screening For Men With BRCA

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Dr. Preston Sprenkle is an Assistant Professor of Urology at Yale University.

Prostatepedia spoke with him about a trial he’s running on targeted prostate cancer screening.

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Why did you become a doctor?

 

Dr. Preston Sprenkle: My father was a physician. I liked the idea of helping people and doing something that was both intellectually challenging, yet also socially and intellectually rewarding.

I wasn’t sure, though, so after college I worked in consulting for a little while also volunteering in an ER and in some free clinics. I really valued those experiences with patients and the one- on-one interactions. I recognized how much good you can do and how much you can help someone by just listening and being attentive to their needs and concerns. Those experiences solidified my desire to go into medicine.

When I started medical school, I quickly realized that I really enjoyed anatomy and surgery. Urology is a fantastic specialty because you come in contact with a wide variety of patients—from children to very old patients, men and women. Even though most people think urology just centers on men, we actually take care of a lot of women too.

Urology involves a lot of surgeries that can be complicated and take a lot of time and energy, but there is also a lot of one-on-one patient-based care dealing with very personal things like sexual function or urinary function. Urology is somewhat unique among surgical specialties in that we not only operate on patients, but very often follow them for many years, allowing for long-term relationships with our patients.

I then became interested in cancer care. The current challenge is to improve the way we take care of cancer patients. Cancer is scary. Fortunately, in many cases it is very treatable and even curable. But hearing the C-word can be terrifying. Most people shut down and don’t really hear much after learning they’ve been diagnosed, so it can be a little longer process to help them understand that there are opportunities for cure.

What is the thinking behind the clinical trial you’re running?

Dr. Sprenkle: We opened this trial to better understand the relationship between the BRCA2 mutation, or BRCA2 deletion, in men and the incidence of prostate cancer.

There have been several studies showing that men with prostate cancer who have a BRCA2 mutation have a more aggressive prostate cancer more likely to have lymph node positivity.

What we have not been able to identify is where that starts. These men were arguably diagnosed with prostate cancer because they had an elevated PSA. Is their risk higher because they were diagnosed later in the course of their prostate cancer, or is their risk higher because the BRCA2 deletion causes them to have higher-grade prostate cancer?

When we started this trial, there was no information and no long- term prospective studies. (I believe there recently has been a trial that suggests that on a stage-for-stage basis it actually may not be much worse to have BRCA2, but that was not around when we started this trial.)

We are trying to understand the incidence of prostate cancer in this population of men with the BRCA2 mutation. This is, in part, a registry for all men who have a known BRCA2 mutation. We offer them prostate cancer screening with standard techniques: PSA blood tests, DRE, etc. But we also offer an MRI and MR-targeted biopsy to evaluate if there are any radiologic characteristics that could be used.

If 28-30% of men in a general population have prostate cancer with a PSA cut-off of 4, is that the same for men with a BRCA2 mutation?
 Or should we be screening men with this mutation earlier? Or biopsying them with a lower PSA? Do men with this mutation have a 30% rate of prostate cancer with a PSA of 2?

There is a famous trial called the Prostate Cancer Prevention Trial that used a medication to shrink the prostate. During the trial, they biopsied men 
if they had an elevated PSA and then at the end of that trial. Even men who didn’t get treatment were biopsied
 at the end, independent of what their PSA was. The trial gave a tremendous amount of information about what the likelihood is of developing prostate cancer when your PSA is as low as 1. Based on the results of this trial,
 we know that approximately 8%
 of men with a PSA of 1 or less have prostate cancer on a random biopsy—even though we typically don’t biopsy those men.

This current trial is an opportunity
 for us to gain information about how—or if—the incidence of prostate cancer is different in a population of men with a BRCA2 mutation.

Are you just looking for men without prostate cancer with the BRCA2 mutation?

Dr. Sprenkle: Yes. Any man who
 has at least a 10-year life expectancy qualifies to be screened.

Subscribe to Prostatepedia to read the rest of the conversation.


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Dispatches From The Hill: Prostate Cancer + The US Government

Mr. Jamie Bearse is the CEO of ZERO — The End of Prostate Cancer. ZERO is a United States based nonprofit with a mission to end prostate cancer.

In the first of a quarterly series, Mr. Bearse updates us on American policies impacting prostate cancer patients.

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Each year, prostate cancer advocates from across the United States storm Capitol Hill to fight for patients and families on important issues like: increasing prostate cancer research funding, expanding access to care, and generating awareness.

I’ve worked at ZERO for more than 5,500 days, attended 15 ZERO Prostate Cancer Summits, and met thousands of families fighting prostate cancer from all across the country. They come to D.C. ready for battle to make sure no one else goes through the pain and suffering they’ve endured.

We have had many successes through advocacy. The Department of Defense (DoD) plays a key role in fighting cancer. Through the Congressionally Directed Medical Research Programs, the DoD funds cutting-edge research. Specifically,

ZERO’s advocates spearheaded the creation of the $80M program years ago, stopped a $16M cut in 2011, and stopped it from being eliminated in 2013.

In my tenure, I haven’t seen a federal budget proposal that did not threaten prostate cancer funding. Nevertheless, our advocates persist.

As a result, the Prostate Cancer Research Program has produced the discovery of three novel and impactful treatments for advanced prostate cancer—Zytiga (abiraterone), Xtandi (enzalutamide), and Xgeva (denosumab)—as well as a genetic diagnosis profile to determine aggressive disease.

But 2017 is a banner year! We have learned that funding for the Prostate Cancer Research Program (PCRP) at the DoD may be increased to $90M this year.

The Department of Defense’s medical research programs are a proven business model and an epicenter for groundbreaking research in many medical fields, including prostate cancer. As part of this unique and successful model, the DoD program includes patients in a peer-review panel that chooses which bright ideas to fund.

With the additional $10M in funding, the PCRP will be able to fund as many as 40 new projects. Studies will investigate new tests for advanced disease, surveys to understand its genetic impact in families, and better markers to find the disease and put men on the best treatment pathway.

I started at ZERO in the communications department and I believe in the power of storytelling. This win is credited to the amazing advocates who never give up and speak with a unified voice to their elected officials every year. I’m tremendously proud of their passion and hard work. They are the champions for the three million prostate cancer patients in the fight now, the heralds of inspiring stories from families that have fought courageously, and the heroes for the generations to come.

Our work is not done. Not until we reach ZERO prostate cancer deaths. Our victory today must be defended. Call your Senators and Representatives to protect the $90M for prostate cancer research.

Funding for the peer-reviewed Prostate Cancer Research Program is appropriated under House Report 114-577 and Senate Report 114- 263 in the Department of Defense Appropriations Act, 2017.


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Crowdsourcing Cancer Funding

In May, Prostatepedia is talking about collaborations within the prostate cancer community.

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Dr. Jonathan Simons, Mr. Andy Astrachan, Ms. Colleen McKenna, and Mr. Tom Andrus are the driving forces behind Prostate Cancer Foundation’s Many Vs Cancer movement set to launch this month.

Prostatepedia spoke with them about the vision behind Many Vs Cancer and how it fits into the Prostate Cancer Foundation’s research funding programs.

How did you become involved with Prostate Cancer Foundation and the Many Vs Cancer movement?

Mr. Andy Astrachan: In late 2013, my family doctor felt a nodule on my prostate during my annual checkup. My PSA was slightly above 1.0 at the time and up slightly from the year before. An MRI was highly suggestive of cancer. I immediately reached out to my friend Mike Milken for advice. Mike referred me to his urologist and introduced me to Dr. Jonathan Simons who runs Prostate Cancer Foundation (PCF). I feel very fortunate to have been able to plug directly into the PCF for guidance.

A biopsy confirmed that I had prostate cancer. A month later, I had surgery. A few months later, Mike asked me to join PCF’s Board. I am honored to serve on the board for the benefit of all prostate cancer patients.

Ms. Colleen McKenna: As Andy said, he was diagnosed several years ago with prostate cancer and subsequently joined PCF’s Board because of his relationship with Mike Milken.

When Andy joined the Board, the primary focus of PCF’s communication was to the medical, research, and scientific communities. As a patient, Andy felt that PCF should also be focused on communicating with patients in a language that can be easily understood to provide them with the same level of information that he received from PCF. Andy understood instinctively that by tilting communication to the patient, PCF would not only help all patients in their times of need, it would also be able to connect and mobilize a massive community.

Step 1 was a brand-new website which was launched in October 2016. Step 2 was an appeal to the community of patients and those who love and support them to crowdfund the money required to expedite a cure. The appeal became a global movement of millions of people called Many Vs Cancer. PCF has done amazing work funding the most critical research over the last 24 years. The results of that work put us on the precipice of a cure. Now is the time to finish the job.

Andy recruited me to work for Many Vs Cancer and I immediately thought of involving Tom Andrus, with whom I’d worked at a company called Symantec.

Mr. Tom Andrus: In 2010, my wife Anne was diagnosed with Stage 4 appendix cancer. It had spread throughout her abdomen. We did everything that well-informed, connected people do. We worked with all the major leading hospitals. We did everything that we could do

One of the things that she said to me was, “I’m hopefully going to be one of the first people cured of this. If not, I’ll be one of the last to die from this cancer.” She made it about two years.

At the time, precision medicine just wasn’t there. You could see, though, that if we knew enough about people’s cancers and their tumors we could come up with ways to precisely treat and not just use blanket radiation or surgery or chemotherapy.

Colleen introduced me to Dr. Simons who explained that in the last five years the prostate cancer arena has changed radically: there are now 19 precise targets in prostate cancer and multiple trials in place trying to figure out what type of treatments you can do for each of those different genetic markers. Dr. Simons also explained that because of genetic overlap, the work we do in prostate cancer research will improve treatments in many other cancers, including, colon, ovarian, and breast cancer.

When Colleen reached out to me, I was ready for something fulfilling to do. Something that would change the world. After listening to Dr. Simons and Andy Astrachan explain their vision for PCF digital to democratize the dissemination of information to all patients and for Many Vs Cancer to empower all patients to participate in curing cancer, I felt compelled to sign on. I have a long history of building tech companies. I thought if I can put what I’ve learned into such an important cause, we could educate patients about the power of precision medicine, empower them to participate in fundraising, and engage them in the science, that would be the best thing I’ve ever done.

What is the Prostate Cancer Foundation’s mission?

Mr. Astrachan: PCF is the world’s leading philanthropic prostate cancer research organization and is certainly among the most effective cancer research organizations of any type in the world. For the past twenty-four years, PCF has raised over $700 million for research, funding over 2,000 groundbreaking research programs at over 200 cancer centers and universities in 19 countries. We’ve funded 3 Nobel Laureates and many hundreds of leading scientists in the fields of genetics, immunotherapy, and big data analytics from cloud computing.

Since inception, PCF has been a pioneer in new drug development, providing key funding for FDA-approved treatments that improve survivorship. Thanks in large part to the work of PCF researchers, in the last decade six drugs for men with advanced prostate cancer have been FDA-approved. Of those six drugs, five were FDA-approved because they actually prolonged patients’ lives, rather than simply easing their symptoms.

The $700 million raised directly by the PCF has attracted an infusion of more than $10 billion additional funding for prostate cancer research from government agencies, venture capital investments, the pharmaceutical and biotechnology sectors, academic research centers, and other philanthropies. In the United States alone, these new treatments have saved the lives of hundreds of thousands of men.

PCF has reduced US prostate cancer deaths by 52% in the past 20 years according to American Cancer Society statistics.

Mr. Andrus: Mike Milken founded PCF when he found out that he had prostate cancer. At the time, there was very little, if any, prostate cancer research going on. He set up the foundation with some very forward-thinking thoughts and processes on how research should be funded.

We’re fast. We’re open. Our approach is to get people funded quickly. We promise to decide on an applicants’ grant proposal in 60 days as opposed to the year or more it takes for a big NIH grant. We also require all our researchers to share their information with PCF in real time and with each other, even before they’re published. We select and coordinate Dream Teams across different organizations and sometimes continents to conduct research.

PCF specializes in early-stage or venture funding of research ideas. A lot of the recently-approved prostate cancer treatments came from our early-stage funding after which drug companies, governments, and other institutions put up a lot of money. But it is PCF that gets the ball rolling by funding the initial science. Thereafter, every dollar we put into research ends up being matched 20 to 30 times by the government or a pharmaceutical company to get drugs to market.

Ms. McKenna: Mike Milken took the model he utilized in his investment career and applied it to scientific research. PCF employs a venture philanthropy model that identifies those researchers with the greatest promise. Included in this model is PCF’s Young Investigator Program. Like a farm team in baseball, the PCF Young Investigators are the brightest young scientists around the world who are identified early in their careers and supported with smaller grants that give them a chance to develop their science. A number of Young Investigators have gone on to develop important research.

Talk to me a little bit more about the kinds of research you fund?

Dr. Simons: One of the best examples of our international collaborations is the PCF Dream Team led by Dr. Arul Chinnaiyan of the University of Michigan, Dr. Charles Sawyers of Memorial Sloan Kettering Cancer Center, and Dr. Johann de Bono at the Institute of Cancer Research/Royal Marsden in the United Kingdom. The Dream Team was awarded $10 million and has sequenced the genomes of over 500 castration resistant prostate cancer tumors and identified the prostate cancer genomic landscape.

Through this team and another Challenge Award team, we supported de Bono’s TO-PARP trial that found patients with DNA damage repair mutations may benefit from treatment with the PARP-inhibitor Lynparza (olaparib). (See Prostatepedia June 2016 for a conversation with Dr. Joaquin Matteo about the TO-PARP trial).

That Dream Team also found that 1 in 9 metastatic prostate cancer patients have cancers caused by inherited DDR mutations, which has implications for treatment. Family members should also be screened for the mutation.

Current treatments we have funded include Zytiga (abiraterone), Xtandi (enzalutamide), and Taxotere (docetaxel.)

We’ve also funded the development of a precision medicine platform for prostate cancer and the development of prostate cancer organoids, or laboratory-grown mini-tumors that serve as avatars for studying tumor biology and drug sensitivity.

Other promising treatment approaches we are funding include therapies that target mechanisms of resistance to androgen receptor targeted therapy, such as inhibitors of glucocorticoid receptor (GR) therapies, which target constitutively active androgen receptor-variants and extreme androgen receptor-pathway inhibition.

We’re also funding several immunotherapies that will enter clinical trials this year: CAR T cells that target Prostate-specific Membrane Antigen (PSMA) and Prostate Stem Cell Antigen (PSCA) and vaccines against Prostatic Acid Phosphatase (PAP).

We’re funding several clinical trials that look at combining radiation therapy with immunotherapy, as radiation may sensitize tumors to immune-killing and promote the activation of immune response. (See Prostatepedia April 2017 for a discussion with Dr. Emmanuel Antonarakis about such a trial.)

Lastly, we’ve recently launched an initiative to bring precision medicine into the Veterans Administration (VA) system, so that every veteran has the best level of care available. The sacrifices American veterans have made for all of us have earned them not only our everlasting respect and gratitude, but also the best standard of care and the benefits of the latest medical breakthroughs. The United States Department of Veterans Affairs (VA) works to make sure they receive both—and more.

We plan to invest $50 million over the next five years in a precision oncology initiative to expand prostate cancer clinical research among Veterans to speed the development of new treatment options and cures for prostate cancer patients.

Approximately 12,000 veterans are diagnosed annually with prostate cancer. Given the demographics of our veterans, prostate cancer is an especially urgent issue. One in eight men will be diagnosed with prostate cancer. It’s the most frequently diagnosed cancer among veterans, accounting for a third of all male cancer cases.

African-American men are 64 percent more likely to develop prostate cancer than any other race or ethnicity, and they’re 2.4 times more likely to die from the disease. Yet we know little about the biological reasons for these disparities.

The timing of this partnership is crucial: never in history have we been so close to solving so many medical research challenges.

Can patients donate to specific areas of research or simply to your organization as a whole?

Mr. Andrus: Right now, they fund the Foundation directly.

Ms. McKenna: We haven’t made a concerted effort to market PCF to the general public. Our Board feels that PCF is the best-kept secret in medical research. But that is now about to change with the launch of the Man Vs Cancer movement. In the past, our focus has been on relatively larger donations that are not earmarked specifically with the exception of grants in support of a specific young investigator or a Dream Team. That too will change with Man Vs Cancer, which will allow more targeted donations by scientist, by gene, or by research center.

Mr. Andrus: One of our goals is to empower people to not only give money, but also to participate.

The Man Vs Cancer movement is your brainchild, Mr. Astrachan. Can you speak a bit about your vision?

Mr. Astrachan: As a PCF Board member, I quickly understood that the rapid pace of medical research demanded greater funding than our historical fundraising model allows. We have now identified all 19 gene targets and their biochemistry in driving prostate cancer. We finally have exact blueprints for precision cures and the miraculous science of how to target genes is thriving. And we have identified the researchers capable of doing this kind of research. This is the golden age of prostate cancer research and now is the time to fund aggressively and finish the job.

PCF now stands on the precipice of curing prostate cancer. Prostate cancer will be the first major cancer to be cured.

At this point, it’s all about money. At one of the earliest Board meetings I attended, Dr. Simons made a compelling case for the idea that $1 billion in venture funding over the next 5 years would be sufficient to put next generation precision drugs into development for all 19 genes that can cause prostate cancer.

When I heard that I said to the Board, how hard can it be to raise $1 billion over the next 5 years? Because $1 billion over 5 years is 4 or 5 times what PCF historically raises, most if not all, of the Board looked at me like I was crazy.

But I am not crazy. I was just doing a different calculation than they were. I understood that by harnessing the power of technology, social media, social networking and crowdfunding, we could mobilize a massive global community of prostate cancer patients and their loved ones into an army with the collective financial power to fund our own cures.

As Dr. Simons talked, I made calculations on the cover of my board book. That math is compelling. There are roughly 3 million prostate cancer patients in the United States and many millions more worldwide in addition to many multiples of that number who love and support us.

That is a huge pool of people. If only 183,000 patients—a tiny percentage of patients—give $100 a year for 5 years and recruit 10 people to support us with the same financial commitment, that amounts to $1 billion.

With that calculation, Man Vs Cancer was born. Man Vs Cancer aims to reach the millions of patients worldwide and the far greater number of people who love and support us. The Many Vs Cancer global movement is by far and away the most ambitious and most powerful patient-lead community ever assembled for any disease by anyone for any purpose anywhere. Crowdfunding the last dollars needed for research from a vast audience of patients and our friends and loved ones means that by many of us doing a little, prostate cancer will be cured for everyone without overburdening anyone.

Some of us will give money, some of us will organize fundraising events and teams, and some of us will do both.

As a patient, I know as well as anyone that all patients are willing to invest in research for their own cure as long as they have justifiable confidence that they’re funding the right research being done by leading researchers and administered by the acknowledged global leader in funding prostate cancer research. I believe our community will respond generously when it understands how close science is to delivering effective medicines, that many PCF-funded breakthroughs are currently occurring in small trials around the world, and how pivotal PCF has been—and will continue to be—in virtually every prostate cancer treatment advancement since 1993.

When does Many Vs Cancer launch?

Ms. McKenna: Mid May. We’ve just asked the first 1,000 members of our community to raise their hands to form teams and stand with us on Day One of launch. I thought it was going to take two months to get the first 1,000 people, but we’ve signed on almost 1,000 in a couple of days. We’re allowing people to take part in their own cure, to have a voice in the battle.

People are sharing their own personal stories. These stories of courage, a fighting spirit, and a strong desire to make a difference are amazing. It reminds me every day that what we’re doing is important and right.


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A Urologist’s View Of Bone Metastases

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Dr. Raoul Concepcion is the Director of The Comprehensive Prostate Center in Nashville, Tennessee and the past President of the Large Urology Group Practice Association (LUGPA.)

Prostatepedia spoke with him about approaches to bone metastases within urology groups.

To read the rest of the article, subscribe or download the issue.

How does a urologist know when a man has developed metastases?

Dr. Raoul Concepcion: Fortunately, the majority of prostate cancer diagnosed today tends to be low-risk and associated with lower Gleason grades. For those men, active surveillance may be an appropriate treatment option. The challenge now is not to just identify prostate cancer, but to identify significant prostate cancer: those at risk for dying of their disease if left untreated. If you have Gleason -3 + 3, what we are now calling Group Pattern 1, or Gleason 3 + 4 (Group Pattern 2), the recommendation is not to do a staging work up. The likelihood of finding metastatic disease is very low. But if you do pick up a higher-grade clone on biopsy in a Gleason 4 or 5 prostate cancer, that man should definitely undergo a staging workup—usually a CT scan and bone scan—to look for metastatic disease.

Bony metastases can be detected in a couple different phases of prostate cancer. Sometimes, bone metastases are found at initial diagnosis during staging work-up. This usually happens with higher-grade tumors. The second phase is when men progress past definitive therapy and adjuvant treatment to we now call metastatic castration resistant prostate cancer (mCRPC). After diagnosis, both low-grade and high-grade patients decide on prostate cancer management.

Lower-grade patients can choose active surveillance, radiation therapy, radical prostatectomy, or even focal therapies like cryotherapy.

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Options for higher-grade patients could include multi-modality therapy of surgery, radiation therapy, and hormones. These patients are really the people at risk.

After an individual has been treated definitively for prostate cancer, we measure his PSA after therapy. If his PSA starts to go up again, he is said to have a biochemeical recurrence.

For the most part, these patients do not have symptoms. They’re not in pain. They don’t have significant fatigue. Again, these are patients who have been definitively treated and are currently not on therapy.

Once his PSA starts to go up, we start to look at the rapidity with which it goes up. We call this PSA kinetics, or doubling time. If there is a rapid doubling time in a man who had a higher grade Gleason Pattern at diagnosis, we know he has a higher risk of developing metastatic disease. We usually go ahead and get a scan when his PSA goes above 10. If that scan is still negative in a high-grade patient with a rapid doubling time, most urologists initiate androgen deprivation therapy.

Androgen deprivation therapy, or hormonal therapy, tries to drive down testosterone levels into castration range. If his PSA then starts to go up again, he now has, by definition, mCRPC. Again, these are patients with prostate cancer that has been definitively treated.

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They have then gone on androgen deprivation therapy until their testosterone levels got to less than 50, and then their PSAs started to go up again.

What is the trigger for the urologist to start looking again for bone metastases?

That has never been really well defined. I participated in a consortium of academic and community urologists, medical oncologists, and radiation oncologists called the RADAR (Radiographic Assessments for the Diagnosis of Advanced Recurrence) working group chaired by Dr. E. David Crawford to answer just that question.

We recommended that in such patients we should go ahead and look for metastases with a bone scan, a CT scan, or some of the new advanced imaging techniques when the PSA gets to 2.

Why would you hesitate to look for bony metastases earlier?

Dr. Concepcion: I think most urologists, unfortunately, extrapolate what they know about PSA in the early stages when patients aren’t on hormones to the castration resistant prostate cancer space.

If a patient had never been on hormones and his PSA is low, usually it means they don’t have a lot of disease. It’s become a real hurdle, an educational challenge, to get urologists to start thinking about that and not to wait until patients are symptomatic.

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Do you think it would make sense for such a patient reading this to ask his urologist to scan him earlier?

Dr. Concepcion: Yes, I think that would be very appropriate. Unless you’re being treated by a urologist with a lot of expertise… A lot of general urologists aren’t going to know about the RADAR recommendations.

Are these scans usually done at the urologist’s office or does the urologist refer the patient to someone else?

Dr. Concepcion: It depends. Most urologists in community practices, especially in bigger groups, have their own CT scans. That part of the workup can be done in the urology office.

Technetium-based bone scans usually require a nuclear medicine department and are done in a hospital.

A lot of times, we’ll get a CT scan in our office and then coordinate with a freestanding imaging center or a hospital-based imaging center to get a nuclear medicine scan.

To read more about bone + prostate cancer, subscribe or download our April issue.